United Therapeutics Corporation Stock

Good morning, and welcome to the United Therapeutics Corporation Third Quarter 2026 Corporate Update. My name is Christa, and I will be your conference operator today. [Operator Instructions] Please note that this call is being recorded. I will now turn the webcast over to Harrison Silvers, Investor Relations at United Therapeutics.

Thank you, Christa. Good morning, everyone. It is my pleasure to welcome you to the United Therapeutics Corporation Third Quarter 2026 Corporate Update Webcast. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties.

We assume no obligation to update forward-looking statements. Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products. These remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for the products is available on our website.

Accompanying me on today's call are Dr. Martine Rothblatt, our Chairperson and Chief Executive Officer; Michael Benkowitz, our President and Chief Operating Officer; James Edgemond, our Chief Financial Officer and Treasurer; Dr. Leigh Peterson, our Executive Vice President of Product Development and Zeno Transplantation; and Pat Poisson, our Executive Vice President of Strategic Development.

Note that James Edgemond and I will participate in a fireside chat and one-on-one sessions at the UBS Global Biopharma Conference and Jefferies Global Healthcare Conference in London on November 16 and 17, respectively. Additionally, members from our management team will participate in a fireside chat in one-on-one meetings at the 45th Annual JPMorgan Healthcare Conference in San Francisco in January of next year.

Our scientific commercial and medical affairs teams will be President present at phenomenal Hope 2026 on December 4 in Boston and at the Pulmonary Vascular Research Institute Annual Congress in Bangkok in late January of next year. Now I will turn the webcast over to Martine for an overview of our development pipeline and business activities. Martine?

Thank you, Harry, and good morning, everyone. We have slides available for reference, and I encourage you to review those at your leisure. I'm not going to speak directly to the slides. As we look back on the third quarter, I'm incredibly proud of what our teams have accomplished. .

We executed at a high level across our business and across our company, delivering for patients while advancing one of the most ambitious growth strategies in biotechnology. The significance of this quarter extends beyond any individual results or milestone. It reflects the broader transformation underway at United Therapeutics as we build a comprehensive cardiopulmonary and respiratory medicine franchise capable of reaching dramatically more patients than ever before.

For most of our history, UT has been known as a pulmonary hypertension company. Today, that legacy serves as the foundation for a much bigger UT. Over the next several years, we expect to introduce wave after wave of innovation across multiple therapeutic and device platforms. From nebulized and dry powder therapies to softness inhalers, once-daily medicines and combination products.

We have 14 programs in development. Together, these advances are intended to address some of the largest unmet needs in pulmonary fibrosis and pulmonary hypertension. We are building an integrated portfolio designed around the needs of individual patients.

Our strategy is to keep innovating, so we can offer more patients the right therapy in the right format at the right time. The scale of that opportunity extends far beyond our historic pulmonary hypertension market across IPS, PPS and PH-COPD alone, we are pursuing patient populations totaling approximately 1 million people in the United States. Supporting this strategy are significant and durable competitive advantages.

Our portfolio features extensive intellectual property protections, including fibrosis-related patents, device protections and composition of matter protection for ralinepag, many of which extend into the 2040s, just as important, our market advantages include decades of expertise, extensive engagement with physicians, specialized commercialization capabilities manufacturing investments and a proven ability to bring complex drug device combinations to market.

We are building on our strength through the philosophy that has guided us for years, approve, then improve. We first established a therapy as quickly as possible because our patients do not have time. Then we continue to enhance convenience, administration and treatment experience through new devices, formulations and next-generation medicines. This disciplined approach creates a pipeline in which every new product builds on the foundation established by the last and provides improvements for the next.

And as compelling as our cardiopulmonary and respiratory franchises are they represent only 1 pillar of our long-term vision. In parallel, we continue to advance our manufactured organ alternatives programs and build the infrastructure we need to address one of medicine's greatest unmet needs. We believe this platform has the potential to revolutionize transplantation over the next decade, just as our therapies have revolutionized pulmonary hypertension over the past 2 decades.

When I step back, I see a United Therapeutics stronger than at any point in our history with a growing commercial business, late-stage assets of significant potential multiple upcoming launches and a clear strategy for creating value over the long term. In closing, thank you to our fellow Unitarians, patients, physicians, shareholders and our other stakeholders for helping us fulfill our purpose. And with that, I'll turn the call over to our President, Michael Benkowitz, for an overview of our commercial performance for the quarter. Mike?

Thanks, Martine, and good morning, everybody. For the third quarter of 2026, we delivered record total revenue of $833 million and record Tyvaso revenue of $504 million. Highlighted by strong sequential growth and underlying demand. 3 months ago, I said confidence is earned through execution, not projections.

This quarter's results are best quarter ever demonstrate that execution and reinforce our conviction that our business has regained meaningful momentum. A huge shout out to all of our commercial, commercial operations and medical teams for their hard work, persistence and performance.

Tyvaso's performance was driven by strong underlying demand as the patient metrics we highlighted last quarter translated into commercial results. Starts, referrals, patient demand, increased dosing and physician engagement all continue to support growth and emphasize the value of differentiated products, disciplined execution, a clear understanding of physician and patient needs and our expertise and support in the field of pulmonary hypertension.

Most importantly, we see meaningful room to grow from here. The investments we made earlier this year in resources and sharpening our messaging are working as intended by expanding our reach deepening physician engagement, increasing disease awareness and driving greater penetration across PAH and PH ILD. We have greater conviction in our strategy than ever. Elsewhere, the recent court decision upholding our intellectual property, together with the settlement we reach, provide important clarity and reinforce the long-term durability of our base business.

The terms of our settlement were highly favorable for United Therapeutics, ultimately removing PH-ILD from the tropo label, preventing its promotion and marketing into that indication and prohibiting Liquidia from encouraging off-label usage, which we will be monitoring very closely. With no direct branded competition on the horizon, we can remain focused on growing the large underpenetrated PH-ILD market.

Based upon the provisions contemplated in the settlement and damages structure, near-term expectations for transitions from UTP to Tyvaso should be moderate. The larger opportunity in PH-ILD continues to remain focused on expanding physician awareness, identifying more eligible patients and growing new prescriptions.

That gives Tyvaso a long runway for largely uncontested growth. Step back, our story is not about stabilizing our business. It is about building on renewed momentum from our durable commercial foundation with 2 of the most important potential launches in our street still ahead. Once approved, we expect nebulized Tyvaso and IPF and ralinepag in PAH will each address significant unmet need. Both are supported by compelling clinical data and both have the potential to become multibillion-dollar growth drivers for United Therapeutics.

These opportunities do not replace our current growth story, they accelerate it. In closing, our base business is performing. Our commercial strategy is working. Our competitive position is strong and we expect to enter 2027 with substantially more momentum than we had entering 2026.

To highlight this continued momentum, we received over 1,000 referrals for a UT product in October, the most ever received in a single month. We remain focused, accountable and committed to continue delivering compelling results. And as proud as we are of this quarter, we believe we are just getting the full scale of what we are determined to achieve. And with that, I'll pass the call back to Harry to run the Q&A.

Thanks, Michael. Thanks, Martine. Great updates from both of you. [Operator Instructions] Operator, you can start.

[Operator Instructions] Your first question comes from Joseph Thome with TD Hain.

Maybe could you talk a little bit more about the patient switch dynamic now that PHLD will be off-label for you [indiscernible] , what are sort of your expectations of current patients switching over? And maybe for new start markets, you mentioned that you are monitoring their off-label use potential. Can you just kind of go into how you're doing that in the field. .

Thanks for the question, Joe. I'm going to pass this 1 to Michael.

Sure. Yes. So Joe, thanks for the question. On the patient switch is the -- per the terms of the settlement agreement, we sort of contemplated -- we didn't -- there was no requirement or expectation that patients would have to switch from [indiscernible] to Tyvaso DPI and so we kind of contemplated that in the damage structure, as I mentioned.

And so I think, obviously, we're going to continue to talk about the benefits the differentiation of DP relative to Trebia, but it's really going to be, I think, a physician patencies to whether or not they want to transition existing patients over to Titaso-DPI. But that's not something that's going to be required for the terms of the settlement.

So like I said, I think what you're going to see is if you've got patients on Metropia that for are having issues, obviously, Tyvaso remains an option, you can switch, but there's not -- I think if a patient's doing well on. There's not really going to be, I think, a push on the part of doctors to switch patients over. So as I said, the real opportunity here is with new prescriptions and continuing to penetrate the pH ILD market, which we're starting to see with the benefit of the expanded sales force.

In terms of monitoring that, I mean, look, we kind of -- I'm not going to really get into kind of sources and methods of how we're going to do that. But I think we have pretty good visibility into how things are playing out in terms of prescriptions and indications, and we're just going to continue to kind of keep an eye on that and see how that plays out along with what we're hearing in the market through our interactions with physicians.

Thanks, Michael. Operator next question.

Your next question comes from the line of Olivia Brayer with Cantor.

Michael, I just quickly wanted to follow-up on PHLD. Are you guys actually seeing any acceleration in new starts on Tyvaso in the fourth quarter just on the back of that settlement? Or do you really expect that to become more meaningful as patients come up for reauthorization in January? Just trying to kind of reconcile your comments around October trends. And then I'm sorry, Harry, -- but my real question is on the softness inhaler program, where are you guys in the submission process at this point? And is a filing still on track for the end of the year? And then as you think about softness kind of looking ahead to PH-COPD, what have you guys actually seen in the SMI product profile that's giving you so much confidence that it could succeed in this patient population, just given some of the challenges that we've already -- or that others have experienced, right, with prior approaches?

Sound more like 3. I'll give Michael the first question. And then if you could pass it to Pat on the NDA expectations for SMI and then perhaps we can close it off with expectations in PH COP.

Yes. Olivia, you never disappoint with your multi question. So on PLD, so if you kind of think about the time line of everything, as I said, I think even before the settlement, right, going back to like mid-September, I think we saw this inflection in the referrals coming in. Really across both cations, PAH and PLD for Tyvaso that has persisted through the end of October into November, in terms of working out the litigation decision, the settlement, I mean, all of that stuff really didn't really get worked out until, I guess, what was that second, third week of October.

So still a little early to see I think another sort of inflection in terms of PH ILD. I would expect that we're going to start to see that here over the next couple of weeks. And into December than obviously the first part of the year. So that's kind of where things are right now. I mean we do expect to see that I've seen -- I kind of monitor the daily referral trends. We have a couple of days where we spiked, but I expect us to see kind of a new baseline in terms of referrals here over the next few weeks. Pat, do you want to take the other question?

We recently met with the FDA to discuss our NDA filing strategy, and that was preplanned. And following that discussion, we've now determined that additional work is going to be needed to support the application. So as a result of that, we now expect to submit the NDA in 2027 and not at the end of this year. We are actively working with our development partner to complete the necessary activities and establish an updated filing time line. Leigh pass it on to you.

Yes. As far as PH-COPD, goes, our Phase II trial, as you know, we have IND clearance for that study. And in terms of the biological rationale for COPD, mean the pharmacology of inhaled treprostinil is really well characterized with our commercially approved treatments for PH and PH-ILD.

And as you know, in these patients with [indiscernible] with group through PH, such as ILD and COPD, the inhaled treprostinil directly targets more ventilated portions of the lungs. And so that can minimize the VQ mismatch that's with the concern with more systemic therapies that are also vasodilators.

So it's really important to note that not only do we have a more robust design in our study. But we've really, really looked very carefully at the patient population that was enrolled into the prior study, COPD study and really worked hard with our steering committees to enrich this current population through the inclusion exclusion criteria to improve the chances of success as well as just decrease the risk of this program.

Thanks, Lee. That was a great overview by all 3 of you.

Your next question comes from the line of Ash Verma with UBS.

So on ralinepag, I wanted to ask about this open action indicated that you have mentioned in the Q about this API manufacturer. Can you talk about what is the contingency plan ahead of the potential regulatory approval for this?

Thanks for the question, Ash. Pat, we'll kick that over to you.

Yes. Thanks, Ash. So as you saw in the Q, our API supplier has an OAI compliance status as the result of an inspection earlier this year. We're actively working with them to remediate their compliance status so that it doesn't impact our PDUFA date. So that's kind of priority one.

We do have some alternative plans that are progressing in parallel. But on a positive note, they've recently provided FDA updated information on their corrective actions. And there's open dialogue between the parties. So we remain hopeful that this will get resolved fairly quickly, but we do have contingency plans in place.

Great. Thanks, Pat. .

Your next question comes from the line of Roger Song with Jefferies.

Great. Maybe related to the triplet oral pill, since the bioequivalent study is not sufficient for filing. So what is the current plan for development and funding plan for the [indiscernible]

Thanks for your question, Roger. Pat, can I ask you to answer this 1 again?

Yes. So we had a discussion with FDA and they share that, that was their feedback to us. And so right now, we're looking at what our options are really, if there's an alternate path that they would accept that's going to take us a little while. So -- but right now, we're just treading water. And while we work on different options that we can present to them. .

Your next question comes from the line of Rowan Ruiz with Leerink Partners. .

A quick question. Could you elaborate on the -- what you saw as the biggest drivers behind the Tevas strength in the quarter? And if any could increase into year-end? I'm specifically focused on if there is more traction from the upsized field force or any inventory or seasonal dynamics that we should consider in addition to underlying demand growth?

For your question. This 1 will go to Michael.

Sure. Yes, thanks for the question. So no inventory or seasonal dynamics really, I think, played into the quarter. I think it's really kind of a multifactorial thing. One is just honestly, just great execution by the sales team. I think we've like we talked about in the last quarter came out of the quarter with really strong momentum. .

We've been able to maintain that through -- even through October, as I talked about earlier. I think as we've talked about on prior calls, I think some of the challenges we faced in the prior quarters are we'd have 2 really good months and 1 soft month and the 2 good months weren't enough to offset the soft mine. So we've been kind of flat for several quarters. But now we've got, I think, really consistent performance month to month to month. And so we're stocking good months on top of good months. And so that's really just, I think, plays into really strong execution by our commercial teams.

I think the other thing that we've seen is at the beginning of the year, we -- we introduced a 80-microgram cartridge. So one breath gives you the equivalent of 15 nebulized breath and then some higher dose kits. I think there's been this misinformation out there that you can't get to higher doses on Tyvaso DPI. I think we've effectively debunk that for patients that have started on Tyvaso DPI since we introduced those cartrids.

We introduced those higher strength kids, like 1 in 3 patients are, have achieved these higher doses which is twice what it was beforehand. So that certainly, I think, played into the performance is that we're getting patients to higher dose which helps from a revenue standpoint, but also helps from a retention standpoint because patients are obviously benefiting from the product.

I think in terms of the effect of the sales force expansion. I think in terms of region frequency, that played a role in some of the consistent performance month-to-month. But in terms of like what we've seen in terms of increase in referrals increase in starts. I think we -- as I said, we start to see kind of this inflection point, probably mid-September. As a result of that. So that didn't really you can't really -- I don't think you can draw a straight line through to the revenue line for Q3. I think we'll start to see the benefit of that here in Q4 and then into next year. But it's clear that the expansion is working, and we're seeing the benefit of that. But probably limited revenue impact of that in Q3, but we certainly expect to see that, like I said, this quarter and heading into next year.

Great color.

Our next question comes from the line of Jessica Fye with JPMorgan.

Congrats on the quarter. a quick follow-up. I think it was 1 of Olivia's questions. Pat, can you just expand on what was new that's needed for the softness filing?

Yes. It's not necessarily anything new. It's just additional data in some areas that we need to provide. So really -- it's really just that. It wasn't anything you've asked us to do in addition to what we had already planned.

So [indiscernible] versus generating more data.

It's just generating additional data. And I don't think we're particularly worried about it. It's just a lead time to do it. .

Great. Thanks, Jess, for the question and Pat for the answer.

Your next question comes from the line of Ben Burnett with Wells Fargo.

I want to ask about ralinepag and just what was behind the decision to buy out Arena's economics to ralinepag. And I guess how did you value that transaction?

Thanks for the question, Ben. I'm going to pass this 1 to James. .

Yes. Thanks, Harry. Ben, overall, this transaction to buy down the royalty demonstrates really our confidence in the revenue opportunity for oral ralinepag which, as you know, has a pending new drug application under review by the FDA for pulmonary arterial hypertension, which you know is a PDUFA date of June 24 of next year. .

But in addition, the reason why we pursue this opportunity is we have conviction in the new dry powder inhalation formulations that we're developing for a variety of pulmonary indications going forward. And I would say the price was the result of really extensive negotiations, and we're not going to get into the details regarding that. But we looked at this more as an opportunistic use of capital kind of in our overall capital allocation waterfall. So thanks for the question.

Thanks for that, James. Operator, we have time for 1 more question. Go ahead.

And that question is going to come from the line of Lisa Walter at RBC.

Congrats on a strong quarter. Maybe another 1 on ralinepag, DPI. Curious as plans have changed around developing this for PAA -- or is PH still part of the plan, along with PH-ILD, IPS and PPS? And how are you thinking about the clinical development plan for ralinepag DPI in these indications? Any color here would be helpful.

Yes, absolutely. Good to hear your voice, Lisa. I'm going to pass this 1 over to Leigh to provide some color.

Yes. Thanks for the question. So we are in the process, as you know, of conducting the IND-enabling studies as well as planning for the Phase I study in healthy volunteers. Now that Phase I study prestudy safety. That will actually inform any other registrational study that we want to do. So we're initially planning on doing a PH-ILD study and they're very, very soon thereafter or essentially at the same time, seeking approval for IPF, PPF, all of those will require some pivotal studies assessing the safety and efficacy.

But again, we're confident that the mechanism, both of the very, very potent drug, self the ralinepag being a very, very potent IP receptor agonist as well as the inhaled route for these indications where there's either some fibrosis or later for COPD, but that's not in the immediate plan. But anyway, this inhaled route to minimize VQ mismatch is really probably will make what we're calling route pie, a very transformative product in these larger indications.

Excellent overview, Lee, and that will conclude the Q&A. So I'll pass it back to the operator to close this out. .

Thank you for participating in today's United Therapeutics Corporation's earnings webcast. A rebroadcast of this webcast will be available for replay for 1 week by visiting the Events and Presentations section of the United Therapeutics Investor Relations our website at ir.unither.com. This now concludes today's call, and you may now disconnect.

Thank you so much for joining us today. We're really excited here from our Healthcare Leaders and Disruptors Conference. It's excellent to have such a great community be here to hear from what I would say are healthcare leaders and disruptors, and we're here to talk to our next set from United Therapeutics. I have the pleasure to introduce Dr. Martine Rothblatt, Founder and Chief Executive Officer, as well as James Edgemond, Chief Financial Officer. Before we get into Q&A, we're going to spend a couple of minutes where both of them have some prepared remarks. So, I'll turn it over to them.

Thanks so much, Jeffrey. Super happy to be here at the Bernstein Conference. United Therapeutics is poised right now for an exponential growth trajectory, unlike anything that we've yet experienced and really unlike much that you can ever see in the biotechnology industry. We're right now in the middle of launching 14 significant products that will completely transform the revenue and profit profile of our company.

Those 14 products are a nebulized form of Tyvaso for IPF and PPF. These are 2 different lung fibrotic diseases. The NDA for Tyvaso for IPF has already been accepted for filing by the FDA with a PDUFA date coming up early next year. And this drug in its Phase III trials demonstrated the greatest improvement in patient outcome of any drug that had ever been tried or developed in pulmonary fibrosis. So, just a radical improvement in life expectancy for patients with pulmonary fibrosis.

Drug launches #3 and #4 are our DPI Tyvaso again, for IPF and PPF. DPI Tyvaso is a product that is already approved and the #1 product prescribed in PH-ILD. And this product will next be launched into the IPF and the PPF market so that patients in that huge 400,000-patient indication -- 100,000 in IPF and 400,000 combined with PPF and IPF -- will then have an option of either using nebulized Tyvaso or DPI Tyvaso.

So, those are product launches 1, 2, 3, and 4. Then coming right on the heels of those launches, we plan to launch a new product called CoughLess Trezmi, and this product will be launched for ILD, IPF, and PPF. This is a coughless inhaled product based on a soft mist inhaler, and the NDA for this product will be filed before the end of the year, and we expect to launch that product next year. So, that's product 5, 6, and 7.

Then, we've got 3 new products beyond that called once-daily Ralpi. And this is a brand-new molecule that has the best efficacy ever shown in pulmonary hypertension and even stronger antifibrotic activity than treprostinil in pulmonary fibrosis, plus a PK profile that allows you to use it just once a day. So, this product will be developed for IPF and PPF as well as ILD. Those are products 8, 9, and 10. And so, we feel that we have an amazing spectrum of products that can each address ever larger portions of the population with IPF, PPF, and even ILD.

So, beyond those products, we have some other amazing products that are being very soon launched. The one that I think is most dramatic is Jenraldi, a once-daily pill for pulmonary hypertension. This is something that this entire field has clamored for, for many years. We developed this product internally, and it has a strong IP protection out into the 2040s. But most significantly, it's the only drug ever tested in the pulmonary hypertension field that showed clinical improvement in the patients with pulmonary hypertension, not just slowing the rate of decline, which it certainly did that as well. So, this product will be -- has been submitted to the FDA. It's been given a PDUFA date of June 24, I believe, of next year. And we expect it to become the #1 product prescribed in pulmonary hypertension.

Right on the heels of that product, we have another product which is a triple combo form of Jenraldi -- that's Jenraldi plus the 2 most commonly prescribed oral drugs, a PDE5 inhibitor and an ETRA. So, that will make the patients' pill burden easier. And again, just 1 pill once a day, all formulated in there. On top of all of that, we have a development of our development of our Trezmi product for a condition called COPD-PH. This is the 13th product I mentioned. This is an indication with 600,000 patients in the U.S., Jeffrey, not one single approved drug for that indication. And these patients are hurting. So, we feel very confident that this new product, Trezmi for COPD-PH, will be able to capture a lion's share of those 600,000 patients.

And when you stack them with the 400,000 in the PF IPF, you're looking at 1 million patients that we'll be able to address over just the next handful of years. Last but not least, we have a 14th product in development, which is a rescue inhaler for PAH, something the field has never had before. It's called ILO Tra. It's a combination of 2 different prostacyclin-type molecules.

So, we are busy as can ever be, Jeffrey, and the amount of drug development, product development at United Therapeutics, I would say, is more robust, certainly in the pulmonary space than any other pharmaceutical company, any biotechnology company, and we look forward to exponential growth in revenues over the next few years. Counting all that money is our great CFO, James Edgemond.

Great. Thank you, Martine. And Jeff, thanks for having us again this year. And as Martine talked about, we are poised right now for explosive growth going forward. And a lot of questions that we've had this morning were really around use of capital for us. And so, we try to be very good financial stewards, make thoughtful investments that grow the organization.

And one of those uses right now is that we're repurchasing our shares. We think with this explosive growth on the horizon and where we see the value of the stock today is one of the best uses of capital that we are pursuing right now. And so, we actually are in the market, completing what the Board authorized earlier this year, which was a $2 billion share repurchase authorization. So, we are in the market because we believe at this point, based upon all the products Martine talked about, this is a great use of capital at this time.

That's great. I mean, that was a lot of drug development that you just covered. I mean...

It's a full-time job.

It's full, I mean, 32 minutes, we need to get to the highlights of all of that. So, it's on me and it's on us to make sure that we dive into the details of what you just talked about for some select programs.

I'm actually going to start with a question that you just asked me before we started. You asked me, is United Therapeutics a leader or a disruptor? And I said, from what I know, both, and it's because of the drug development that you've highlighted and because of the results you've had so far, but I'm going to put this back to the 2 of you. So, what is your answer to that question?

My answer is we are a disruptor, okay? And the reason for that is currently, we sit with about a $20-something billion market cap. And it's really hard for me to consider that a leader in the pharmaceutical or even in the biotech area. Within the particular indications, the leader in pulmonary fibrosis is a great company called Boehringer Ingelheim, and they have been in this indication for a long time.

In the pulmonary hypertension field, there are -- there's a plethora of drugs approved. There are at least 12 different drugs approved. And it's, again, pretty hard to identify any one company as an absolute leader with so many different drugs approved. Now here, we're coming in saying we have the first and only drug shown to achieve clinical improvement in pulmonary hypertension. So, we're going to disrupt the hell out of that space.

And this is going to be the drug that physicians reach for, for all of their newly prescribed patients and for all of the patients on background therapy and maybe for all patients, except the ones who are really virtually on the transplant wait list that perhaps it's too far down the pipe. Now coming into the IPF space, I'm sure the folks at BI are, kind of, saying WTF. I mean, here, they had a, kind of, a nice plantation that they were running there and clipping the coupons for a couple of decades. And here comes a company with dramatically improved clinical trial results, not in 1, but in 2 separate Phase III trials, already a fully enrolled trial in PPF. And there is no doubt that we are the disruptor in the pulmonary fibrosis space.

Finally, with regard to biotech in general, I think with these 1 million patients that I referred to that I'm confident we'll capture, the average reimbursement price for these drugs is in the 6 digits, $100,000 to $200,000. Even at $100,000 a year, you're talking about $100 billion per year of pharma revenue. That would put us into the very top tier of not only biotech, but pharma and would definitely -- we would be the big disruptor in pharma and biotech, and we will be over the next few years.

Okay. James, I'd like to hear your answer, too.

Listening to Martine and having a brief conversation before, I think he's right in terms of being a true disruptor. I think at this point, we've done very well, but I think this clinical trial read from TETON 1 and 2 that produced these clinical results that really converted the company from a PH company to a PF company going forward. And so, I think that -- and based upon how the Unitharians at UT operate, we are fully engaged to make sure that we can deliver to patients the best therapy and disrupt, kind of, the landscape that's in front of us going forward.

I would love to actually take a step back to learn a bit about the company because there are so many drugs to talk about, but it would be great to talk about the company itself. You mentioned its Unitharians. Could you describe, either one of you describe, what a Unitharian is and what that means?

So, Unitherian is what internally at United Therapeutics we call ourselves, and there's various criteria that we, kind of, enable us in terms of nimbleness and various characteristics. But I think at the end of the day, our focus really is on doing a couple of things. One is making sure we produce the best therapies for the patients period going forward.

And as we align around that, that not only transcends where we have been in the pulmonary arterial hypertension space, but going forward in the pulmonary and the fibrotic space and ultimately, some of the questions you'll get to in the organ transplant space. But it's really a set of individuals who truly believe that we can accomplish these audacious goals going forward, and we're all embedded and engaged in this going forward.

Yes. Our domain name is unither.com. So, everybody's name is -- email is first initial last name, unither.com. So, it became easy to call ourselves Unitherians. It was, kind of, fun that it rhymed with Unitherians. That's who we are. The culture is -- it's a crazy culture, Jeff. We have average revenue of $2 million per employee. So, that's a very, very high ratio of revenue to employees. I believe it's topped only by Gilead, which I would consider a leader in our industry and like Vertex, another great company, industry, and a leader in our industry.

So, our culture is one of, kind of, a Darwinian business. When people say like, well, I need more resources, I need more people. We say, well, if we give you just a little bit less resources than you think you need and a little bit more people, a little bit less people than you think you need, you will try your hardest. And we will weed out the people that are not really fit enough to survive in this Darwinian environment that we've created at UT.

And it has worked out that way amazingly because 1,700 people are able to produce these 14 new products in development, not to mention the half-dozen launched and commercialized products, not to mention the entire organ manufacturing part of the business that is the leader in fields like xenotransplantation, where we have the most patients. In fact, we have the only patients in clinical trials with xenografted xeno-kidneys, and next will be xeno-hearts walking around, some right here in New York City.

Really. Can you -- maybe we take a segue where, if you don't mind, I'd love to hear a little bit about the originations of that business and how you think it stands out and why it's so novel compared to other biotechs.

That's an amazing question, Jeffrey. Thank you so much. So, the business started because my youngest daughter was diagnosed with this illness called pulmonary arterial hypertension, which at the time she was diagnosed was a universal death sentence. There was no drugs approved by the FDA for what's called PAH, pulmonary arterial hypertension.

And she was diagnosed as a little kid and the doctor who ended up being the Head of Pediatric Cardiology at Washington National Hospital said, "I've got sad news for you. We did a cardiac catheterization of your daughter's heart. She has like 5x the normal pressures in between her heart and her lungs. But it is possible to be able to get a lung transplant that has a 100% track record of curing pulmonary hypertension. However, you -- it is very, very difficult for a little tiny kid to get a lung transplant. And also, once you get a transplant, you're going to be on chronic immunosuppression for the rest of your life."

So, Jeff, I was devastated. I don't know if any of you ever saw the movie Lorenzo's Oil, but I was like in -- there's a scene when the father gets the diagnosis on his son, and he just rolls down the interior stairwell of the hospital seeing nothing but black, and that was me, Jeffrey. So, at the time, I was the CEO of SiriusXM that I had started previously, and I decided to use my money from its IPO to try to fund doctors to come up with a cure.

After a couple of years of funding doctors who were trying to -- who sent me proposals, I saw we were no closer to a cure. My daughter was fainting all the time. She couldn't go to school because she would faint and hit her head. So, I just decided this was my calling was develop a cure for, her name is Jenesis with a J. So, I threw -- I formed United Therapeutics, and I threw myself into it.

And I don't know if this is wood, but, fortunately, we were able to develop a first drug that is approved by the FDA, a second drug, now 5 drugs for different types of pulmonary hypertension. Today, we are just past our 25th birthday, and Jenesis is alive, doing well, and we have converted pulmonary hypertension from a disease 2,000 people a year die from to a disease that today 50,000 people are living with.

Wow. That is a tremendous story. First of all, congratulations.

Thank you, Jeff. Thank you so much.

And I -- it's a question of, sort of, an aside, but you said you founded SiriusXM...

Yes, I did. Absolutely.

If you don't mind, just, sort of, a side question here is I'm curious what it's like to lead and found that type of company versus a biotech, biopharma because you're probably -- without knowing that -- I imagine you're the only person that's ever led both those types of companies.

You're absolutely right. The only one I know of, only one I know of...

I feel pretty comfortable saying that without any facts behind it, so go ahead.

Well, it's funny. When one of the times that Howard Stern had me on the show, he was very, very grateful and thankful for SiriusXM. He says it saved his career, made his life. And then one time he invited my daughter on to the show. And he said to my daughter, "Well, are you single?" I will say she's very attractive. And she said, "Well, I'm engaged." And he said, "Your dad didn't save your life in order for you to, like, marry some guy." So, it was, kind of, funny.

But it is -- I never took biology in college. I mean -- and probably that was a good thing. I didn't know what I was getting into. But I've been very fortunate in surrounding myself with amazing talent like James Edgemond here and all of our great scientists. I love science. I've always loved science. That's how I came up with SiriusXM.

So, over time, I began to realize that the body is just another kind of technology. Instead of it being satellite-radio technology, it's biotechnology. And instead of, like, frequencies having to have a match between the sending signal and the receiving signal, its molecules have to link up with receptors. So, I began to look at the body as technology and lead groups. And I'd just say that I'm just so happy, Jeff, I've been able to achieve success in 2 very different industries.

But to this day, to your question, a lot of people come up to me when I'm at a group like this, and they reach into their pocket and they pull out, like, one of those orange amberish bottles of pills and they say, "Thank you for Orenitram," one of our medicines or another of our medicines. "This medicine has kept me alive, got me into college, got me into my job." But for every one person who has thanked me for the life-saving drugs of UT, at least 10 people have come up to me and said, "Can I give you a hug because SiriusXM has changed my life? It's made my life everything it is." So, it's just an interesting comment on human nature, how important communication, broadcasting. And I'd say in the U.S., SiriusXM is to our culture.

Yes, absolutely. And by the way I would say...

Are you a subscriber?

I'm not a subscriber, but I have listened and a fan of a lot of SiriusXM.

Well, please subscribe.

I will get -- I will start just because of synergy, and you can hold me to it.

You got it. And every time you hear it, you'll think of me.

Yes. But as an aside, I would say that your commentary and your way of describing the biology and human physiology is perfect. And it's great that somebody who comes from a background outside of that can simplify and condense something that I've always told my colleagues at Bernstein, I say biotech, pharma, it's just like everything else. It is actually not more complicated. The only difference is that you don't get -- you drink Coke, you drink Pepsi, you experience these other products. So, you have an perspective on those products day in and day out. And so, you feel more comfortable on the sales side, maybe talking about that or maybe taking that research, taking that takeaway, and speak on it.

But I would just say that I feel like you've capsulated it perfectly that it really is just the same, and these are technical words that we don't typically talk about on a day-to-day basis.

You're so right, Jeff. I mean, there's, like, a talk that you have to talk, but -- but functionally or, what they would call, from a systems level, it's the same thing. Biology is technology.

And our keynote that we just had, I don't know if you had a chance to listen to that, but where Leora is -- and she's SVP of AstraZeneca -- where she is really strong is her ability to synthesize down simplistically, this is what an ADC is. This is how drugs work. And I feel like that's really the best part of medicine is taking something that may sound complicated and synthesizing it down to be very simple, which is back to then the achievements you had for your daughter, which is tremendous. And congratulations again on that.

I do think it's you highlight Unitherians, you highlight all of the drug development you've done. So, we sort of talked about your high-level achievements in terms of drugs coming on market in terms of the culture of the company and your strategy. So, maybe I would like to hone in on maybe a couple of them because we've got 17 minutes, but I want to make sure that we touch on the key readouts, the key things that you'd like to talk about. So, maybe in the condensed time, is there some -- would you like to go to IPF? Where would you like to focus, I guess, the next part of our conversation? Maybe we can do a couple of questions on that.

Well, I think the IPF one is a really good example of how we are a disruptor in that the -- our development of this therapy began with another clinical trial study we call the INCREASE trial, in which we tried to develop our drug for a related but different condition called PH-ILD, interstitial lung disease.

And we had an amazing result in that indication. We got FDA approval for that indication. And when we did that indication, us being entrepreneurs, we said, let's see if we can kill 2 birds with 1 stone. Let's make all of the primary endpoints, the ones that would satisfy the FDA for gaining approval in ILD. Let's make the secondary endpoints a de facto Phase II trial for IPF and PPF.

So, we did that, and we hit all of our primary and our secondaries. We got the approval for ILD, which produces over $1 billion a year in revenue for us. And we went to the FDA and we said, we would like to do a single study in IPF with nebulized Tyvaso. And here's all the in vitro data that shows the antifibrotic efficacy of the treprostinil molecule. Here's the result we had from the secondary endpoints in the ILD trial. That constitutes our Phase II trial.

Now, that's not the normal way to do a Phase II trial. It's an entrepreneur's way to do a Phase II trial because it's a shortcut to get to Phase III. The FDA looked at it and they said, we believe in your mechanism of action. We're going to go ahead and clear you to do a Phase III trial in IPF, but we're going to require you to do 2 adequate and well-controlled Phase III trials. We went back and we said, but this drug has already been approved. And usually under the FDA's rules, just one adequate and well-controlled trial is enough in a new indication for a drug which is already approved.

The FDA -- and this was the pulmonary division of the FDA -- they said that, well, those previous approvals were from the cardiorenal division of the FDA, and we will require you to do 2 adequate and well-controlled trials. That's double the cost, could be double the time and whatnot and so forth. So, here's how we approach that, Jeff, is like, do you sit there and you complain about that? Do you sit there and like you keep going back and back and back to the FDA.

We actually looked at the positives of it, but like the FDA cleared us to do this drug. If it works in 1 trial, it's going to work in 2 trials. So, we said, yes, sir. We marched off when we did it, and we got this amazing result. And as a result of that trial, we will now be able to say to all of the doctors treating pulmonary fibrosis that this is the only drug that reduces the patient's decrease in forced vital capacity by so much that it's equivalent to the patients having years of additional life. I mean, years, that's crucially important. And this disease that generally affects people in their 6th or so decade of life.

So, it's an instructive story, and we have recently doubled our sales force to launch into IPF. We plan to launch it in Europe as well. And then we went to the FDA, and we said all the physicians who are enrolling patients in the IPF study, they would like us to go into an adjacent disease called PPF, progressive pulmonary fibrosis. Now, IPF has 100,000 patients, PPF has 300,000 patients. We went to the FDA, and we are ready for them to say you have to do 2 adequate and well-controlled, but they said you did such a beautiful job in your core study -- which, by the way, has 2 articles on it published in the New England Journal of Medicine, that's what a high-caliber result it was -- you just do a single study in PPF and that will be adequate enough.

We've already fully enrolled that study. We'll unblind the results next year. And like magic, we went from, as James said, a pulmonary hypertension company last year to a pulmonary fibrosis company next year from a company with a maximum number of patients we can help of 50,000 in pulmonary hypertension to a company with the maximum number of patients we can help of 10x more in pulmonary fibrosis.

Yes. And that is great and great outcome. Successful interactions with the FDA are -- should be celebrated because they're not always the case. And I speak from experience having some good ones and some bad ones. I would love to talk about the organ side of the business. But before I do, is there anything you want to highlight on IPF or PPF before we switch over to organ?

Folks love the organ part of United Therapeutics, Jeff.

Go ahead.

This is what we call an unmet medical need. There are 100,000 people on the organ transplant list just waiting for an organ, many dying every single hour, every day. What a lot of people don't realize, and I'm happy to share at this Jeffrey conference, at this Bernstein conference -- sorry, is that there are 5x more people that are dying on dialysis off the transplant list than on the transplant list.

If everybody with end-stage renal disease was put on the transplant list, the odds of especially younger people being able to get a kidney, it would almost vanish.

So, United Therapeutics is very tightly focused on these 500,000 people with end-stage renal disease on dialysis. So, you know exactly where they are. They're being treated by doctors. And we would offer these individuals a xenograft. Xenograft, for the audience who's not aware, it's a genetically modified pig organ. And in our case, it has 10 genetic modifications that makes it appear to the body and be treated with immunosuppressants no different than an allograft. That means a kidney from another person.

We have successfully done a lot of these preclinically and the FDA authorized us to do a registration trial, which we are in the midst of right now. And the registration trial has already enrolled and transplanted the first 4 patients with the xeno-kidneys. Two more will be done this year. And at that point, we wait until 3 months after the sixth patient has been transplanted to present the data to the FDA. And if they are pleased with the data, then they say, "Okay, you can go to the end of the trial," which we expect to be 30 patients total, including the 6. We have every expectation that, that trial will be fully enrolled in by '28 and then we'll be able to launch the product commercially not later than 2030.

In anticipation of that, we have built 3 commercial xenograft production facilities: one in Virginia, one by the Mayo in Rochester, and one by Baylor in Houston. These 3 commercial organ production facilities by 2030 should be turning out about 1,000 -- each of them, 1,000 xenografts a year. So, that will be thousands of people that we'll be able to save from end-stage kidney disease as well as the FDA has also authorized our 10-gene pigs to be used for the heart. So, we have a heart clinical trial in parallel to the kidney clinical trial.

And we plan to expand these what are called designated pathogen-free facilities or DPF. It's what GMP is with pigs. And so, we could ultimately, I think, make a huge dent in the need for organs. One last thing I'll just mention quickly, we have yet a third clinical trial that the FDA has approved based on our successful preclinical work, which is completely, Jeff, so amazing and revolutionary that to me, it is to organs like SiriusXM is to radio. It is like revolutionary.

And that is -- it's called a thymokidney and a thymoheart. So, what happens is the thymus, each of us has a thymus. It's right in front of your heart. And the thymus is what trains all of the T cells in your body that you're you and other things are not you. So, if you're attacked by a bug, you get like an infection or something, the T cells say, "Okay, that's not this person. I'm going to attack it and quash it."

So, when you bring the xeno-pig thymus along with the xeno-pig's kidney or the xeno-pig's heart -- that trains the recipient, the human recipient to see the xeno-pig and the xeno-heart as itself. So, these patients, we believe that within 2, 3 months after transplant can be weaned off of all immunosuppression completely and live a normal life.

It's a little bit like there's a few cases in medicine where a person who donated bone marrow to somebody else because they had a cancer and they needed a bone marrow transplant. Later on, that recipient has a failed kidney.

And there -- when they go back to the bone marrow donor and have asked them whether they'd be willing to donate a kidney and that individual has agreed to donate the kidney, the recipient needs no immunosuppression at all because the bone marrow has already trained their immune system to recognize that individual as part of themselves. So, that trial is also, I think, will complete its enrollment by 2030 and will completely revolutionize the field of transplant medicine.

Amazing. Did you -- James, did you want to add any introductions to the organ side of the business?

One thing that's worthwhile to add on to what Martine said is previously, we were talking about DPF or designated pathogen-free facilities that were very large, requiring capital of $1.5 billion to $2 billion to build a sizable organ plant that would grow these pigs that we actually got smarter over time. And so, as we talk to investors and we looked at the program, one of the things we realized is that we can scale back our capital investment to use it for things like share repurchase now, but build these 3 facilities in Christiansburg, Virginia, in Minnesota, and down in Houston, Texas to have a smarter, more financial awareness and better deployment of capital.

So, we're able to actually build these facilities at a scale that we learned a lot from doing the construction work and doing the initial operations work. But now we're poised that as this clinical trials go forward, we can invest the capital to build these facilities to match their commercial demand. And so, maybe to add on to what Martine said, it's a very involved program from clinical trials all the way through to these facilities that we actually came up with a better way and we're better financial stewards of our capital to deploy it now, for example, in the 14 products Martine talked about, share repurchase, et cetera, and be poised to deploy capital in the future as these clinical trials go forward and we approach commercialization in 2030. So, just more of the financial side to it that kind of complements what Martine talked about on the opportunity as well as the clinical development side.

And that's great to hear. I have a note here about CLIMB, the Computational Laboratory for In Silico Molecular Biology. I like to hear a little bit about that.

Sure. Thanks so much for asking, Jeff. So, several years ago, we formed an AI lab at UT with the task of creating an accurate digital model down to the level of all the membrane-bound receptors on all of the molecules in the lung. And that's a very tall challenge because you have to cover both the airways as well as the vascular side of the lung. We ended up hiring the entire AI computational biology team from Johns Hopkins and moved them over to United Therapeutics.

And this team worked assiduously and built up what I'm sure is the world's most detailed digital AI model of the lung and specifically tuned for testing drugs in the diseases of interest to us, which is pulmonary hypertension and pulmonary fibrosis.

I didn't mention in the previous discussions of our molecules that those molecules were tested and validated for those indications first in our digital model. And it's remarkable to me that, for example, we ended up improving -- I'll just round the number here a little bit -- by 100 milliliters of oxygen, the improvement in forced vital capacity of the patients in the pulmonary fibrosis study. In the digital model, which we've completed before we did this study, the estimate was 105 milliliters, which is insignificantly different.

So -- and it also accurately predicted the success of our ralinepag molecule, pulmonary hypertension. It actually predicted accurately the failure of other companies' molecules that James was getting ready to possibly have to write a check to license these other. And the model said, don't do it. It's not going to work. And in fact, it didn't work. So, we are like total believers in AI's ability to develop new molecules and new diseases, specifically in the lung, and we're now very honored that multiple big pharma partners are interested in us testing their molecules within our digital lung.

Well, I'm going to put a plug in. Courtney has -- my colleague, has an AI panel that's going to discuss AI and drug development right after this, in case you're interested.

Yes, very interested.

Like you have something to add to that conversation. So, that will also be either here or in the other room. But then back to you guys. So, we've got just a couple of minutes left. And I think it would be nice to sort of -- you have a lot of drugs that you sort of gave in the overview. So, I'd like to give you, 2.5 minutes here maybe to highlight something that we haven't had a chance to talk about, whatever that might be, even if it's you intend to start another satellite radio business.

No, no. What I'd like to talk about is my favorite drug being queued up right now is a drug called Rilopirox. So, it takes the superior pharmacokinetics and pharmacodynamics of ralinepag over treprostinil, which, for example, includes just once daily dosing and applies it to these vast indications such as pulmonary fibrosis, and progressive pulmonary fibrosis. This molecule actually has stronger antifibrotic and anti-inflammatory activity than does treprostinil.

And it's got both composition of matter protection and pulmonary fibrosis patent protection out into the 2040s. So, I think our development of Ralpi will be the greatest drug that we could possibly develop at UT. It will take us up towards that $100 billion a year in revenues. And by the time we complete its clinical trial and start marketing it, which is scheduled for basically 2030, that's the same year that we will be launching the commercial organ manufacturing that we can provide thousands upon thousands of people with commercial organs, completely disrupting UNOS, which is, kind of, sharing for the human donor organs, completely disrupting the entire immunosuppressant pharma business.

So, for us, being a disruptor is not a laurel to rest upon and then you become a leader. For us, a disruptor is a culture. And going back to your great question, Jeff, on what makes UT click. If you take a look at our annual report, you will see this is a company that all the directors not sitting there in a fig-leaf fashion with their hands. Every annual report is disrupting. Our culture is disrupting. Our #1 mantra is question authority and identify the corridors of indifference like organ development, pulmonary fibrosis and then run down those corridors of indifference.

That's great. Well, this has been a pleasure.

My honor to be here. Thank you so much, Jeff. I appreciate it.

Thank you so much.

Thank you.

All right. Well, thanks so much for joining us, everybody. I'm Terence Flynn, Morgan Stanley's U.S. Biopharma Analyst. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

I'm very pleased to be hosting United Therapeutics this afternoon. Joining us from the company, we have Martine Rothblatt, who is the company's Chairperson and CEO; and Pat Poisson, who is EVP, Strategic Development. Thank you both so much for taking time on your day to join us. Really appreciate it and looking forward to the conversation.

Maybe, Martine, first, I'll just turn it over to you to maybe make some framing comments before I launch into my questions, but thanks so much.

Sure, Terence. Thank you so much for inviting us here. We appreciate it. It's great to have the opportunity to give some framing comments because this is a very unique point -- it's -- you need down to the -- no other point is like this quarter in United Therapeutics' entire history because this is the quarter that we have gone ahead and inflected ourselves from being an orphan drug pulmonary hypertension company.

Which was our history, developing great medicines, multiple great medicines for pulmonary hypertension and building ourselves up to a few billion dollars a year in recurring revenue and inflecting ourselves into a pulmonary fibrosis company that will be treating hundreds of thousands of patients with a best-in-class drug for idiopathic pulmonary fibrosis. And we're pretty confident we'll soon show similar results in progressive pulmonary fibrosis, which is not an orphan disease.

On top of all of that, due to some new products that we've developed, such as our Coughless Tresmi Inhaler, we'll be launching studies next year into a form of COPD called COPD-PH, which can be uniquely treated by our drug and has a prevalence in the United States of 400,000 to 800,000 patients.

So it's just amazing, Terence, I know you've been with us for quite a number of years monitoring the company to be at this point in time when you look behind you and you see, okay, you've gone from nothing to being, I guess, the largest player in pulmonary hypertension, building up this several billion dollars recurring revenue.

And then looking forward and saying, Oh my God, we're about to launch into becoming like a major bracket biotech company with something like $50 billion to $100 billion in pharma revenue, mostly in non-orphan indications, all based on clinical trial results that have been now submitted to the FDA and in the estimation of all of the experts, whether in PAH for our medicine JENRALDI, once-daily pill for pulmonary hypertension or in IPF for our medicine Nebulized Tyvaso in everyone's estimation.

These are the best drugs in these 2 different diseases with the best clinical trial results that have ever been shown. So it's a hell of a point to be giving you a framing comments right now.

Great. I appreciate the update. And again, I'm looking -- we were talking earlier about how far the company has come. I think I've been covering the company for 20 years, but obviously, a lot has changed since those days.

Yes. I pinch myself actually because I remember when we were like 5 people and now 2,000 people with 14 drugs in active development, it's truly amazing.

Great. Well, I think I know the answer to this question already given your framing comments. But I think the official long-term guidance you guys have given is $8 billion in revenue. Now again, as you just think through confidence level there, but maybe what are the drivers to get to that $8 billion before we talk about the $50 billion?

Sure. So the $8 billion we see coming from all of our core business where we are continuing to grow in all of our legacy products like Remodulin, Orenitram and Tyvaso -- and -- but especially in the newly launched projects, which include, first of all, Nebulized Tyvaso for IPF. We've submitted that to the FDA. We've got our PDUFA dates.

So we're pretty confident of launching that product in the middle of next year. That product will be launched into an indication with 100,000 prevalence in the United States. The only alternative drug that has been shown to give an improvement over some very old, very toxic medicines is a BI drug called Jascayd. We're really happy to see that medicine launched.

But our medicine Nebulized Tyvaso showed in 2 separate Phase III well-controlled studies, dramatically greater improvement than Jascayd. And when like you break it down to how many years of life an average patient can expect, they would be able to expect multiple years more of life on Nebulized Tyvaso than on any other product in the IPF space.

So we certainly expect several of those billions of dollars a year to grow in IPF. In the meantime, Terence, we just fully enrolled another study in a much larger indication called PPF. And we fully enrolled the study, 700 patients. We'll have data about this time next year. And we feel very confident that our drug will work in that indication as well.

So when you look at the combination of 100,000 patients in IPF, 300,000 patients in PPF, that's 400,000 patients, and that will take you far beyond the $8 billion revenue run to what we expect will be in the fibrotic type conditions like this, a $40 billion pharma revenue.

So that's the near term. And then as I mentioned briefly in the framing remarks, I'll just touch on very quickly. Other products that we are developing for the IPF market, including DPI Tyvaso and cough-free Tresmi and then once-daily wild-type, we will be bringing those products in to further solidify our hold on the IPF and PPF market.

So $40 billion is of course, a lot of money. But we have a straight shot at it. We have the clinical trial data for the base of it. And I should mention that the company has been able to successfully garner intellectual property protection for its fibrotic applications of its medicines out to the 2040s and composition of matter IP protection for ralinepag also to the 2040s.

Great. Maybe we'll unpack a little bit of that on the Tyvaso for IPF front first. Again, maybe just speak to about the confidence in an FDA approval here. Again, if there's any outstanding issues or questions that FDA has raised at this point. I know it's still early in the review process.

Well, super great question, Terence. But actually, I can say having looked at the FDA's comment letter, I can't remember any letter back to us on a filing from the FDA in the past 20 years with fewer comments. So it's not surprising that it will be a very clean situation because the FDA has been approving Tyvaso in various indications for quite a few years for like over 10 years. So it's known to be a very safe and effective molecule.

Also, the device that we're asking the FDA to approve it for in pulmonary fibrosis, the nebulizer device is a device that the FDA has previously approved and has an excellent track record. And last but not least, the pulmonary division of the FDA asked us to do 2 separate trials in stand-alone IPF without any confounding patients from PPF.

We said definitely yes, sir, and we executed those. And wow, the results were mind-blowing. I'm talking about round numbers, 100 milliliters of oxygen improvement compared to baseline and that's like way beyond anything that nintedanib, pirfenidone or even Jascayd ever showed.

So I'm super excited. Everybody at UT is super excited that we are going to be able to literally promise tens of thousands of patients with pulmonary fibrosis, more years of good quality and good quality life. And that's a beautiful thing to do in this industry.

Great. Maybe talk to us about the launch preparation. So you guys have, I know, expanded your ILD Tyvaso sales force. Is it possible that you can leverage some of that existing build? Or do you need another build-out here to push further into the community pulmonology setting? So maybe just talk about the prep you're doing on the launch front for a second.

Yes, Terence, that's a fun question because I can answer yes and yes, which is the best. So yes, very definitely, we will be leveraging the new hires. We doubled our ILD sales force. And a goodly number of those people in the doubled force already have a great deal of expertise in IPF.

So when they -- when we're ready to launch the product, they now will have familiarity with how to submit expense reports in the UT system and all that kind of normal and customary stuff. And we'll be able to flip -- flip over to detailing full-on straight-up IPF prescribing doctors.

In addition to that, to be able to satisfy our 100,000 patient market, we're going to be doubling that sales force multiple times. And I expect that at the rate of our product introductions into IPF, into PPF that you'll be hearing from Michael Benkowitz, our Head of Commercialization, our President, that there'll be another doubling of our sales force just focused on IPF each year for the next 2, 3 years.

Okay. So doubling every 2 to 3 years. And that will cover though, the PPF indication as well?

I think that's just for the IPF and then there'll be yet additional hiring for PPF. PPF is a form of pulmonary fibrosis caused by an array of kind of other conditions and/or causes. And it's 3x larger than the IPF indication. So that takes us up to the 400,000 patients.

And I feel pretty confident just thinking a little bit on the fly here up on the stage that to adequately cover the entire 400,000 patients, you would need upwards of at minimum 1,000-person sales force which UT, fortunately, we've built up all these different sales forces. We're good at that. And we're committed to leave no pulmonary fibrosis patients behind.

Okay. Great. You talked about the patient prevalence numbers already. I guess the other one is just how to think about treatment duration here for Tyvaso and IPF relative to PAH or maybe even current IPF drugs. I know the current drugs struggle with some of the tolerability issues, their TKIs have a lot of GI side effects, among other things. So how do you think about the treatment duration here for your product in IPF specifically?

Yes. Thanks, Terence. So we actually kind of pre-thought about the therapy duration in these patients. And that's why we've queued up a line of 4 products that can basically address ever greater arrays of patients.

And people are diverse and some people can tolerate a product, even the ones with GI side effects for a longer time, other people can't. So the first product introduced is a Nebulized Tyvaso. And then coming on the heels of that, we have the DPI Tyvaso, which is already approved by the FDA in ILD and PH, as you know.

And that product is a lot easier because it's a shorter number of inhalations, more rapidly get it accomplished, you can put it in your pocket, more portable. So that will be the next product introduced in the indication. Then to yet further reduce people dropping off therapy, we'll next introduce this coughless Tresmi product, which is a softness inhaler.

And as the name implies, for those patients who have difficulty tolerating dry powder, which is not most patients, but a significant number. And as I said, we don't want to leave any patient behind, will then introduce the softness powder inhaler into the market.

And I think that will yet further keep patients on the drug, reduce the number of dropouts. And then the fourth of these is the once-daily Rpi product with what we believe is the most effective treprostinil-like agent, ralinepag, into this indication that you only have to take one inhalation once a day, beyond a doubt, the easiest one of all of them to stay on. Dropouts in our other ralinepag studies were very, very low.

So between those 4 products, my hope is it could be just de minimis single-digit percent of patients drop off these therapies. And more important than that is keeping the patients alive for much longer than was ever the case with previous drugs.

When do you think you would have some survival data? I mean you mentioned keeping patients alive. I know these trials in IPF weren't designed for that. Their lung function endpoints. But as you -- similar with PAH, we saw the field evolve from, again, 6-minute walk distance to now you have longer-term outcomes.

So when do you think you could see some of that longer-term outcome data for Tyvaso and IPF?

Well, a lot of that data, you can actually get right now just using arithmetic. And Pat, if I might be able to ask you to kind of explain the differences there.

Yes. So if you look at decline in FVC on a patient who's not being treated, typically, you would see between 200 and 250 ml annually. Jascayd showed a vast improvement. They're down, say, 100ml to 125 ml so if you kind of think about years, that extends that time period by a year. When you look at Tyvaso, which was down in the 40 to 50 range, when compared to someone not on treatment, that's a 5-year change in decline.

Contrasted with someone with a healthy person where you'd see 25 ml. So you're seeing a difference really just a 20 ml from a patient -- a sick patient with IPF on Tyvaso, which is very close. So there's a drastic difference in clinical efficacy, very compelling.

Yes. Okay. Great. I guess you mentioned PPF here, and you're going to have some data second half of '27. Maybe just talk to us about why you're confident that the IPF data will translate to PPF. And you guys have a lot of models you use for the IPF in terms of running scenarios and things like that. But where does the confidence level come from? And just is it similar biology, different biology? And then I have a couple of follow-ups.

Sure. So with regard to the PPF, our confidence was first built up from our Phase II equivalent study, which we call the INCREASE study that we did in ILD patients that had a mixed population of some IPF and some PPF. And we saw the drug was quite effective in those patients with PPF.

In fact, based on that study, we went to the FDA and asked them if we could do a single combined study of IPF and PPF. The FDA pushed back and they said, this is a new drug and a new indication, and we want to get as clear a read as possible of everything.

So notwithstanding the favorable Phase II equivalent data, we want you to do a separate IPF study. In fact, we want you to do 2 well-controlled IPF studies, which we did, and those are called the TETON 1 and TETON 2 studies, and they produced the remarkable results that Pat just described. So then we went back to the FDA and we said, okay, we've got TETON 1 and TETON 2 underway. We'd like to do a PPF study.

By now, I think the FDA was becoming quite comfortable and familiar with the device, the drug, the indication, use in the indication. And they agreed that we could just do a single PPF study of 700 patients. Now while we were enrolling the study, we were being -- received constant incoming from all the IPF docs saying, you guys got to develop this drug for PPF.

And there's nobody that really knows their patients better than the physicians treating them. So whether it was in Europe or the U.S., I mean, across the board, IPF docs were saying, please develop this for PPF. So we did that. And Karen's remarkable result was that we had the fastest enrollment of a clinical trial study ever in our 20-year history.

Just all the way up to 700. So fully enrolled now, and we'll have the data next year. I might add that the -- in answer to your question that we've also run all manner of in vitro cell activity -- cell studies to test the efficacy of the treprostinil molecule against fibrotic tissues and whether the tissues are sourced from IPF or PPX, you repeatedly see that treprostinil is effective.

Okay. Great. Before we go on to some of the other products, I just want to touch on kind of Tyvaso in market. ILD has been a newer indication in terms of the forward, PAH was the first indication. ILD is the second. Maybe just give us an update on kind of where you stand as of second quarter and how to think about the outlook for that franchise on market into the second half of this year.

Sure. I think we're going to continue growing in the ILD market, ILD-PH market. We are already the most prescribed drug in that market. As you may have heard on our last earnings call, we now have record starts, new patient starts in that market. The availability of both the Nebulized Tyvaso as well as the DPI gives you kind of 2 shots on goal.

Getting back to your question earlier about patient dropouts when there's different ways for the patient to take the drug and different ways for them to reach different levels of concentration of the drug, it helps you build the patient census up. So I expect us to continue growing in the market. What's changed is the indication itself, which once seemed kind of significant at, I don't know, 20,000 or 30,000 patients, after we unblinded the TETON 1, the TETON 2 results and saw the rapid enrollment in PPF, it's like, oh my God, this is not even 1/10 of the market for United Therapeutics products.

This is actually like 1/20 of it. So the company's focus has very much shifted to pulmonary fibrosis and progressive pulmonary fibrosis because that market is literally 20x as large as the ILD market. Our nature as a company is to continue to pay attention to these orphan indications.

You may recall, Terence, that we continue to serve the ultra-orphan neuroblastoma market with Unituxin, in which we save 500 kids' lives every year, year after year from cancer, which would otherwise kill them. So we're dedicated to maintaining our presence in the ILD market. I'm sure we'll remain the #1 seller in the ILD market, but it has become kind of a small thing in the overall landscape of UT.

Okay. Maybe just pivoting over, you mentioned your Tresmi or softness program already. Maybe just remind us there of the target profile and then what's gating to the NDA filing here?

Sure. Maybe it's a good opportunity. Pat's in charge of product development and strategic product development. So Pat, if you could talk about that. So we're planning to file an NDA for that by the end of the year. And that NDA will be for the PAH and PH-ILD indications.

Once that's accepted, I think we'll be far enough along in the IPF review where we can engage with FDA on what's needed for a bridging study to get the SMI approved for IPF as well. We intend to do the same for PPF once PPF is filed.

Okay. And just...

By the way, just not to interrupt you, Terence, but just to add one more link on TPA chain is with that filing of the coughless Tresmi device at the end of this year, we can then go ahead and launch into the clinical trials of COPD-PH, which is the largest of all of our indications with 600,000 patients and roughly a $60 billion TAM.

So if we can capture even half of that TAM, which would be the first and only product approved in that indication, that will take us north of the $50 billion in pharma revenue we expect over the next few years.

Okay. Great. Maybe just remind us, I know you said coughless, but again, anything else about the target profile that we need to keep in mind for Tresmi?

Yes. I think the big thing is really beyond that convenience in that you'll be able to inhale multiple breast equivalents to the nebulizer in one breath. So much like we did with DPI, where we started with a series of strengths and expanded that. We'll do the same with SMI.

And is that -- that's an internal device that you guys develop to as well?

It's a partnership. It's a partnership.

Okay. Have you disclosed to the partner is on that?

No, we haven't.

Okay. And the IP on that device goes out, how far?

I mean there's both IP and trade secrets. It's a fairly complicated device to manufacture. So...

Okay. Okay. Maybe, Martine, you mentioned COPD-PH. So maybe just elaborate a little bit there on kind of the biology and why you guys decided to pursue that indication.

Sure. We originally led to this one also by physicians. I guess that's kind of a trend at UT is it's the physicians lead the way. So we listen to them. One of the great physicians in this field of treating COPD-PH is Dr. Waxman over in the Boston area.

And so he had basically off-label and investigator initiated kind of studies, used our Nebulized Tyvaso in the COPD-PH patients, found remarkable improvement and encouraged us to do a study, which we started in the beginning of 2020, and that was called the PERFECT study. A little degree know but that was the same time COVID started. So it was some bad luck there and...

Not perfect timing.

It was an imperfect study and timing for kind of perfectly named trials. So anyway, enrollment was all but impossible during COVID and it went year after year.

We had to invent some things on the fly, like our patients could not go into the hospitals to do their endpoint measurements. So we had to invent equivalent endpoint measurements that they could do at their house. As the company's CEO, I made a difficult decision because I know that there's a lot of these people and they need this drug. But I made the difficult decision to cancel that study just about at the end of COVID because it was very hard to enroll it.

And I was nervous that these non-validated measurements in lieu of regular hospital measurements would result in too wide a variability of data and might fail the study, and I don't want that. So I stopped the study, but I decided I'm not going to stop the indication.

So it was about that time that we began working on our softness inhaler, which would give us a much better inhalation device for this patient population. We also, in parallel, ramped up our efforts into other inhaled avenues such as ILD and IPF.

And now we are at the point that, as Pat said, we're filing the NDA for the softness inhaler. It is, in fact, the ideal -- it is the perfect product for that indication. But because the team running that clinical trial in COPD-PH is the same team that ran the TETON 1 and TETON 2 trials, their name for the COPD-PH trial is the SUMMIT trial, and they have successfully Summited more than once.

Just for the audience's knowledge, COPD-PH is a form of COPD in which the PH symptoms are out of proportion to the COPD symptoms. So while upwards of like 14 million Americans have COPD and COPD and COPD emphysema are the largest causes of lung transplant, just a fraction of them have such a severe form that the PH symptoms are out of proportion to the COPD symptoms, and that's about 400,000 to 800,000 patients.

So based on Dr. Waxman's work, based on our own earlier perfect work, which we have all of that data, based on the new development of our SMI, we feel we have all of the pieces in place to succeed. Nevertheless, we're going to go step by step and quickly after the SMI device is submitted, -- we're going to start a Phase II trial in COPD-PH and then very rapidly follow that in '28 with the Phase III trial.

We think that the interest is going to be so strong that, that trial should be able to wrap up by '29, allowing us to file for approval in '30 and then launch this product at the beginning of the 2030s. As Pat said, we've got intellectual property protection on the device and trade secrets going out to the 2040s.

Great. What -- just remind us the -- I know you had to adapt the endpoints because of COVID, but what would the endpoint be for this new Phase II trial? Would it be the original perfect trial endpoint? Or is it a new endpoint? Like what's the endpoint?

Yes, you'll have to wait until you see the filing and the protocol on clinicaltrials.gov. But the old endpoint were a combination of endpoints, including 6-minute walk, spirometry and some other stuff. There's a different clinical development team in charge of this one, and I don't want to prejudge any of their final decisions on the protocol, much less in interactions with the cardiorenal division.

There may be different changes in endpoint. The field of COPD is always moving. So what I can tell you with a high degree of confidence is it would not be the kind of morbidity mortality endpoint that you saw us successfully achieve in pulmonary hypertension.

I don't believe that that's necessary. I would also point out that the controlling division of the FDA for this will be the cardiorenal division and not the pulmonary division and the cardiorenal division has a high degree of familiarity with the indication with our treatment.

Okay. Great. Maybe just moving on to ralinepag, again, another upcoming product launch. Just how do we think about inputs into the pricing decision here? Obviously, you have Orenitram already on the market with an oral prostacyclin. And so is that the best analog to think about here? And then how should we think about the early uptake curve for this drug?

Sure. So kind of taking the 3 points of your question. There is no doubt that ralinepag or its commercial name JENRALDI is a better drug than oral treprostinil. And I say that despite the fact that Orenitram spells Martine-ro, of my last name backwards. Notwithstanding that, ralinepag is a better drug.

I was just trying to do the backwards on JENRALDI, and I couldn't figure out.

You can't figure it out, but the person that we started this company from for my daughter, her name is Genesis with a J. So you can kind of get the gen and roll from ralinepag. It beats paying somebody $0.25 million to come up with a drug for you, right?

That's what they charge, the Grand Institute or something like that. And some of them came pronounced. So one, it is a better drug. even though that would command a price premium, I don't really think there will be a price premium compared to Orenitram. And I think the uptake is going to be quite strong because it will uniquely among all the drugs in the PH space, be able to claim that its registration trial showed that about half the patients achieved a clinical improvement in their clinical status.

Nobody else has ever shown that. So it will be a pretty good call for the sales reps to say, if you want to tell your patient that they can improve instead of slow the decline, JENRALDI is the only way to do that. And then if the physician says something like, well, my patient has at least been kind of stable on an ETRA or a PDE5i.

Fortunately, those were most of the patients all were on that background therapy. So we showed synergy with that. And if the physician thinks they don't want to take their patients off of, say, something like WINREVAIR, we could show, well, we've already seen a lot of synergy between the prostacyclin class and WINREVAIR.

So I think not only is ralinepag the most efficacious drug for pulmonary hypertension, it's also, I believe, the most polypharmacy-friendly drug in pulmonary hypertension.

Okay. Great. Well, I think we're up against time. But again, really great to see you both. Thank you so much for taking time out of your day to spend with me and best of luck.

Thank you, Terence.

Thank you too.

Hi. Good afternoon, everyone. Welcome to Day 1 of our Cancer Healthcare Conference. Hopefully, you guys can hear me okay. My name is Olivia Brayer. I'm one of the senior biotech analysts here at Cantor and really excited for this fireside chat. We have Martine Rothblatt, Founder and CEO of United Therapeutics. And of course, James Edgemond, who is CFO. Thank you both for joining us.

Thank you, Olivia. And I'm also happy to mention that Harry Silvers, our Head of Investor Relations is right there in the front row and available a few questions afterwards.

Harry, we'll make sure he keeps us all in check up here on stage. Well, it has been quite a year for United Therapeutics. Big year clinically. I think people are really excited about the momentum and what 2027 has to bring. So I mean maybe just set the stage for where the company is today and how you think about what could be a very big inflection and transformation for the company from here?

Olivia, you are so right that we are in the absolute best position we have ever been in the company. It's very rare in a company's life that you get to see present when it kind of inflects from, say, like a kid to an adult type of company, that sort of thing. And that's where we are with United Therapeutics. We started off as a pulmonary hypertension company. And now because of the amazing results that we had from the TETON 1 and TETON 2 trials in pulmonary fibrosis, it's very, very clear that we have now inflected over to become a pulmonary fibrosis company. And those not like within a half year after we fully enroll those studies and reported the results by far, the best results ever reported for any drug, from any company in 30 years in pulmonary fibrosis, I mean, really making a difference. Then we very rapidly almost overnight, enroll another study, TETON 3, in progressive pulmonary fibrosis which is something like a 3x larger indication.

So this amazing indication of pulmonary fibrosis where we had the best results. Now we rapidly enrolled the other one. And we're looking at now a capturable market that is in the neighborhood of north of 0.25 million U.S. patients compared to the maximum capturable market that we ever had in pulmonary hypertension of 25,000 patients. So a 10x jump based on solid data, NDA is now in the hopper, accepted by the FDA, PDUFA date issued [ April 26 ]. So it's super awesome.

Okay. I'm going to come back to that in a minute. [ April 26 ] is the PDUFA date?

Yes. That's the PDUFA date. [ April 26 ].

So I mean, would you ever -- I know you just put some numbers around epidemiology, but would you ever put some numbers and kind of characterize the opportunity set that you think that you have across the pipeline and some of the newer launches that you have coming up. Obviously, IPF, you eventually will hopefully have PPF when that data comes out next year. You have ralinepag in PAH. So I think a lot of investors are trying to put the pieces together. So I don't know if there's anything that you can say to maybe help contextualize it for us.

Sure, Olivia. Fortunately, in these types of indications, it's possible to do that because the prices of the therapies for treating patients in these indications are well established and have been reimbursed by both public and private payers for many years. All of these therapies are, by their nature, chronic therapies that patients take to extend their lives. So it makes sort of like sizing the opportunity a little bit easier because you don't have to make a lot of assumptions about how many new patients are going to be captured to replace patients that have already been successfully fully treated by your therapy.

And in our case, if you take a look at the combination of the pulmonary fibrosis and progressive pulmonary fibrosis markets by most conservative estimates, you're looking at 400,000 patients. And then another indication, which we've announced that we will now be commencing enrollment in our clinical trials next year, therefore, is the indication called COPD with pulmonary hypertension that is dominant in the COPD patients. That's an indication of 400,000 to 800,000 U.S. patients, so on average about 600,000 in the middle. So now having nothing to do with pulmonary hypertension at all where we started as our youth going up, now as adults, we find ourselves in a 1 million patient population and that's the addressable market. Our drugs fortunately have shown that they are best in class for pulmonary fibrosis, best-in-class for pulmonary hypertension.

So you're looking at -- even if it is a 50% capture against these numbers, time something like $200,000 per patient per year for the normal reimbursed amount, you're looking at United Therapeutics now as a $100 billion pharma revenue company compared to just last year when we were only pulmonary hypertension, maybe the maximum potential would be around $10 billion. So again, a 10x transformation during the past year. We are -- everybody in this company were just like going full speed out for it.

Good for you guys. And that first kind of proof point will be your IPF launch coming up next year, like you said, you do have an official PDUFA date. Maybe just to start, I mean, what are you all doing as a company to get ready for that launch from a sales force perspective, from an awareness perspective, I'm sure some of your team was just at ERS this past weekend? What has been kind of the feedback from the community? And what are you all doing to make sure that you do end up having a successful launch come next year?

It's so great that you asked that question, Olivia, because speaking about the ERS, I kept getting text messages from my team of the slides that we showed where you see the improvement in forced vital capacity on Tyvaso compared to like the baseline background therapies like pirfenidone and nintedanib and like we're -- you don't usually see curves like separate and keep separating like this, but we saw them, they say Dr. [indiscernible], everybody is just totally amazed that there is a drug which is now going to be hopefully shortly available for the patients with pulmonary fibrosis.

And so we have rapidly doubled our sales force, including many people who are highly experienced in interacting with doctors for pulmonary fibrotic conditions. And the doubled sales force are beginning to learn our medicines in the context of our approved indications of PH-ILD. So that's given them good practice, good understanding of treprostinil, how it's different from pirfenidone and nintedanib and other medicines in this area. We are preparing for the combination of our medicine also with Jascayd, which is a very nice new development from BI. So we've opened up an open-label extension arm of our TETON studies, where we can now enroll patients who are going to be on nebulized Tyvaso as well as Jascayd. So when we launch, we can present safety information to the prescribers, showing whether your patient is on no background therapy. Any of the legacy background therapies for IPF, or even on the brand-new Jascayd, you can expect to have a safe and improved response as a result of adding on nebulized Tyvaso.

We're also very hard at work at UT. We are just like relentlessly improvers. In fact, our mantra for all 2,000 of us is approve and then improve, approve and then improve. We never stopped. So right away on the heels of nebulized Tyvaso, hopefully being launched in the middle of '27, we're going to be rolling out the clinical program, which I think will be a very simple PK bioequivalent sort of thing for what we call, DPI Tyvaso. So now DPI Tyvaso is already approved in PH and PH-ILD. So it's got a stellar safety record. So we expect that that's going to be warmly receptive by the regulatory agencies, patients in IPF.

Now you're going to go from having, okay, you've got a nebulizer, that's great. Now you also have a DPI that you just stick in your pocket. We're also going to be filing at the end of this year, our next-generation product, which is called a coughless Tresmi. And this is a product which Tresmi acronym for treprostinil soft mist inhaler. The studies we've been doing in human volunteers already have shown like no cough from these patients. So that's like an amazing new thing in this indication as well as in yet another new study will start next year that I just mentioned before, the COPD study. So we've gone from having, let's say, 1 or 2 pivotal registration studies a year. That's for like the past few years. We now have 14 new product launches, all going on simultaneously for 2027, '28 and '29. And this is why based upon 14 product launches, we can feel confident that UT will be a $50 billion to $100 billion pharma revenue company at the beginning of the 2030s.

Yes. And you brought up the DPI and the SMI formulations. I know maybe you guys aren't ready to share today exactly what the time lines are and next steps there. But is the hope that you could have DPI and SMI launch shortly after a nebulized product? Or is that maybe a little bit more of a forward thinking come 2028 or 2029? I'm not exactly sure what you guys have put in the public domain at this point.

Sure, Olivia. I think it is shortly after. And the reason for that is that our treprostinil product has such a good track record for safety. And that we have such an amazing core competency in United Therapeutics and drug formulation and a drug device combination product. The one that might take a little bit longer is this yet another new product that's in that 14 product portfolio that we call once-daily RAL-DPI. This is an inhalation therapy where you just take 1 cough a day, and that will be your treatment for pulmonary hypertension and ILD. And we'll have to show, but I believe it will be a treatment for pulmonary fibrosis as well as progressive pulmonary fibrosis. So this population of 100,000 IPF patients, 300,000 PPF patients. We plan to just introduce wave after wave of products, Tyvaso nebulized, Tyvaso DPI, coughless SMI and then once-daily RAL-DPI. And every patient will find therapies that work both for them, best for them. Our goal is just to leave no patient behind.

Yes, a lot going on and a lot of different life cycle management strategies. So good for you all for staying in front of that. You brought up Jascayd, obviously, having an incredibly successful launch. I'm sure you all are tracking that very closely. Maybe to start, I mean, what have been some of the learnings from that launch? Have you been surprised by how quickly Jascayd has by just the commercial trajectory and the uptake of that product? And are there any commercial learnings from that launch that you can hopefully apply to your launch coming next year?

That's an amazing question, Olivia. I think that I second everything that you said that it was an amazing launch for Jascayd. And BI serves like enormous credit for developing that drug and bringing it to the patient.

When we saw the significant improvement that Jascayd offered over the legacy treatment, we were not surprised to see a rapid launch. This patient population it's just horrible how they have suffered. And frankly, I know people even in our own company who have pulmonary fibrosis. It is a terrible indication. So for literally decades, the patient population has suffered with a couple of drugs that have, for most people, intolerable GI side effects. And so only a small fraction of the diagnosed patient population are actually treated with like on-label approved products. So it wouldn't surprise me in the least for when patients come in for their doctor visits or even being called in by the physician saying we have something new for you that could make a difference. So we were really, really heartened by that.

I do think that our study in TETON 1 and TETON 2 showed that a polypharmacy approach is the way of the future in pulmonary fibrosis as well as pulmonary hypertension. So I think that we're going to see many patients on both Jascayd as well as nebulized and DPI Tyvaso. I do think that our uptake will be certainly, I can't say patient to patient, but will be as rapid, a rapid explosive type of launch. We are planning for 10,000 patients in our first year on nebulized Tyvaso. And given the difference between an inhaler and a pill, 10,000 for 1 year in inhaler is likely a much larger number for a pill.

Okay. And you mentioned earlier that a very small proportion of patients with IPF are actually receiving medication. Why do you think that is?

I think it's because the only medication that's been available has been intolerable. And the one thing that we've learned with a lot of orphan diseases is if you want the patient to stay compliant, to stay on the drug, you got to make the patients feel better. And it's not just common sense, like why -- if you're already sick, why do you want to just stay on a medicine that's only making you sicker? I mean you could deal with like, okay, I got to wait a couple of weeks for it to get better. But after 2 months, you're not any better and you're actually feeling a lot worse. You're going to drop the drug. And I would -- from the research I've done, Olivia, it seems to me that more than 3x as many people have tried pirfenidone and nintedanib have dropped off it and have remained on it.

Yes. And you actually brought up a really interesting point, which I didn't realize until just now is that you are enrolling patients on Jascayd in an open-label extension study. Can you talk about the decision to do that? And then data collection perspective, will you actually have some data to present or send to the FDA as part of your review application cycle?

So first of all, there is no real intention on our part to modify the label for the open-label extension inclusion of the Jascayd patients. The reason for that is like crafting an NDA is like crafting like a MonaLisa painting. I mean you want it to be picture perfect. And the last thing you want to be doing is like, oh, I just want to like change something at the last minute that could introduce any basis for delay. If that was essential for a product launch, yes, you have to do it, but it's the opposite of that for us. There's no possible way that Jascayd by its own can cover this whole pulmonary fibrosis market. So it's not essential. There's plenty of time to amend the label in the future. So we don't see a need to rush any of that data into the FDA.

The reason that we decided to do it is that we have become highly convinced through the TETON 1 and TETON 2 studies that polypharmacy is the way of the future in this indication. We did see synergistic benefits between the antifibrotic activity of treprostinil and that of differentially nintedanib and pirfenidone in the TETON 2 study -- in the TETON 1 and TETON 2 studies. While it's a different indication, we've seen amazing synergy of the polypharmacy in pulmonary hypertension with, for example, sotatercept being an amazing drug introduced by Merck, it turns out like it works even better combined with treprostinil as well. And that's the same thing for things like ETRA receptor antagonists and PDE-5 inhibitors.

So we are very, very comfortable with polypharmacies. We're actively engaged in creating compounded new products that would, in fact, put the whole polypharmacy in one dosing. So you don't have to like grab from here and grab from there. So Jascayd lifted the bar from where it was with pirfenidone and nintedanib up to a higher level. That's awesome. However, the objective fact is that the improvement in the patients' forced vital capacity from Jascayd came nowhere near what was demonstrated independently twice to insane p-value levels in both TETON 1 and TETON 2. So it is -- I mean, we'll wait until the FDA approves it. But based on the scientific data right now, nebulized Tyvaso is a best-in-class drug for treating patients with pulmonary fibrosis.

Yes. And to that point, what do you make of the agency's decision to give you all a standard review rather than a potential priority review?

I think it's really just a consequence of the FDA managing their resources. We did a calculation, and we saw that if we did receive a priority review, it would have occurred about Christmas Eve. And I can imagine, like with all of the drug applications pouring into the FDA with the difficulty, with headcount and everything these days that they just felt the best way to manage their resources was to provide us a standard review. It really doesn't matter. It's 4 months later. And [ April 26 ] will be here before any of us know it. We have a ton of things to do to get ready for that launch, and we're doing them.

And then you mentioned pricing earlier. How should we be thinking about pricing for Tyvaso? I mean we obviously know the price in PAH and PH-ILD. Anything different as we think about IPF and the consideration?

Olivia, I'm so glad you asked about pricing because we have our Chief Financial Officer right here on the podium.

Thank you. It's a good question. We've gotten in often. At this point, we don't -- one, we don't talk a lot about pricing for. But at this point, Tyvaso is approved, it's reimbursed. So we don't anticipate any change from what we currently are getting reimbursed for. So we don't expect any change at this point. We'll talk about it more closer to around [ April 26 ].

Okay. Great. And then last question on IPF before we move on is something that comes up quite often with my investor conversations, is the discontinuation rate that you all saw in the TETON studies. Obviously, it wasn't just the Tyvaso arm, right? We also saw it in the placebo arm. What do you make of that? And how do you reconcile that as you think about persistence numbers when you think about how big of a drug and how successful the launch Tyvaso could have in IPF?

Yes. I think discontinuation numbers in the -- even in the 20s percent, 20% plus discontinuation numbers are not something which has locked us from having other successful medicines in this space. When about let's say, 1/4 of the patients will go ahead and discontinuation -- discontinue their therapy, as long as a larger number of patients are coming on to the therapy, you're going to have an increasing total number of patient count. And for example, in a typical -- let's talk about having nothing to do with pulmonary fibrosis, just in pulmonary hypertension, you'll see whether you're talking about United Therapeutics therapies or competitors' therapies, the average duration that the patients stay on these drugs is something on the order of between 12 and 24 months.

And so within that time period, there's patients dropping off at 3 months, 6 months, 9 months, all along the way. Yet a larger number of patients are coming on the medicine. Oftentimes, the reason that they drop off are because of just progression of their disease. And unfortunately, these are not medicines that are an absolute cure for their disease. And unfortunately, unlike in -- with ralinepag, which we demonstrated in pulmonary hypertension and actually affects a clinical trial improvement, the clinical status improvement of the patients. Here, we're able to reduce the rate of decline of the patients in pulmonary fibrosis, which is, of course, hugely important. So I think the dropouts at the rate that we saw are in TETON 1 and TETON 2 are entirely consistent with us expecting a rapid net growth in the total number of patients on drug in IPF.

Okay. Makes sense. And then Phase III PPF data coming next year, second half of next year. Maybe just as you think about the probability of success for that study, given the success you've had in IPF, what is the biological read-through to a PPF patient?

Yes. So the differences between PPF and IPF are nuanced, I think, would be the fairest way to say it. And in fact, PPF is a relatively recent construction of the medical field as a stand-alone indication. We, in fact, originally intended to do a combined trial of all comers of IPF and PPF in the TETON studies, kind of with the FDA's pulmonary division, who I think very wisely pushed back and they said, PPF is a more diverse patient population with more diverse etiologies of the disease. Whereas in IPF, it's a little bit of a pure population without so many secondary causes of the pulmonary fibrosis. We really would prefer that you did a study just in IPF. And in fact, we prefer you do 2 studies in IPF to make sure that this drug is safe and effective in that patient population.

Well, I believe the FDA was very wise because we crushed it twice in terms of p-value and efficacy and safety in IPF. And when we came back to the FDA and said, okay, now we're ready to enroll TETON 3 in PPF, they said just one study will be adequate and sufficient. So I think they too feel that there's going to be a super good biological read-through from the TETON 1 and 2 to the TETON 3.

What is your Phase III PPF study powered for? Can you run us through some of those numbers if they're disclosed?

I can't. I can't because it's like too many numbers for me to remember. But the study -- probably like Harry, you can remember better than me, but the study is around 350 patients. There you go.

Okay. Just to repeat that, it's 90% powered for an 80-milliliter FVC improvement.

It's better than AI. Just have to carry it with you.

And then you mentioned, obviously, from a patient population number, PPF is a bigger market than IPF. Is that also how you feel about the commercial opportunity? Do you think of PPF is a bigger market for Tyvaso than IPF? Or should we think about it differently?

I do. I think it's very linear. I think it's very, very linear. And whether somebody ends up on one side or the other of the fence, just results is related to the etiologies of their fibrosis. So I think the people suffer just as much. The mortality is just as bad. And it is, roughly speaking, a 3x opportunity compared to IPF. We actually looked very hard to see if we could fit PPF under 200,000 patients so that it would have orphan drug status. And the research was unanimous across every single source that there are more than 200,000 Americans suffering with PPF.

Yes. I'm going to throw a little bit of a curveball your way. You brought up orphan drug status. I have heard rumors that IPF, you all obviously have orphan drug status. Do you think there's any chance in the future that IPF is no longer viewed as an orphan indication because of the growth? Or have you heard that?

I've never heard that. I've never heard that. It would -- I hope not because it's a terrible disease, I wouldn't want more people to suffer from it than otherwise. But what I have heard is that in a company that I think knows IPF better than any other company in the world, which is Boehringer, that in their own view, it's 125,000, which is a long way from 200,000. And we try to be even more conservative than that, looking at 100,000.

Okay. Very helpful. And then ralinepag, obviously, another big priority for the company launching next year. Where does ralinepag fit in, in all of this? Obviously, IPF and PPS is a big, exciting, large opportunities for you all. But ralinepag is something that you guys have been very excited about as well.

So it's exciting for everybody because IPF and PPF is like what the UT company is on fibrosis rather than pulmonary hypertension. But it should be remembered that the ralinepag molecule is like the treprostinil molecule, but better, okay? And because of that, it's produced the best data in pulmonary hypertension that anybody has ever produced. How is it going to be introduced into this market? It's going to be introduced as upfront frontline therapy. And if a physician feels that they want to start their patient with a couple of cheap generics like a PDE-5 inhibitor and ETRA, that's all good, but they are not going to be able to say to that patient that this therapy has been shown to provide clinical improvement to you. All they can just say is that it's reduced the rate of decline.

But the United Therapeutics data shown in the outcome study, the more than 50% chance of clinical improvement. So of course, our people are going to explain that to the doctors and then to make it even easier that once-a-day ralinepag therapy, which we call Genraldi, is going to be followed right on its heels with another therapy called triple Genraldi, which is Genraldi combined with the PDE-5 and ETRA all in one single pill. And so this is going to become the dominant treatment for pulmonary hypertension. I have no doubt about that at all. But there's more because like I said, this is treprostinil but better. So we are already working on the development of bringing ralinepag into IPF. And we already have data in our AI digital lung model that shows that inhaled ralinepag works even better than treprostinil inhaled. So as I mentioned at the beginning of our fireside chat, the once-daily RAL-DPI will provide a therapy for patients with pulmonary fibrosis and progressive pulmonary fibrosis with using our DPI device just one inhalation, one times a day, I think it's going to end up showing even better results than treprostinil. And patent protected in 2040. So cool.

Well, maybe just to end because we are out of time, you have IPF, you have PPF, you have ralinepag. Hopefully, xeno transplantation works out as well long term. That's going to be a lot of revenue, right, and a lot of cash. So as you think about positioning the company longer term, what do you plan to do with all of that?

I think like one good answer is that the present is like a view of the future. So we've been really happy to be able to announce that at this great conference, an accelerated stock repurchase agreement, $0.5 billion. We've received great feedback from everybody attending your conference about that. And I think until the stock price reflects the fact that this is not like a few billion dollar pulmonary hypertension company, but a tens of billions of dollars pulmonary fibrosis company, the stock will be too cheap and the only logical thing to do, the economic thing to do, the economically rational thing to do is keep buying back the stock.

Okay. Great. Well, Martine, James, thank you very much. Great discussion.

Thank you.

I think we're ready to go ahead and get started. My name is Ben Burnett, biotech analyst at Wells Fargo, and I'm pleased to be here with United Therapeutics management team. We have Martine Rothblatt, CEO; and James Edgemond, CFO. So thank you for being here.

Thanks, Ben.

I think maybe just to kind of, kick us off, just kind of start by giving us a quick overview of sort of the business and some of the near-term events that we should be focused on.

Sure, Ben. Glad to do so. United Therapeutics is right now at a major inflection point where we are rolling out 14 new products over the next few years that cumulatively will provide us, we believe, somewhere between $50 billion to $100 billion a year in pharma revenue, moving us to the very top tier of pharma companies and I'll maybe march through these new products, Ben, quickly.

So the first one that I think most people are aware is the NDA that we submitted a few months ago and now has its PDUFA timing, which is nebulized Tyvaso for idiopathic pulmonary fibrosis. In its pivotal trial, it produced far and away the best clinical trial data ever from any registration study for pulmonary fibrosis.

Coming right behind that is our development of that same product for progressive pulmonary fibrosis or PPF which is a 3x larger indication. And we just announced about a month ago or so that we have fully enrolled that study already. So that's on its way for its 12-month endpoint measurement.

Then right behind those 2 products, we have our dry powder inhaler for both IPF and for PPF. Then right behind those 4 products and all of these coming at a very rapid clip of more than one new product introduction per year, we have a coughless product called coughless TreSMI for both ILD, PPF and IPF. And that product is a truly amazing one in terms of its convenience and its ability to get rid of the #1 side effect that patients in these indications have.

Coming right behind that product is a once-daily inhalation product called RAL-DPI, which we're developing, again, in 3 different indications, ILD, IPF and PPF. So right there, Ben, is 10 new products over the next few years. And there's even more. The one that I have to say, people often ask me which is my favorite, probably my favorite is the TreSMI product for PH-COPD.

This is a very debilitating condition. It's a small proportion of people with COPD for whom their pulmonary hypertension is all out of proportion, and they are the people with the severest disease and the rapid decline into fatality.

Our coughless TreSMI for PH-COPD can address a market of somewhere between 400,000 and 800,000 patients in the U.S. alone. And now moving over to pulmonary hypertension, we already filed an NDA, have a PDUFA date for our [ Genraldi ] product, once-daily pill for pulmonary hypertension, again, produced the best clinical trial data of any product in pulmonary hypertension ever.

That one will be queued up for FDA approval in June of next year. And then right on its heels, we have what we call triple [ Genraldi ], which is a once-daily pill together with the 2 background medications we demonstrated efficacy over PDE-5 and ETRA.

That takes us up to 12 new products. And then last but not least, we've got 2 very, very exciting products to roll out on top of all of that. We have a treprostinil/iloprost combination product that can be used as a PRN, meaning that you just use this product as necessary during the course of the day.

And it doesn't matter if your background therapy is one of our therapies or one of our competitors' therapies. This will be the first "rescue" inhaler for pulmonary hypertension. So you add all of these 14 products up. You're looking at a half million patients with PH-COPD. You're looking at 400,000 patients with the pulmonary fibrosis type of conditions, another 100,000 patients with the pulmonary hypertension conditions.

So it is a million addressable patients. All million should be captured by one product or another. But even with a 50% capture rate, we're looking at $50 billion in pharmaceutical revenue over the next few years. And that's really the reason, Ben, that we are excited to announce at this conference, at this Wells Fargo conference that we have done an accelerated share repurchase of -- with [ $0.5 ] billion, bringing up our total repurchases just in the past near term to upwards of $4 billion. And the reason for that is it just makes no sense to us at all that the company is at a market cap of around $20 billion when based on produced clinical trial revenues, filed NDAs, best results in the industry, multiple moats in terms of intellectual property protection to the 2040s, composition of matter protection for ralinepag to the 2040s. We have a super clear straight shot at $50 billion to $100 billion in pharmaceutical revenue.

Okay. That's great. Well, let's start with -- so a lot of areas to dig into. Let's start with PAH and PH-ILD. So there's -- your products are out there. There's other products that are in development or on the market now. So I guess the question is, how do you see the PAH market evolving with your products and competitors? And where do you see that kind of end state?

I see the market evolving to a place where the physician will ask themselves, do I want to slow my patient's rate of decline? Or do I want to provide them actual clinical improvement? Only one product out of the 12, 13, 14, I've actually lost track of products approved in pulmonary hypertension has shown in its Phase III clinical trial data, actual probability of having a clinical improvement and that's this product we call [ Genraldi ] ralinepag with the trade name [ Genraldi ].

Furthermore, that product is the easiest to take, just pill once a day. So I think physicians are going to move their patients from whatever other therapies they are on into just one pill once a day to actually get a clinical improvement in their patients. Now some physicians will say, well, my patient has been on a background PDE-5 or ETRA for a long time. And that's why right on the heels of [ Genraldi's ] approval, we plan to file for approval what we call triple [ Genraldi ], which is a single pill in which the [ Genraldi ] has been blended together in a very specific technical way with a PDE-5 and an ETRA. So you get 3 mechanisms of action, endothelin receptor antagonist, phosphodiesterase 5 inhibition and the super prostacyclin activity that [ Genraldi ] offers. One pill, once a day, 3 MOAs.

I think more than 80% of all the PAH patients are going to be on that certainly by the end of this decade.

Okay. That's fantastic. What are the time lines for that?

So that one, the NDA we filed for [ Genraldi ], and we received an acceptance of the filing from the FDA and a PDUFA date, best of my recollection, June [ 27 ] of next year.

And then coming right on the heels of that would be a filing of triple [ Genraldi ]. And we think because the basic [ Genraldi ] would have already been approved that we would have a rapid turnaround from the FDA on the triple [ Genraldi ], not more than 12 to 24 months later.

So well on time for those. First, we would get the physicians that say, well, this pill demonstrate improvement even in patients who were not on background therapy. So I'm going to go ahead and take all my newly diagnosed patients and put them in [ Genraldi ]. But for other physicians that say, well, the pill -- the [ Genraldi ] was also proven very effective in patients on background therapy, I'd say to them, look, in addition to your, say, one ambrisentan pill that you're taking and maybe your one Adcirca pill, I want you to just take a third pill of [ Genraldi ]. So for them, it will be 3 pills, but just once a day, which is a tremendous relief and knowing that those will be the only patients in pulmonary hypertension that have a probability of clinical improvement. That's the holy grail.

I mean, frankly, Ben, I started this patient, this business to save my daughter's life, who has pulmonary hypertension. That's well known on the web. And I feel like for the first time ever, like hope is better than ever that she'll actually be able to improve instead of just getting weaker and weaker.

That's amazing. Very cool. Well, let me turn now to the inhalable franchise. So with Tyvaso, we've seen some decline kind of quarter-over-quarter. Do you envision the soft mist inhaler in that format, maybe returning that sort of franchise back to growth?

I absolutely do, Bill. Ben, sorry about that. The soft mist inhaler is a truly remarkable product. And it will allow a patient with just 4 puffs a day. And when I say 4 puffs a day, I mean like 1 puff 4 times a day. So it's vastly easier for the patient to take to be able to get their treprostinil medicine down into the deep lung without the cough.

So as a coughless product, we call it TreSMI for treprostinil soft mist inhaler. And I think that this product is going to kind of sweep the floors with the competition. I mean, just to be very blunt, it's such a more convenient product.

Now our goal is to first get this product approved in ILD and then to move this product into IPF, which is frankly, about probably 4x, maybe even a 5x larger market and then move it into PPF, which, as you know, we just completely enrolled our nebulized product in that PPF franchise, which is around 300,000 patients. So the forecasts are so great for this coughless product that we've actually had to open up 2 separate manufacturing sites to be sure that we have adequate clinical trial supply for the entire market.

Okay. That's fantastic. And actually, I'm glad you mentioned that because I think we're all looking forward to the Tyvaso nebulizer and the IPF opportunity. But that's put the cart before the horse too much, but we're also kind of looking at where the other formats could kind of go that direction. What have you said about the path to getting some of these other formats such as the DPI, such as the soft mist inhaler into IPF? What kind of studies would you need to run?

Yes. So they all run a kind of a somewhat similar algorithm. And that algorithm is that what we call it UT, United Therapeutics, we have a kind of mantra inside the company. And if you ask anybody working in the company, any of 2,000 of us say, what's the main mantra of the company, everyone will say, approve and then improve, approve and then improve.

And it's not a litmus test, but it makes so much logical sense to them that they get it. So first, you get treprostinil, nebulized approved for IPF. Now why that one first? Well, treprostinil is already approved in ILD and nebulized treprostinil is already approved in ILD.

The FDA is very familiar with it. It already demonstrated efficacy in this patient population in the INCREASE trial back before the TETON trial. The FDA is familiar with the molecule, familiar with the device. We presented to them. They said, yes, this is like 12-month endpoint, go for it. And we went for it.

Then why next, how can you improve it? Well, one way to improve it is instead of having a kind of large nebulizer, why not a little DPI that you can stick in your pocket. You've seen the MannKind DPI. It's like a whistle really about the size of a whistle.

So we went to the FDA. Now why the DPI next? They had already approved it for ILD. They felt very comfortable with its safety and with its efficacy. So we said to them, we'd like to next develop this into IPF. Now the FDA then makes an analysis, okay, well, what type of bridging study or efficacy study should we need in this new indication? What type of safety data? And different parts of the FDA will ordinarily look at things based on their own area of competency.

So you're going to have the cardiorenal division, look at things one way and the pulmonary division look at things another way. United Therapeutics respects the FDA and all of their competencies. So we meet with them and we take the guidance, whether it's like a smaller bioequivalency or a bigger, whatever it is that they want, we do the development that each part of the FDA wants us to do. And I think that the track record with our Tyvaso DPI has shown that it's so similar with the nebulized DPI that we're going to have a very fast track route for that Tyvaso DPI into first IPF and then after we could get a nebulized Tyvaso approval in PPF, then PPF.

Then the next thing is the SMI. The FDA said, wow, that's something new. We didn't previously approve an SMI but we did previously approve treprostinil. And now we want to see should we do the TreSMI as a bioequivalence, a bridging, what data do we need? And again, we have these discussions with the FDA. And the reason that UT is always able to do the shortest path for each new drug device combination is we're very careful to change just one thing at a time.

We don't change like multiple things at a time, just change one thing at a time. And that's why I can say to you confidently that I believe all of those products that we just reviewed will all be in the marketplace this decade, this 2020s and we'll be making major contributions to taking us towards that $50 billion of pharmaceutical revenue before the end of this decade.

Okay. Well, that's great. And maybe we could talk a little bit about the IPF opportunity specifically. So I guess the question is, what do you envision that commercial opportunity kind of being? And I think the context that a lot of us have here is we've watched Jascayd, which is sort of a new launch into IPF. It's been a while since we've seen a new launch in IPF. But I guess looking at that and kind of the adoption curve, like what should we expect with Tyvaso and IPF?

Yes. Jascayd was an awesome introduction to the space. And by the way, we have now Jascayd patients in our open-label extension patients of nebulized Tyvaso. So we are already showing the ability to enroll patients and show a kind of a combinatorial benefit of Tyvaso on top of Jascayd as we showed beyond a doubt with [ nintedanib ] and pirfenidone.

So the key thing to look at here is what's the size of the market, as you said, Ben. And there's some bouncing around that people estimate something like 100,000 to 150,000 patients in the United States with IPF. And what are some of the limiting factors in addressing that population? Well, with [ nintenamide ] and pirfenidone, there were some pretty challenging GI side effects that caused a very large amount of dropout.

So you have to factor all of that in. And then we have to kind of -- we're in a casino here, right, some kind of casino. So we have to put a bet on the table in that we can't just snap our fingers and have thousands of patient drug -- patient doses available.

We have to spend money to build up a launch inventory based on how many patients we think we're going to ramp to during the first year. It could take a few months to build up product. So we try to say, okay, we're getting ready to launch. Things are looking great for the FDA approval. How do we want to launch with? And that gets to your question, right? So we put a bet. We actually made a $100 million bet. We bet that we would need 10,000 patient starter kits for the first year of product launch.

So that's what we're looking for, for the first year. And I think that's not dissimilar from what Jascayd is looking at. And I think it's not unreasonable in a patient population of around 100,000 patients to be able to capture something like 10% of that population in the first year, especially when you have the amazing data that we have in TETON 1 and 2 of 100 milliliters of oxygen improvement from baseline.

Very cool. And on PPF, were you surprised at how fast that study enrolled?

Blown away, blown away. Ben, I have never seen in the pharmaceutical industry that a company enrolls a trial faster than like the business people thought it was going to be enrolled and then even their clinical people. So it's usually like you say, "Hey, we're falling below the forecast we gave to the street for enrollment." This time, the clinical drug development people said multiple times, Martine, we have to move the schedule to the left. Like what? I didn't know clinical trial schedules could move to the left. I thought they only move to the right. So it was astonishing, but the physicians were just pushing patients on the drug after they saw the remarkable effect that nebulized Tyvaso had on their IPF patients, and they know these poor PPF patients, I mean, mean survival just ask your AI, it's 3 to 5 years. I mean it's horrible. So they're really pushing their patients on the PPF study. So I was blown away surprised, Ben.

And so what does that mean from the commercial perspective? Like if you look at some of these drugs that have both an IPF and a PPF approval, you see a disproportionate amount of drug sales from, I believe, IPF, but the numbers of patients that have PPF are a lot higher. So what do you see as sort of the addressable kind of PPF market? And how does that compare to your thoughts on IPF?

Yes. So I think the starting point is that it's very important that things be on label to be able to be accessible to the patients. First of all, physicians will not even be all that well educated about things that are not on label. Secondly, it's going to be difficult, if not impossible, to get reimbursement for a diagnosis, which is not on label.

So the FDA themselves required us to do a separate study for IPF and PPF because the pulmonary division feels that there are different clinical aspects of the IPF and PPF on patient population that requires different clinical data sets for each patient population. So I think they did the right thing requiring a separate clinical trial for PPF. I'm very hopeful that we're going to have superb results. I will say that my hope in addition to based on the physicians rapidly enrolling the study is based on our digital AI lung model, where we have run this patient population as we did our previous IPF population and shown a high likelihood of successful results. It's also based on the fact that in our Phase II trial, the INCREASE trial that we did, there were PPF patients in that trial who did just as well as the IPF patients.

Still, the FDA made us do a separate IPF trial. And frankly, I was nervous about doing a parallel PPF trial before it was proven in IPF. So in retrospect, you could say I was too cautious and I would say [ joe gets charged ]. But nevertheless, that's the way it happened. And now I feel very confident about the results in the PPF trial. And I think finally, this population will get the drug they need with the FDA approval. It will be on label specifically for PPF and insurers will not bulk because their diagnosis will match what the label is for.

Okay. Excellent. I want to turn now to ralinepag, and you gave some helpful comments early on about sort of the efficacy profile, the oral. But the format -- the DPI format that you're developing, I guess, number one, is it fair to assume that, that is going to be developed kind of along the same sort of pattern as Tyvaso in terms of the number of indications and sort of the path forward?

Yes, Ben. So we're going to follow the same, what you could almost call the UT algorithm, which is approve and then improve. So the approved is PO once daily, which, as I mentioned, we have the PDUFA date for that coming next year.

And then the improve is how can we get this to patients that really need to take their therapy via inhalation route so that they don't get into a realm of VQ mismatch between cardio output and inhalation. So that improved requires an inhalation formulation. So we work very hard with our great partners, MannKind, and we developed like an amazing inhalation formulation, which with once-daily pharmacokinetics, will allow us to improve on Tyvaso DPI because the Tyvaso DPI, we got it approved first for ILD. Next, we'll get it approved for IPF.

But now we want to improve on that by having it once daily instead of 4 times a day. So the same approved and improved algorithm. So we're going to apply the RAL-DPI as a once-daily inhalation solution for ILD, IPF and PPF.

So that will be 3 more labels there. We are so bullish on this one, Ben, that once again, to say like we kind of put our money where our mouth is, especially in this beautiful encore resort that you have here that we have built out a 50,000-patient annual production facility dedicated for RAL-DPI. That's the once-daily inhalation formulation of ralinepag.

It will have its ribbon cutting October of this year. And thereafter, it will ramp up during calendar year '27 to be FDA approved as a site of production. You have to have your safety efficacy and your production all approved by the FDA. So we should have it approved by the -- all that in the bag by the FDA by the end of '27, could possibly roll into '28. And thereafter, we'd be able to launch a once-daily inhalation therapy with the best in the industry pharmacokinetics. Very important, but not everybody understands the best in the industry pharmacodynamics because the fact is ralinepag is a better molecule than treprostinil.

We proved that in our outcome study, and we will prove that also in our studies for the inhalation version of the product. So you have better pharmacokinetics, better pharmacodynamics. And I think that this RAL-DPI is just going to sweep through the IPF and the PPF landscape. And I will probably end up outstripping the 50,000 production capacity of this plant, but that will be a high-class problem.

Well, and that was the follow-up I had, you just touched on this a little bit. Is the hypothesis that this will be more efficacious than treprostinil? And is that based on the oral experience?

It is. That is my strong belief that the changes in the molecular structure between ralinepag and treprostinil dictate a better antifibrotic activity for ralinepag even than treprostinil.

Okay. And other formats would you explore like soft mist with ralinepag at some point?

Approved and improved. Approved and improved. We're like robots. We just approve and improve.

Very cool. Okay. I want to also talk about -- you've given out a $4 billion kind of revenue guidance. What are the puts and takes around that?

Well, I think the main put and take is it should be looked at as like the first step forward to a much higher pharma revenue run rate with these 14 new products that we're really first announcing at this Wells Fargo conference. We've not really shared the full panoply of the products.

So these will be coming one after another very rapidly, all in the next handful of years, all with tremendous protection against kind of copycat or worse than copycat concepts, for example, in the pulmonary fibrosis and progressive pulmonary fibrosis, we have patent protection out to the 2040s with whole patent families there.

With regard to all the great features of ralinepag that you just elucidated, Ben, we have composition of matter patents out also into the 2040s. With regard to idiopathic pulmonary fibrosis, which is where the big breakout from pulmonary hypertension begins, we have, upon approval, orphan drug exclusivity into the 2030s. So there are a lot of moats protecting these new type of devices, these SMIs, they have their own intellectual property protection. So with all of this, this $4 billion revenue run rate growing on the growing traction of our products in ILD and in PAH will be the next step toward an inflection that I talked about at the beginning of my talk here today up to tens of billions of dollars per year of revenue from first, the IPF market and then the PPF market and then the soft mist inhaler into the ILD market and into the IPF market.

Great. And if there are any questions in the audience, I want to make sure we have time to work that in, just let us know, we'll work in the conversation. I want to ask just about the spending side of this. So as you think about the expansion into all these different opportunities and the improved kind of part of that equation, I guess, how do you see kind of the R&D and SG&A kind of trajectory over sort of the medium to long term?

Well, fortunately, we have our Chief Financial Officer, James Edgemond, to comment on that.

Yes. Thanks, Ben. It's a great question in light of what Martine actually just outlined in terms of products and product developments. So as you know and what others know, we actually apply a budget algorithm to our spending model that says we don't spend larger or more than a percentage of prior year revenues.

And historically, we've talked about 50%. We're going to tweak that a little bit going forward to raise it to 55% of prior year revenue on just cash operating budgets. So it doesn't include business development or facilities. One, to be able to support what Martine outlined is a vision going forward. So we're going to tweak that budget algorithm a little bit.

And why we do that is we want to have good visibility into what we're giving folks within the organization from a budget perspective, but we really want to be good financial stewards of investors' money. And we think it's very important to have good budgets to have good clarity and it helps you make great decisions. For example, one of the areas you might touch on is corporate or business development.

With this huge cadre of things ahead of us, we don't feel the need that we need to rush out and do a corporate development or business development opportunity unless it makes real sense. Folks within UT are extremely busy, and we want to be thoughtful of how we allocate this budget algorithm within the organization. So again, good financial discipline going into, again, planning for '27. We're going to tweak up our number a little bit just to make sure we have enough money to accomplish these great goals, but we're still going to be very good executors from a financial discipline perspective going forward.

James, can I add a code to that?

Sure.

Okay, Ben. Yes. So I'm really glad that James highlight the fact that it doesn't include the capital expenditures on the facilities because one of the biggest dilemmas that I'll say I face as CEO of United Therapeutics right now is we are on the cusp of a revolution in a much larger field of medicine even in IPF and PPF and COPD, and that is organ transplantation.

We have 3 INDs approved by the FDA to create an unlimited supply of transplantable kidneys and transplantable hearts from our genetically modified herds of pigs. And we're marching very well through this, and we expect to have the first of these 3 INDs resulting in a BLA before the end of this decade. That's only like 3 years from now.

Now when you're talking about the unlimited supply of transplantable organs, unfortunately, it's a lot of CapEx because building these facilities, there are 500,000 Americans in dialysis. So to build a facility that can provide 500,000 kidneys a year, it costs tens of billions of dollars to build that type of facility. And I have a lot of people asking me how long until I can get a xeno kidney for my relative, they are on dialysis.

How long until I can get a xenoheart because a half million Americans a year die of end-stage heart disease. So the build-out of our xenotransplantation facilities is going to involve tens of billions of dollars. And when you come to a CapEx type of question like your question, that has to be taken into consideration.

And just one follow-up on that. What is the kind of cadence you would expect to have sort of clinical data presented from that program?

Yes. So the xenotransplantation team led by Dr. Peterson, they expect to be sharing the first stage of clinical trial data, which is the data that the FDA allows you to go to the end of the registration study. It's like a stopping point.

They expect to share that data at the end of this year, 2027. And then the final clinical trial data from the whole cohort of the registration study would be shared at the end of 2028. And then we would submit that data to the FDA in -- at the beginning of 2029.

Okay. So end of next year, potentially initial data?

Yes.

That's great.

It's like after being far away for a long time, it's suddenly like right here.

Awesome. Well, thank you so much. I think we're out of time, but I appreciate the conversation.

Thank you.

Thanks, Ben.

Good morning, and welcome to the United Therapeutics Corporation Second Quarter 2026 Corporate Update. My name is JL, and I will be your conference operator today. [Operator Instructions] Please note that this call is being recorded. I'll now turn the webcast over to Harry Silvers, Investor Relations at United Therapeutics. .

Thank you, JL. Good morning, everyone. It is my pleasure to welcome you to the United Therapeutics Corporation's Second Quarter 2026 Corporate Update Webcast. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties. We assume no obligation to update forward-looking statements. Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products.

These remarks are intended solely to educate investors and are not intended to serve as basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for the products is available on our website. Accompanying me on today's call are Dr. Martine Rothblatt, our Chairperson and Chief Executive Officer; Michael Benkowitz, our President and Chief Operating Officer; James Edgemond, our Chief Financial Officer and Treasurer; Dr. Leigh Peterson, our Executive Vice President of Product Development and Zeno Transplantation; and Pat Poisson, our Executive President of Strategic Development.

Note that Martine Rothblatt, James Edgemond and I will participate in a fireside chat in one-on-one meetings at the Wells Fargo Healthcare Conference, September 8 in Boston, the Cantor Fitzgerald Global Healthcare Conference in New York on September 9. Pat Poisson will join us for the Morgan Stanley Healthcare Conference in New York on September 14. And then lastly, the Bernstein Third Annual Healthcare Forum in New York on September 23. Our scientific, commercial and medical affairs teams will be present at the European Respiratory Society Congress in Barcelona, September 5 through 9, and the American College of Chest Physicians CHEST 2026 Annual Meeting in Phoenix October '18 through '21.

Now I will turn the webcast over to Martine for an overview of our development pipeline and business activities. Martine?

We have slides available for reference and I encourage you to review those at your leisure. I'm not going to speak directly to the slides. The first half of 2026 has been one of the most consequential periods in United Therapeutics' history. First, we delivered exceptional clinical results from our ADVANCE OUTCOMES study, demonstrating ralinepag's potential to become a major new oral therapy for patients with PAH. Then we unblinded TETON 1, which surpassed the impressive TETON 2 results we reported last September Together, these results put us in an extraordinary position, a new molecule advancing towards the PAH market and a potential new occasion for nebulized Tyvaso in IPF representing an opportunity meaningfully larger than our currently approved markets and the new option for patients.

With these highly statistically significant clinical results we recently submitted to the FDA, but we believe are two of the most important new drug applications in rare pulmonary disease. The sNDA for nebulized Tyvaso and IP and the NDA for ralinepag in PAH. And we are not stopping there, additional filings planned later this year, including an IND for ralinepag and an NDA for treprostinil SMI, we are moving with us toward what we believe will be a pivotal change in our growth trajectory as we plan to bring pioneering advanced inhalation technologies to patients. We expect potential approvals in 2027 for Nebula Tyvaso in IPF, ralinepag in PAH and the SMI device in PAH and PHILD, these not incremental opportunities, we believe they are a multibillion-dollar catalysts with the potential to redefine patient treatment paradigms, improve outcomes for patients and fundamentally transform our growth profile and competitive position.

Looking further ahead, enrollment in our TETON PPF trial is nearly complete, paving the way for another substantial Phase III readout in the back half of 2027. Based on the successful TETON 1 and TETON 2 studies as well as the similarities in underlying fibrosis and disease progression between IPF and PPF we have a high degree of confidence in our ability to report another positive outcome. If successful, TETON PPF would open the door to an even larger opportunity, at least double that of IP and position nebulized Tyvaso to become a leading therapy for patients with pulmonary fibrosis.

Turning to our organ pipeline. We continue to make strong progress toward our goal of expanding the availability of transplantable organs. The UKidney EXPAND study continues to make great progress with completion of the initial 6-patient cohort expected later this year. In parallel, we soon anticipate initiating the used SIMO kidney extend registration-enabling study. Lastly, with recent clearance from the FDA, we are working to commence our Express Heart Study Moreover, by the end of this year, we will complete construction of our two additional commercial scale DPF in Minnesota and Texas. With three authorized clinical trials, United Therapeutics is not just participating in the future of [indiscernible] transplantation. We are leading it -- we believe this work can redefine organ transplantation, save countless lives and create one of the most significant growth opportunities in our company's history.

Our deep organ pipeline represents a bead and differentiated extension of United Therapeutics mission with the potential to transform how patients access life-saving organs and how United Therapeutics will create substantial value over the long term. We will be sharing with you more details about these programs as each moves through their development time lines. Our ability to pursue these opportunities is supported by a disciplined approach to capital allocation through our budget algorithm, which has positioned us near the top of our industry in operating efficiency.

We have also been thoughtful in deploying capital toward internal growth objectives while remaining mindful of returning capital to shareholders -- as an example, we recently deployed capital to acquire Thymmune Therapeutics, adding a promising Thymmus based regenerative medicine platform that fits squarely within our mission. This acquisition broadens our organ alternative strategy and strengthens our ability to pursue therapies that could restore immune function for patients with serious diseases. We see tremendous potential ahead, and we're excited to welcome the Thymmune team to United Therapeutics.

To close, we believe United Therapeutics is entering a defining era, one shaped by scientific ambition, innovative platforms, and a pipeline with the potential to transform care across some of the most challenging areas of medicine. As these opportunities advance, we see a future in which our impact on patients, our industry and our growth trajectory can reach an entirely new level making United Therapeutics a growth story unlike any other in biotech.

And with that, I'll turn the call over to our President, Michael Benkowitz, who will provide an overview of our commercial performance for the quarter. Mike?

Thank you, Martine, and good morning, everyone. For the second quarter of 2026, we generated approximately $783 million in total revenue, essentially flat with the first quarter. While these results were below our expectations, they do not change our confidence in the strength of our business, the opportunities in front of us or our ability to create substantial value over the coming years. I want to start by acknowledging something directly. Over the last several quarters, we understand investors have been looking for a faster acceleration in growth, and we recognize that confidence has earned through execution, not projections. So our focus is on improving results.

As we evaluate the current state of the business, we believe the underlying fundamentals are strong, and we believe we are positioned to deliver improved performance in the second half of the year. Simply put, we exited the second quarter with considerably more momentum than the reported revenue line alone would suggest. Based on the trends we're seeing today, we expect the second half of 2026 to be stronger than the first half of 2026, and we remain focused on accelerating revenue growth as we move through the balance of the year. That said, we are not reaffirming or updating any prior revenue growth expectations for '26 today.

Turning to Tyvaso. Total revenue for the quarter was $453 million. Nebulized Tyvaso remained pressured by competitive dynamics within the inhaled [indiscernible] category as patients and providers evaluate an increasing number of treatment options. We expected this market to become more competitive over time, and that's precisely what we are seeing today. Tyvaso DPI meanwhile, continued to demonstrate growth and more importantly, exited the quarter with what we view as significant underlying momentum.

As we have discussed previously, quarterly sales are not always the best measure of underlying demand. starts, referrals, total patients and commercial patients all read record levels exiting the quarter. Those metrics give us confidence not only in the durability of the franchise but also in our ability to translate that momentum into a stronger commercial performance over the second half of the year. So we remain confident in the strength and long-term value of our existing commercial portfolio. Our conviction is grounded in what we believe are highly differentiated therapies that offer meaningful advantages in efficacy, convenience, dosing and long-term tolerability. We continue to believe these characteristics matter deeply to patients and providers and position us well for sustained growth. Recognition of these benefits, particularly in a highly competitive environment, are taking time to crystallize with physicians.

However, we believe our commercial strategy has us well positioned to accelerate that process and the underlying trends we are seeing reinforce our belief that we are moving in the right direction. As we discussed last quarter, we significantly expanded that has roughly doubled our sales force. Those representatives enter the field in early July, and are already increasing our recent frequency of engagement with physicians across both PAH and PH ILD. We recruited an exceptionally strong team with deep relevant experience, and we expect their efforts to meaningfully enhance awareness of our therapies, accelerate adoption and support stronger commercial performance over time.

To round out this section, we believe the combination of record patient metrics, increased commercial reach, the strength of our differentiated portfolio and growing physician awareness positions us well to accelerate performance in the second half of the year. At the same time, it's important to recognize that our store is not solely about the next quarter or the next year. We continue to believe that we have two potentially transformative opportunities in front of us. First, nebulized Tyvaso at IPF, second ralinepag and PAH. Both represent areas of substantial unmet need, both have the potential to become multibillion-dollar opportunities and both have the potential to further strengthen our leadership position in respiratory and cardiopulmonary disease.

For Tyvaso and IPF, we continue to see strong interest from physicians following the TETON results, and we remain excited about the potential impact this therapy could have for patients with limited treatment options today. For ralenepad, we believe the opportunity to introduce the first once daily prostacyclin could represent a meaningful advancement for patients and providers seeking a differentiated treatment option. We have previously projected a $4 billion revenue run rate by the end of 2027 with our existing commercial portfolio. We still see a path to achieve this, although it has certainly narrowed. Factoring in some of the revenue from our anticipated IPF and ralinepag launches next year should get us there and beyond.

Our strategy is straightforward. We are focused on executing and growing the business we have today while simultaneously preparing the organization for what we believe could be two important future launches. We do not view these future opportunities as replacing our current growth story. Rather we view our concert portfolio as providing a strong, durable and growing foundation while Tyvaso and IPF and ralinepag offer meaningful upside beyond that foundation. That combination gives us confidence not only in the long-term potential of United Therapeutics, but also on our ability to accelerate growth in the near term and create value across multiple time horizons.

Before I close, I want to share with our investors something that is an important part of our culture and how we work. Across the company, we have a rallying cry called LTFI, which stands for [indiscernible] While there are certainly exciting opportunities on the horizon in 2027 and beyond, LTFI is a reminder that our responsibility is not to focus on future possibilities at the expense of present execution. We have patients, providers, shareholders and fellow Unitarians counting on us today.

LTFI is our commitment to all those stakeholders. It's a reminder that while we are excited about what may come next, our focus remains on what we must deliver now. And we believe the trends we are seeing today position us to do exactly that. We are focused, we are accountable. We are committed to accelerating performance in the second half of the year. And we will continue to be LTFId as we deliver for patients, providers, our colleagues and our shareholders.

With that, I'll pass the call back to Harry to start Q&A session. Harry? .

Great. Thank you, Michael, and thank you, Martine, for the excellent overview this morning. Before I give this over to JL to start the Q&A session, I would just like to remind those on the call asking questions. please try to limit yourself to 1 question with respect to the long queue that we have. JL, you can go ahead.

[Operator Instructions] Your first question comes from the line of Joseph Thome of TD Cowen.

Maybe just as we're thinking about some of the other offerings, either ralinepag and PAH or the resi in PAH and PHLD, I guess how much do you think you're going to be able to kind of recapture maybe some of the momentum that you did lose by increased competition in the space? Yes, just kind of your thoughts around that.

Yes. So I think in terms of ralinepag as I think both Martine and I said our other or March, we look at that as a multibillion-dollar opportunity. we talked about the notion that this is a super prostacyclin. We think the data that we saw and the announced outcome study certainly support that. I think the initial reactions and feedback we're getting from physicians is very positive. And I think the combination of -- it's not just it being a once-daily oral prostacyclin, which we think is differentiated in itself.

But more importantly, actually, the clinical benefit that we saw in the trial, I think, is really going to position us well for an exciting launch. And like we said, a multibillion-dollar opportunity. I think with -- similarly with SMI, I think we look at SMI as really being a really differentiated way to deliver inhaled therapies across eventually all of our indications. And so I think when we believe that it's going to be I think very well received by both the physicians and the patients. We think there could be potentially some tolerability benefits -- and so we look at that as really being again, another way to kind of differentiate ourselves relative to competition.

Your next question comes from the line of Roger Song of Jefferies.

Great. Also on the line, in terms of those new product launch, appreciating the 2027 guidance reaffirmation, how should we think about the the launch ramp-up for those new products, including the nebulizer IPF tariff and then nanopagantrasmi.

Thanks, Roger. Michael will answer that question for you.

Sure, Roger. Thanks for the question. I think -- we're going to have more information to share on launch trajectory or launch ramps as we get to the back half of the year or early 2027. And I think part of -- we're working through that now. As we said, I think we certainly look at both as being a multibillion-dollar opportunities. I don't think that's really a question how quickly we get there. I think we're kind of working through that. And then obviously, a lot of that's going to depend on when we're able to launch. Do we get priority review or not. So I think as we get a little bit more information on the status of our regulatory filings and the timing of when we could see an approval and just kind of continue doing kind of our work on the commercial side to prepare a launch directory. We'll have more information share later this year, as I said.

Your next question comes from the line of Jessica Fye of JPMorgan. .

I guess this is for Michael, and I appreciate the comments on how you see the business set up for a stronger back half than first half. I guess just in the interest of getting consensus numbers in the right place for this sort of period prior to the IPF launch. I think back half Tyvaso consensus is for about $1.47 billion of revenue. Is that achievable based on kind of the larger sales force and the other dynamics you mentioned? Or should -- the Street be thinking about that number a little bit differently? Just want to make sure expectations are in the right place for the next couple of quarters. SP12688.

Thanks for the question, Jess Good to hear from you this morning. We got Michael to answer that. .

Yes. So Jess, as we said, we're not really kind of reaffirming or updating anything at this point. As I said in my opening remarks, we expect it to be -- we expect the second half to be stronger than the first half. And I think we're just going to leave it at that for right now.

Your next question comes from the line of Roanna Ruiz of Leerink Partners.

You have Ryan on for Roanna. Maybe pivoting over to IPF, coming out of ATS in your conversations with physicians, can you kind of talk about your expectations for where you think Tyvaso is going to be positioned in the IPF treatment landscape in between nebulizer DPI and SMI, what do you think is really the main driver of future prescribing for this franchise?

Ryan, thanks for the question. We got Michael again for you. .

Yes. So just to make sure everybody is clear when we launch into IPF next year, we're just launching with the nebul tyvasso. We still have -- we have some engagement to do with the FDA to understand exactly what we're going to need to do to get approval in that indication for both DPI and SMI. So the launch next year will totally be nebulized and IPF. And I think it's -- the feedback we're getting is, as I said in my remarks, really, I think a lot of excitement around IPF around the data or other treatment option. And so I think as we've kind of talked to some of the top KOLs, they said whether they use it first line or whether they add it on, it's really going to be patient dependent. But I think they also said ultimately, it doesn't -- it probably doesn't really even matter because I think what they're saying is IPF is moving towards what we're seeing in PAH in terms of a polytherapy approach to treating these patients.

And so I think the vast, vast majority of the dots we're talking about have said they're going Tyvasso in combination with other products. And so whether it's sequenced first or second, it kind of a matter, but they're going to quickly get to polytherapy.

Your next question comes from the line of Ben Burnett of Wells Fargo.

I just wanted to follow up just on IPF. Just -- what's your expectation for the type of data that you would need to generate to get the DPI and the SMI into IPF? Like would this just be bridging data? Or would you anticipate to generate any more efficacy data?

Ben, thanks. I think for part of the question, with the SMI perhaps Pat to address that and maybe, Lee, if you want to add any commentary on bridging to the Tyvasso DPI. .

Yes, you want me to start, Harry? .

Yes.

Yes. I mean we were engaged with FDA to have those discussions to understand what they need to see for Tyvaso, DPI. So it's yet to be determined. And I'll pass it over to Lee to maybe add some color to the clinical approach.

Yes. So as Pat said, we're engaging with FDA. We have some good ideas and for bridging and with regard to our current population that's enrolled as far as potentially new starts. We have a proposed strategy that we'll be presenting to them, and we look forward to seeing what they have to say, similar to what we've done in the past with regard to bridging -- so -- and that goes for both SMI and DPI.

Your next question comes from the line of Ashwani Verma of UBS.

Can you talk about the sales force expansion heading into the IP and a potential approval? How much of the sales force is already deployed -- and I'm assuming the physician calling point is a little bit different. So how much does that help with the current Tyvaso indications?

Thanks for the question, Ash. Good to hear from you this morning. Michael can take that 1 for you.

Sure, Ash, yes, so we've talked about in the past and what I mentioned in my opening remarks is -- our plan has always been to roughly double the size of the sales force to support both the IPF and ralinepag indications. -- and we've done that. So we accelerated that process. I made that decision earlier this year to accelerate that process and get those sales reps out in the field by July 1, which we've essentially done. I mean, look at maybe 1 or 2 openings that we have to fill. But essentially, we've expanded the sales force now.

Of course, rolenacagand IPF are not approved indications. So they're not out detailing those to product certifications, but we're using them, I think, to really kind of get a little bit more leverage or a little bit greater reach and frequency to providers in our approved indications of PAH and PH ILD. And so that -- like I said, we got them out in early July, and so they're out and starting to call from those physicians. I think the -- your point on the call point is it's a little bit different in the sense that with IPF, those patients are much more in the community than the academic centers, and that was really sort of the rationale behind expanding the sales force and IPF is because we knew we were going to have to go deeper into the community than we previously have had to because that's where those patients reside.

So -- so it's not necessarily a different physician. It's just a question of getting deeper into the community than we currently have.

Your next question comes from the line of Olivia Saunders of Cantor.

Are you able to put some numbers around how big of a revenue opportunity you see IPF being maybe kind of overall franchise at peak? And just given how impressive Jascade's uptake has been so far, how does that impact the way that you guys are thinking about your own launch, just given some of the differences between Jacana I also did want to see if there's anything you can say around baseline characteristics of the PPF patients enrolled so far, just given that you're hitting that 95% bus and whether you guys plan to publish those details after enrollment wraps.

Thanks, Olivia, for your questions. I think Michael will address the commercial expectation side of it and then maybe Lee can answer the part on PPF patient characteristics?

Yes. So I think, Olivia, on your first question in terms of opportunity. As I said, I think we do an earlier question, I think we'll start to provide more information on kind of all of that PP potential and ramp and trajectory and all of that as we get to the second half -- deeper into the second half of the year. The Yes, Jascate has had, I think, a very strong launch. I mean there's no question. And so we certainly -- we're certainly looking at that. We're looking at what Ofmanhasbreat Ted and all those things factor into kind of how we're thinking about the Taesa trajectory. But like I said, we'll have more details to share on that as we get to kind of later part of this year, early 2027.

Lee, do you want to take the PPF question?

Yes. So as we mentioned, our PPF study enrollment is actually quite a bit ahead of schedule, finishing up in very, very shortly. And yes, we will present the baseline characteristics of those -- that patient population in upcoming conferences. And so basically, that's your answer, yes, you will be seeing those. And we look forward to sharing -- thank you. .

Your next question comes from the line of Lisa Walter of RBC Capital Markets.

Just a quick one on the IPF sNDA filing. Wonder if you could share the date when it was filed and when we could hear about acceptance of the filing and whether you think there is potential for priority review. Any color here would be helpful.

Thanks, Lisa. Always happy to take your questions. I think Lee can answer that one.

Yes. So we submitted late June, and we will be learning shortly if we're able to receive priority review, probably Well, I can't really give a specific date on that. But again, that would be a 6-month review period if that is received and 10 months otherwise. So that's Basically, what I can say right now.

I think that was perfectly Operator, you can go ahead and wrap up the call. .

Thank you. Thank you for participating in today's United Therapeutics Corporation Earnings Webcast. Rebroadcast of this webcast will be available for replay for 1 week by visiting the Events and Presentations section of the United Therapeutics Investor Relations website at ir.unitedvr.com. that is -- sorry, that is at ir.unither.com. You may now disconnect.

All right. Welcome, everyone, to Jefferies 2026 Global Healthcare Conference. My name is Roger Song, senior analyst cover SMID-Cap biotech. It's my great pleasure to have the fireside chat with our next company, United Therapeutics. We have James, CFO; and then Harry from IR. Good to see you, gentlemen.

Great, Roger, thank you. Thanks for inviting Harry and I, and we appreciate the time we've had great meetings this morning.

Excellent. Excellent to hear. So -- and I'm very happy to have you here as well. So maybe, James, if you want to do like a quick state of art for UTHR because you just gave us a fantastic data at the ATS from TETON and then ralinepag. I think UTHR is in a very good position to -- for the next stage of the growth. And then yes, give us some high level and then we can have a conversation.

Yes, you bet, Roger. Thanks. Harry is going to do real quickly our forward-looking statements as always, and I'll do an overview.

Yes. Thanks for having us, Roger. Thanks for everybody in the room and online listening in as well. Today, we may make some forward-looking statements. And for any risks and uncertainties associated with those statements, I would encourage you to look at our latest SEC filings on Forms 10-K and 10-Q.

Great. Thanks, Harry. And thanks again, Roger. And for a quick overview, it's hard to imagine really another mid-cap biotech that has as many growth prospects kind of in its quiver as we do. And as an example, we just read out, as Roger alluded to, two clinical trials that were incredibly successful with two therapeutics, so in two different diseases that have significant growth prospects. And both of those trials had clinical results that were outstanding. They had p-values of 0.0003 of less than 0.0003.

And those two trials, one was nebulized Tyvaso in idiopathic pulmonary fibrosis. And it was a second of two trials that read out that had great clinical results. I'm sure we're going to get into some of those discussions soon. The other clinical trial was called ADVANCE OUTCOMES, and it was a therapy called ralinepag. So an oral once-a-day very efficacious therapeutic in pulmonary arterial hypertension. So these are two different therapeutic areas. We believe significant growth prospects. And as we'll talk about, we're on track to file both of those with the FDA by the end of the summer.

So with ralinepag, it will be an NDA, so a new drug application, new chemical entity. And for Tyvaso nebulized in idiopathic pulmonary fibrosis, that will be an sNDA. But we are beyond excited the product development teams, the site management teams and everybody that supports these clinical trials did an outstanding job, and it yielded great results that we're incredibly excited about.

Excellent. All right. I think, James, you said it well. As a mid-cap company, you do have your very solid foundation commercial business and then you have a next level growth from those pipeline products. So maybe we focus on the commercial for a minute. So maybe you've been the soft guidance in terms of the growth for the year and then towards the end of next year, 2027, $4 billion run rate and then double-digit growth. And when I look at our model and then also the other consensus from the sellside model, it seems lower than that. Maybe it's a good thing because people want to be conservative and can surprise people in a positive way. So how confident as the user management team about those guidance? And then why you think the Street is missing and that you can give us the positive?

Yes. Thanks, Roger. Good question. So -- as we've talked about recently on our last quarterly earnings calls, we still have the expectation, broadly speaking, to exit 2027 with a quarterly $1 billion run rate. And we've made this assertion previously, and we still expect coming out of 2027, so next year. And that's the growth of our commercial business when we made this assertion. So it's the currently approved commercial products.

Now as we just talked about, Roger, we had 2 clinical trials we're going to file with the FDA later or by the end of the summer. So we could have some contribution from that next year, but our assertions were really based upon our expectation of growing the commercial business. And where that growth is going to come from is in the Tyvaso franchise, specifically than Tyvaso DPI and looking at growth within the PH-ILD disease state. So we feel very confident with the investments that we've made, the investments we're making so that when we end 2027, we will be on that $1 billion run rate going forward.

Great. And then interesting thing is it's -- Tyvaso has been entrenched as a great product and a franchise for PAH and PH-ILD. You have other product in a similar class, and they're also launching pretty well. So within that dynamic, how you think about your scenario, base case scenario can continue to support the growth projection that you are making?

Yes. Thanks, Roger. So from a -- I think it's the Tyvaso DPI kind of perspective you're thinking about. So as an organization, we continue to feel very comfortable about the growth prospects in Tyvaso DPI and specifically in PH-ILD going forward. If you think about the product, the partnership that we have with MannKind, the success we've had, the product profile, the delivery of the drug deep into the lungs, we continue to feel very confident about our own growth prospects as we look forward. We've had many successful and thousands of patients combined with prescribers, and we feel very confident in continuing that success going forward in Tyvaso DPI.

And frankly, when we look across the commercial business. So we're pretty excited. We have conviction. And the other thing that we're doing, and this may come into play, Roger, when we talk about IPF, we're actually investing in the sales force and Michael Benkowitz, who runs -- he's the President and Chief Operating Officer, runs sales and marketing. We've accelerated the hiring of sales teams for IPF and ralinepag, but those are not approved products. So we're going to deploy those sales teams, which sit within the PAH and PH-ILD franchises. So we're going to have more individuals, so feet on the street talking about our commercial business as we onboard those new sales teams members who will pivot going forward into the new disease states.

Excellent. Okay. Great. I like the confidence and the conviction there. And then Street want to be our particularly also we want to be a little bit conservative. But on the other side is we look forward to the growth, as you mentioned, amongst all the competition.

And then let's move on to the IPF because this is very exciting for everybody. So I think you also mentioned on the last earnings call is thinking about with the new product, new indication across different formulation and the presentation, you can double for the $4 billion run rate by 2027 in the coming years. So how much we should think about the contribution from ITF or maybe from other new product like Soft Mist and then some new indications?

Yes, Raj, we're pretty excited, one, about the results of the clinical trial really for the patients that are dealing with idiopathic pulmonary fibrosis. And so there -- from the standpoint of currently approved therapies, we feel that the clinical trial results, and it was pretty clear actually that it will be a superior product and an inhaled product, which is different than the current orals that are approved on the market.

But we think based upon the clinical results and ultimately, the FDA will determine the label, but we have a lot of conviction that this will be a pretty big revenue opportunity for us and run ramp. We haven't actually talked about, Roger, what the run ramp will be. So in time, we'll actually give more information on that. But based upon the currently approved therapies and where we currently price Tyvaso and just the opportunity of having a therapy on the market that has a different profile from the current adverse events profile or what patients are dealing with, then we think this is going to be very successful.

We haven't outlined what that growth ramp looks like, but we feel very confident that we will be able to at least double the revenue size from what we're currently at going forward. So exiting '27, as I talked about earlier, which would be the $1 billion run rate, we've actually talked about doubling that revenue size going forward based upon the contributions primarily of nebulized Tyvaso in idiopathic pulmonary fibrosis, but there will also be contribution, and we'll talk about ralinepag 2 a little bit later going forward.

Excellent. Okay. And then maybe quickly circle up to the ATS data for the IPF TETON-1, TETON-2. I think the top line efficacy looks fantastic, right? So 100-plus and then pooled analysis and across different subgroup, everything seems very impressive. If I have to say, investors ask about it and then it's AE driven the discontinuation a little bit higher. And then how do you think about that? And then also, I think in the comment from the paper and then talk about the nebulizer fatigue because of 4 times a day. So how you will respond to that? And how this will feed into the real-world adoption for Tyvaso nebulizer?

Yes, sure, Roger. It's a good question. Look, when you think about prostacyclin-related adverse events, cough is a known AE there. But I think what's important to note when you look at the trial, the amount of discontinuations due to cough overall, especially severe cough were quite low. Severe cough was a single-digit percentage or maybe even a single-digit end. But as doctors have -- as doctors and patients have experience with using the nebulizer and doctors help coach patients through using the nebulizer, you kind of tend to see that improve over time. So you had the dosing schedule, and you can see in the graphs, the separation of the FVC up to about 8 to 16-ish weeks, patients are titrating. And once you kind of get past that and you can tolerate the cough and get to the higher effective dose, you really see that separation and the benefit of the therapy.

And again, in the real-world setting, these things really can improve over time when doctors have experience using the products. You have patient support programs like our own. And that's even evident in the trial itself at ATS. Dr. Nathan spoke to his own practice and his experience with the drug in the trial. And he actually had a much lower overall discontinuation rate relative to the overall trial because he's somebody that knows how to coach patients through using the nebulizer due to his familiarity with the product.

Yes, some education is needed, just like PAH, PH-ILD. I think when you launch Tyvaso, you also see early on discontinuation due to different reasons, but with more education, those patients will be able to stay on treatment a little bit longer and then with the education with -- from the physician. Okay. Got it.

And then in terms of the pricing, I know PAH, PH-ILD, epidemiology or the prevalence a little bit lower than the IPF and then you price a little bit premium. And then the current standard of care for IPF would not considered generic, but the brand of the drug is about $100,000 per year. So how do you think about the pricing for Tyvaso in this population for IPF if you launch it?

Yes. Thanks, Roger. So Tyvaso, as we know now, is an approved therapy, and we don't anticipate modifying the current price by adding IPF to the label for nebulized Tyvaso, just in summary. And as I mentioned earlier, we -- at some point, we'll be talking from our perspective more about the market size. Obviously, that would play into the pricing aspect. But at this point, we don't anticipate changing by adding Tyvaso to the label.

And honestly, when I look at the data you presented for the TETON-1, TETON-2, you definitely can see the differentiation, even some -- a lot of the advantage compared to the standard of care. I understand you probably will justify the price, either the current price or slightly closer to the standard of care, but we'll stay tuned on that one.

Stay tuned.

Yes. Okay. Good. And then I think, James, you alluded earlier, you are hiring new sales rep and then maybe expanding the current indication, PAH, PH-ILD and then IPF is some synergy with the current -- the market, but also you probably want to increase further the sales force given you want to double in the market size? And how should we think about the cadence of the sales expansion?

Yes. Thanks, Roger. So the cadence of expanding the sales team, some of that is actually underway and has been completed. So when we think about the opportunity in the IPF market, it's pretty significant, as we talked about. And so there's a lot of activities going on in the background all across United Therapeutics to make sure once it's approved, we can actually hit the ground running.

And as Roger mentioned, one of the items was the sales teams that I talked about previously. So Roger, that hiring is actually ongoing right now. We expect them to be in place, trained and up and running, specifically for the PAH right now and the PH-ILD market, so this summer. So you'll see that kind of cost increase on a going-forward basis. Now whether Michael looks at opportunities and resizes things and shift things based upon actually how that pans out over time, that will be a decision later on, and that will be kind of what Michael sees as investment opportunities, et cetera. But that cadence and those hirings are happening right now, have been happening.

Folks internally have been pretty busy. And then beyond that, what we're doing is looking at what are the things that we can do now to prepare for the launch. So we've had questions around nebulizers, inventory builds, things of that nature. And across United Therapeutics, because we want to make sure we can serve and support those patients right out of the gate, we're doing anything and everything we can to get things in place.

Great. All right. Maybe we'll stay on Tyvaso before we move on to the ralinepag considering the pipeline. So you have another pivotal program for PPF for Tyvaso is ongoing? And then where is the status right now? And then how do you think about the TETON-1 translation to PPF. I understand it's a different disease, but they have some synergy and the underlying pathology. And then particularly for the magnitude of the treatment effect you see for the IPF TETON-1, TETON-2 and then how confident you are regarding the PPF at this point?

Yes. So we're certainly not going to speculate on what the magnitude of the FVC delta might be in that trial. But you're right, we are highly confident. As you said, the sort of underlying fibrosis and progression of disease are pretty similar between IPF and PPF. So when you think about the success of what we saw in the TETON trials, combined with what you already see in the space where nerandomilast and nintedanib are approved for both indications, we're pretty confident that we can also see a similar treatment effect in PPF with inhaled treprostinil.

And can I add on one thing. So Harry nailed it. I think just a couple of other things. I mean the PPF trial is another clinical trial that the product development team is actually working on. And we've seen a little bit of a halo effect where with the positive results of nebulized Tyvaso in idiopathic pulmonary fibrosis, we've seen enrollment in the PPF trial going very well. As Harry has mentioned in some prior discussions, it was 75% enrolled at this point. And so there's a lot of great attention on it. Folks are working very hard.

And the opportunity size, as we provided and you see some of the disclosures in the 10-Q that we filed, it's twice as big as the IPF market when you look at the PPF market. So we just think there's a tremendous opportunity. The team is focused on the clinical trial and to get things done right. And we just think going forward, that's just another one to add to the quiver, Roger of prospects for us for continued growth on a going-forward basis.

Excellent. Okay. Great. Maybe another question related to the Tyvaso pipeline is the Tresmi, right? So you announced the Soft Mist 2 quarters ago. And then that's very interesting because you see some dramatic reduction on the cough, which is maybe the only drawback for the current kind of formulation. And then where are you in terms of the clinical and the regulatory status? I believe you say something like you complete the pivotal study and then you're filing later this year? And then how much you can tell us about the readout?

Yes, that's right. So we'll be filing for the indications for which Tyvaso is currently approved, that's PAH and PH-ILD filing later this year. And again, that's based on some healthy volunteer PK work that we've done. As for branching out into the other diseases, IPF and PPF, we're still working on what the clinical development path looks like.

Got it. And then have you completed the study and then ready for the filing or you are continuing to do that trial and then waiting for data before you can file?

We completed a first cohort of healthy volunteers in the second half of last year. And the second cohort is either nearly complete or still going on right now. But we're still on track for later this year filing.

Yes. I think that's -- I think the important part, Roger, is that we're still committing to filing by the end of the year, which I think these underlying activities that we're doing will continue. We're just focused on meeting that deadline that we've committed to.

Got it. Okay. Ralinepag. So that's a super prostacyclin, as Martine said. So how should we think about the data will support early use and then even take over the current drug. We know we have some drug and going generic pretty soon. I think how you're going to position this once-daily oral and then in the PAH, PH-ILD first?

Yes. Look, we're really excited about the potential for ralinepag. The ADVANCE OUTCOMES data was a clear home run, really what this company has been working to from its beginning in terms of a highly convenient, really efficacious product. The data, it's clear that ralinepag, it's QD and really has a high potent receptor affinity. So that's what led to what you saw in the trial with really strong ability to delay the progression of the disease. And we think these factors position it really strongly in the prostacyclin class and could potentially shift it to earlier usage in terms of time since diagnosis, still following an ERA and PDE5, but potentially capturing earlier usage from prostacyclin-naive PAH patients.

Yes, Roger, it's -- and you've seen the clinical results. They was really a home run, as Harry talked about. And this is something that Martine was really focused on when she started the company, which is a once-a-day therapy. And it's hard to imagine why a patient wouldn't be prescribed ralinepag after frontline therapy because of the once-a-day, very efficacious formulation. So we just think in addition to what we've talked about in the IPF, which is a tremendous opportunity, we also think in the PAH opportunity that this is going to be a new chemical entity that will have far-reaching benefits to patients that are dealing with PAH, and we think a huge opportunity from a revenue standpoint as well.

Yes. Got it. And then in terms of the indication expansion, I think you want to make this super prostacyclin across broader than the PAH. So what's the biology or mechanistic rationale to support that because so far, the receptor seems to be more focused on the PAH versus treprostinil is broader into the other indications.

Yes. So it's very clear from the ADVANCE OUTCOMES trial that ralinepag is a highly potent member of the class of drugs that treprostinil is in. And it's clear from the TETON trials that treprostinil is very effective in managing the progression of IPF. So thereby, we expect that ralinepag could also see the same effect. And to your point, we're planning on developing it in a DPI formulation.

Yes. Okay. And then for DPI, it's interesting you choose DPI as the inhaled formulation for ralinepag rather than other formulation. And what's the rationale behind that?

Yes. It's kind of the right now, the path of least resistance in terms of the formulation work as well as the DPI may support -- may better support once-daily dosing.

Got it. Okay. One new indication you raised at the last earnings call is COPD. So it is a massive population. But you said you may not address the entire COPD like a more kind of enriched population. How much do we know about that? And I know last time I asked the question, stay tuned and then you will give us some more updates. And any latest thoughts about this?

Yes. We've disclosed that we're seeking a PAH COPD indication expansion for inhaled treprostinil. And in this trial, we're actually using the SMI relative to the last time that we pursued this indication. And we really learned a lot in the first time that we ran a full clinical trial to pursue this indication. And it's -- we have a lot of learnings that we're applying in terms of design and patient selection. And then, of course, you layer in the SMI, we're confident that we can hopefully see a successful outcome this time.

Got it. Okay. Very good. So this is in the treprostinil and then prostacyclin kind of franchise for PAH, PH-ILD and then related disease. And then you have another transformative angle of the story is the transplant. So it is in clinical right now. You're transplant people, patient now. How should we know the strategy disclosing data and then how we're going to -- when we're going to see the data?

Yes. Thanks, Roger. So this is kind of another one from a longer-term growth opportunity for United Therapeutics, where we're actually doing clinical trials for those new to the story, in kidney using xeno organs, so genetically modified organs. And we have 3 clinical trials right now going on. One is in UKidney, which is a 10 gene genetically modified kidney that we've kicked off. We've had transplants in.

The second one is UThymoKidney, which is using the thymus of a 1 gene-edited kidney or pig with using the kidney. And we announced a couple of Fridays ago that the FDA released Express, which is using a heart, so genetically modified heart. So those clinical trials, as you mentioned, Roger, are ongoing. And we think ultimately, this will be an opportunity to really put a huge dent in the enormous shortage of transplantable organs that are currently -- that exist today. It is -- if you think about it, we're sitting here and there's 500,000 people that are currently on dialysis in need of an organ. And so we're pursuing these opportunities to supply kidneys and hearts through these clinical trials if they're successful.

From a disclosure standpoint, Roger, the approach we're probably going to take is in some of the protocols for the trials we're required to finish 6 transplants and provide data back to the FDA, I'm talking about the UKidney. And so we'll have to see what kind of disclosure comes from that. But we can't today commit to a disclosure plan. But we think once we talk with the FDA and we potentially resize the trial. So right now, it's up to 50 patients that we will be able to communicate more about those clinical trials that are currently ongoing.

Excellent. Okay. All right. With time is up, and then thank you so much for being here, and I thank you, everyone, for listening and watching.

Thanks, Roger.

Thanks, Roger.

This morning as well as Harry Silvers, Investor Relations. James and Harry, thanks so much for joining us today. How are you both doing?

Good morning. Thank you, Lisa. And really thanks to RBC for hosting United Therapeutics this morning. Harry and I are really glad to be here. I'm going to turn it over to Harry to do an opening statement on forward-looking statements before we start, if that's okay.

Thanks for having us, Lisa. Just to remind investors in the crowd and listening in, we may make forward-looking statements. And for any risks and uncertainties associated with those statements, please review our latest filings on Form 10-K and Form 10-Q.

Well, James, Harry, maybe just to kick things off, could you just give us a big picture overview of what's going on with the company and the base business and where things stand with expansion, label expansion of Tyvaso into IPF?

Yes, Lisa, thank you. It's a great question. And I think you'll be hard-pressed, as Martine talked about on the last earnings call, to find a mid-cap biotech company with as many projects and initiatives that are ongoing inside UT. And I think as an example, we just proved beyond a shadow of a doubt in 2 separate clinical trials of clinical efficacy in 2 different disease states that had better clinical outcomes than really any other clinical trial and those being the TETON 2 clinical trial using Tyvaso -- nebulized Tyvaso for idiopathic pulmonary fibrosis as well as the ADVANCE OUTCOMES trial, which is using ralinepag, an oral once-a-day formulation for PAH.

And these indications and opportunities have revenue potential that exceeds what we're expecting as a revenue-run-rate at the end of 2027, basically to double the revenue-run-rate with these 2 indications once they're approved and on the market. So between these 2 clinical trials and all the other stealth programs that we've talked about, we feel the long-term opportunity from a growth perspective at United Therapeutics is significant.

Thanks for that, James. Well, I do want to dive into IPF and some of the data that you shared at ATS over the weekend. But maybe a big picture question for both of you. So there's been some regulatory volatility. The commissioner of the FDA has stepped down. And I'm just wondering if there can be any impact to any of your regulatory plans, either for IPF or some of your stealth products like [indiscernible].

Yes. Thank you, Lisa. It's a good question. From our perspective, and we have interactions and ongoing conversations with FDA, even to the extent as of last Friday, we did a press release that announced the advancement of our UHeart clinical trial for our organ manufacturing products, which is pretty revolutionary. And including that clinical trial for the UHeart, we have 3 clinical trials in organ manufacturing. And just to bring it back to your question, we've had great dialogue with the FDA. Even with transitions at the top of the organizations, we're really working with divisions within the FDA, cardiopulmonary, et cetera.

And our relationships, our conversations have actually been extremely good, extremely consistent. And the reason why I went back to this manufactured organ UHeart discussion is the FDA, our dialogue with them has been very great. And so we're advancing projects and programs on our own and in conversations with the FDA, and it's been a very healthy dialogue. So no disruptions on our part.

Great. That's great to hear. Well, James, Harry, you were both at the American Thoracic Society meeting this weekend. United had a bunch of presentations. But maybe you could share some color on how the presentations for ralinepag, the ADVANCE OUTCOMES study that you alluded to earlier as well as the TETON studies for IPF. How were those received by the medical community?

Yes. Lisa, I'll let Harry actually was there live and in person. So if you don't -- I'm going to defer to Harry on this one.

Yes. Thanks for the question. I am fresh off the plane from Orlando. First of all, it's great to see at ATS, the community come together in pursuit of better outcomes for patients. Just a really great energy there overall, and particularly in our 2 breaking-news sessions, which were accepted in the Clinical Trial Session on Sunday. The receptivity really, I think, mirrors our own excitement in the large opportunities ahead in both IPF and ralinepag for PAH when you think about the -- just the magnitude of the results that were presented, providing better options for patients than may currently be available.

Got it. Thanks, Harry. Let's dive into IPF a little bit more. So the 2 studies really showed unprecedented results in the IPF patient population. And there are really convincing benefits with Tyvaso, not only as a monotherapy, but also as add-on to current standard of care, the antifibrotic drugs. But maybe starting with the regulatory question, the next steps question. What is gating for the sNDA package that you're planning to submit before the end of the summer?

Yes, it's a regular process putting together the Clinical Study Reports. We also have to do the Integrated Analysis Report because there were 2 separate trials, TETON 1 and TETON 2, and just submitting all the regular requirements for the draft package inclusion. So we're on track for a filing by the end of the summer.

And Harry, should we expect to see Priority Review?

It's a good question, one that we get often. What we think is that the magnitude of the data, combined with just the still unmet need of this disease state, could warrant Priority Review, and we're hopeful to get that. I can assure you internally and the regulatory team are looking at every opportunity they can. One is to get the filing done right. We always have time to get it done right. But then two is looking for the opportunity to advance it because of the benefit that you saw in the clinical trials. So we really want to make sure we can get that to the patients.

Does the Commissioner's National Priority Review Voucher count is looking at every angle, every opportunity?

Any insight, but we'll look at every opportunity.

Well, I like to joke that it was called colloquially the [indiscernible] voucher. And well, we all know he's not around anymore. So it's not a nebulous, I think.

Yes.

Fair enough. Maybe let's talk about a potential launch in IPF, which patients would be the low-hanging fruit here? Should we think of refractory patients who are already on oral antifibrotic pill, or those who maybe cannot tolerate the oral therapies?

Yes. I would say it's pretty clear from the data just based on the magnitude of the benefit observed, the consistency across all the subgroups and the safety and tolerability profile, which is well-known, that almost any patient could and should benefit from this therapy.

Do you think doctors are interested in using Tyvaso as a first-line monotherapy? We saw with the combined TETON results that it was statistically significant as a monotherapy. Is that something that doctors are talking about at ATS maybe?

Yes, absolutely. You certainly hear the -- that bubble up in the conversations, and we ourselves have said the same thing kind of again, mirroring my first answer, it's very clear from the data when you look across every patient in the study really seems that they could benefit. So -- and you think about the first -- the existing antifibrotics agents, too, like they're so intolerable and the efficacy really seems to be waning over time for those drugs. So I think positioning this ahead of those could be beneficial. And certainly, you'll probably see doctors try that.

And are any doctors interested in trying Tyvaso as an add-on to Jascayd, the most recent IPF antifibrotic that was launched?

So obviously, there's no clinical data. The TETON studies did not contemplate nerandomilast, but I think there is a very clear scientific reasonableness to try out the combo and suspect doctors would do that.

Got it. That's helpful. And maybe just a last one here on IPF. You announced during the first quarter that there was going to be plans to develop not just nebulized Tyvaso, but Tyvaso DPI for IPF. So given that you have the TETON 1 results in hand with the nebulized formulation, what do you need to do to get the DPI formulation across the line and get it to IPF patients?

Yes. Again, a question that we're getting a lot. And we certainly can appreciate the opportunity in terms of the convenience of the DPI. What I would say is we're still working out the clinical development pathway when you think about branching out into the fibrotic disease with an entirely new compound into that space, entirely new device into that space. We certainly look forward to sharing more as we finalize those plans.

Got it. Well, I do want to talk and spend a little bit more time talking about the Q1 results as well as some of your forward-looking guidance, like the $4 billion run rate and beyond. And maybe for you, James, we can just dive in here. So Q1, the Tyvaso franchise came in a little bit light versus consensus estimates, but it sounded like this was partially due to the awful winter weather that we had and maybe some challenges at one of your specialty pharmacies, yet you are continuing to guide double-digit-top-line growth for 2026. So my question is, how do we get there? How do we get to double-digit growth for this year?

Yes. Thank you, Lisa. It's a good question. So at a top level, we do remain very confident in the long-term growth of Tyvaso DPI. And we say that with conviction. We believe that as a device, it is very simple, easy to use from a dosing perspective. It has unlimited dosing. And we think the benefit that has already been realized by the thousands of patients and prescribing physicians sets it up for the long-term growth opportunity. It's a space that we know extremely well, and it's a network of prescribing physicians that we feel we're going to continue to grow in that space.

So as you alluded to, there were some anomalies that occurred in the first quarter that is something that we have addressed internally, and we really look to the long-term opportunity that Tyvaso provides to the patient population, including better tolerability, for example, over the long term. So, there's many attributes and reasons why I believe this it's for us to own. And over the long term, we still believe at the end of the day, we're going to be the best prostacyclin prescribed for Tyvaso DPI in the market.

And do you think now that the TETON data is widely available now, you have The New England Journal of Medicine publications. You have all these presentations just this weekend at IPF -- could we perhaps start to see doctors try to find PH diagnosis in their IPF patients to essentially get them to a true PH-ILD diagnosis and get more patients on to Tyvaso?

Yes. So from an approved product perspective, PAH and PH-ILD are the approved indications. PH-ILD is obviously the growth driver for us and will continue to be until these 2 new indications, one being Tyvaso nebulized in IPF. I think you're right, though, from an awareness perspective, with all the presentations, publications, I think physicians are highly aware of it. Now how they diagnose and look at their patient populations will be really up to them, but we think the awareness and the opportunity to improve the patient outcomes is there for sure.

Got it. And I do want to talk about your competition, your competitor, Liquidia. They -- in Q1, they beat estimates and their product, Yutrepia arguably now has about 30% of the inhaled treprostinil market. I guess we could debate that number on a revenue basis. And so hearing in terms of feedback from doctors in terms of how their experience compares with Yutrepia versus how it compares with Tyvaso? And where can you win in PH-ILD patients with Tyvaso?

Yes. I think where we win is, to some extent, Lisa, what I just mentioned too. I think this is a long game. I think our device, the delivery mechanisms, the deep into the lung penetration, things we've talked about as benefits with the device itself in the long term will resonate with physicians and will actually be a benefit, we think, to patients. So there is some internal, as you alluded to, logistics, shocking things going around right now with competition. But we do think from a product perspective, we do have a superior product.

And we think over the long term, that's going to resonate best with patients and physicians. So we're confident in that regard. And I think time will tell. I think the sales force that Michael talked about is there should see some expansion later this summer as we onboard new sales teams for in advance of the IPF launch. They're going to be specifically focused on PH-ILD, will give us more voice feet on the street, again, to raise awareness. But I think in the long term, what I think will resonate best is really the product profile of Tyvaso DPI as a product and benefit to the patients long term.

So, I do want to touch on the 2027 $4 billion run rate that has been reiterated multiple times now. And that means you're going to reach at least 1 quarter with $1 billion in revenue that year. So, what are the key drivers? How do we get there? And is this mostly going to be driven by the IPF launch as well as the ralinepag launch in PAH?

Yes. Thanks. Good question. So what we've talked about now for some time is that by the end of 2027, Lisa, we'll be on a quarterly revenue run rate of $1 billion. So it will be a $4 billion run rate. When we started talking about this, the basis for that was really going to be driven off the commercial business, so the existing business, which would be obviously the growth in for us, Tyvaso DPI and in the indication of PH-ILD.

So that's really the commercial foundation and commercial footprint of our current commercial products to get to a $4 billion run rate. The doubling of revenue to get to the $8 billion run rate that we've talked about would be with the approved indications for ralinepag in PAH and for Tyvaso nebulized in IPF. So right now, this $4 billion run rate is off the commercial portfolio, driven primarily off PH-ILD and Tyvaso DPI.

Got it. That's really helpful. And the $8 billion run rate, does that include also some of your other products like TreSMI or ralinepag DPI?

It could, but I think primarily, it's going to be off the indications of Tyvaso nebulized and IPF as well as ralinepag and PAH. Certainly, if there's any contributions from other products that are in development and in stealth mode and some not in stealth mode actually anymore because they came out on the last call, there could be revenue contributions, but the real focus has been to get to the $4 billion to $8 billion on IPF as well as PAH for ralinepag.

Got it. Well, maybe this is a good segue to talk about some of those new products that have been released to the open so TreSMI and [ ralinepag ] -- on TreSMI first, is everything on track for the FDA filing later this year and potential launch in 2027?

Yes, to be clear, so you're talking about treprostinil SMI. Yes, our expectation is later this year, we'll be filing for the indications where Tyvaso is currently approved, so PAH and PH-ILD.

Got it. And when or if could treprostinil SMI be expanded into IPF?

Yes, kind of similar to earlier when we talked about Tyvaso DPI into IPF, we're still working out the clinical development pathway. It's an entirely different division of the FDA than we typically work with. So Cardiorenal Division covers the pulmonary hypertension indications and the Pulmonary Division covers the fibrotic diseases. They have less familiarity with treprostinil with some of the bridging studies that we've done before. So it's possible a bridging study may look different and less expeditious than what we're seeing in PAH and PH-ILD, but we're still working on those plans and excited to share more.

Got it. And ralinepag DPI, this is your once-daily inhalable answer to Insmed's TPIP. This was brought out of stealth mode during Q1. There's a lot of excitement about this. When can we get our first look at clinical results of ralinepag DPI?

Nothing to commit to right now on timing for when you might see any data. We are planning to move into Phase I later this year in the PAH indication with ralinepag DPI.

Got it. And maybe what are the goals here with ralinepag DPI? Should we just think of this as a convenience play? Is this life cycle management? Is this a hedge just versus the competitors out there? Or could this be a best-in-class inhalable prostacyclin agent?

Well, I think we can start where you ended. It could be a best-in-class for sure. I think one thing you'll find the data with ralinepag and the ADVANCE OUTCOMES was so compelling that it does set up the opportunity to go into other indications as we talked about. As an organization, what you find with UT is we actually have the concept of what we call multiple shots on goals. So going back to your earlier question, ralinepag DPI, it's not necessarily response to anybody, but it's more our own innovation going forward of how we want to develop our products to satisfy the multitude of what Michael Benkowitz called on the earnings call, every patient is like a Snowflake.

They are very different in kind. And we want to make sure we're developing not only therapies, but platforms and delivery devices to best suit and satisfy the needs of the patient ultimately, and their relationships with the prescribing physicians. So whether it's ralinepag or whether it's your prior questions around TreSMI, or SMI, it's just really a philosophy and a development program where you're seeing the outcomes of the product development team and the clinical development teams actually accomplishing an enormous amount of work -- they're taking us to levels, new heights and new levels at United Therapeutics that we haven't seen yet. So a lot of kudos to them.

And I think, Lisa, coming back to your question, we're really going to take the opportunity based upon our product set, things you know about, some things you don't know about that are still in stealth mode to ultimately provide the best opportunity for treatment for our patients for the long term. Again, it goes to the platforms we talked about in organ manufacturing. So you just saw or heard about last Friday, this press release on the advancement in organ manufacturing for the UHeart. Again, these are opportunities for us to think about ways to satisfy what we call the corridors of indifference overall, where we have a lot of opportunity to run very little competition, and we can help and support and serve the patients the best we can.

Well, maybe on that note on the xenotransplant program, you have the xenotransplant program going on, the EXPAND study in kidney and of course, the UHeart program, which was just launched into the clinic last Friday, which you announced. So I guess, when should we expect to hear any updates on these programs going forward?

Yes. So I think going forward, we'll work out what the disclosure strategy looks like. The way the studies are designed, at least the ones that are currently enrolling right now between the 10-gene kidney and the 1-gene kidney with the thymo attached, it's cohort-based with the first cohort of 6 patients, after which time you meet with the FDA to get a green light on the second cohort, which becomes registrational. So there may be a natural point in time after the first cohort where we could have a data package to share, but nothing to commit to at this time in terms of when, where, or in what format you might see data.

And maybe a bigger picture question for the xenotransplant program. Is the goal -- for instance, in kidney, is the goal to delay dialysis? Is the goal to bridge patients to potentially receiving a transplant with a human kidney? Or is the goal to get a new kidney as needed because these are off-the-shelf and you could possibly do that?

We think in the long term, it would be a replacement, for example, to an allograft. So we don't want to be in a situation for somebody to live to only be -- have that opportunity if somebody passed away. So this is a chance to provide an unlimited supply of organs to patients that could have similar duration in terms of length as allografts that you currently see or even longer.

So, this is an opportunity, we think, to be able to provide and satisfy this huge demand. As we sit here today, there's 500,000 patients on dialysis who are in need of a kidney. We think that we can give them -- ultimately, if this is successful, a kidney that would last as long as an allograft or longer, just as a comparison, and maybe not need a new one. But should they need one, we would be ready to provide them one as well should the program be successful.

Well, James, on that note, we are out of time. So we'll end things there. James, Harry, pleasure to have you both this morning. Thanks so much for joining us.

Thanks for having us.

Good morning, and welcome to the United Therapeutics Corporation First Quarter 2026 Corporate Update. My name is Jay, and I will be your operator today. [Operator Instructions]

Please note that this call is being recorded.

I will now turn the webcast over to Harry Silvers, Investor Relations at United Therapeutics.

Thank you, Jay. Good morning. It is my pleasure to welcome you to the United Therapeutics Corporation First Quarter 2026 Corporate Update Webcast. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties.

We assume no obligation to update forward-looking statements. Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products. These remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses.

Full prescribing information for the products is available on our website. Accompanying me on today's call are Dr. Martine Rothblatt, our Chairperson and Chief Executive Officer; Michael Benkowitz, our President and Chief Operating Officer; James Edgemond, our Chief Financial Officer and Treasurer; Dr. Leigh Peterson, our Executive Vice President of Product Development and Zeno Transportation; and Pat Poisson, our Executive Vice President of Strategic Development. Note that James Edgemond and I will participate in a fireside chat and one-on-one meetings at the RBC Global Healthcare Conference in New York on May 19 as well as the Jefferies Global Healthcare Conference in New York on June 3. Our scientific, commercial and medical affairs teams will be present at the American Thoracic Society International Conference in Orlando, May 15 to the 21. Now I will turn the webcast over to Martine for an overview of our development pipeline and business activities. Martine?

Okay, folks, it's going to be a great and exciting call today. is doing so frick and amazing that it is hard to imagine any other mid-cap biotech right now with prospects as good as ours. Here's what I mean. We just proved beyond a shadow of a doubt with a p-value of less than 0.0001 in that we have 2 different therapeutics in 2 different diseases of substantial size, each of which has been shown to produce better clinical outcomes than any other drug ever approved for either indication. Wow, that's got to sink in. I personally have not seen anything like that from a single pharma company all accomplished within 6 months. The 2 diseases we will be the best therapeutic for based on the completed Phase III trials, our IPF with Tyvaso and PAH with ralinepag. Each of the 2 products will exceed our total revenues of today, a revenue run rate of $3 billion going to $4 billion by the end of 2027. Let's take ralinepag first. every patient with PAH should be prescribed that once-daily pill because it actually gives them their best shot at clinical improvement.

Specifically, we showed a threefold reduction in disease progression compared to background therapy where ralinepag hit this and all other primary endpoints with better hazard ratios than selexipag and durably through 4 years. Frankly, this is the drug I dreamed of in starting United Therapeutics. This is why we've been calling ralinepag a super prostacyclin there is simply no reason that virtually every PH patient shouldn't be on it. Hence, I fully expect within 2 years of launch, it will double our number of PAH patients to over 30,000 in total. Next, let's look at Tyvaso for IPF. I said this will become the most prescribed drug for IPF, and because it improves forced vital capacity far more than the 3 existing drugs. if and only if boosted FBC to over 100 milliliters of oxygen and it did so quickly and it did so durably. With tens of thousands of PH patients and tens of thousands of IPF patients, it is nearly certain that these 2 drugs once approved, will lap our 2027, $4 billion revenue run rate twice over. And coming right behind Tyvaso for IPF will be Tyvaso DPI for IPF and right behind that, Tyvaso SMI for IPF. Our goal is to leave no IPF patient behind regardless of how their particular body best absorbs Tyvaso. Now let's take a breath and reflect back on United Therapeutics. UT has been ahead of schedule as a habit. We were ahead of schedule on outcomes on blinding.

We were ahead of schedule on TETON on blinding. And today, I am excited to announce another ahead of schedule. The next blockbuster product to emerge from stealth mode in our Skunk Works division and inhaled formulation of our new chemical entity, ralinepag, called [indiscernible]. In Stealthmode, a few months ago, we activated our exclusive option with MannKind for a second DPI. We now feel confident based on subsequent PK computational biology via our proven climb digital lung model and the results of the outcomes and TETON studies, that this will be our biggest product ever.

As you can see in the distributed market capture graph, we foresee our road time product rising to tens of thousands of treated patients through PAH, ILD IPF and PPF. Indeed, we will need all the capacity of the Danbury Connecticut mankind production plant and all the capacity of the new United Therapeutics, North Carolina DPI facility to keep up with the Tyvaso DPI and raw tie demand. Now let's delve into the science to better appreciate what a generational product rate will be for IPF. Rolenepag is the most potent member of the class of drugs that includes treprostinil. This is super clear from the extraordinary results of the OUTCOME study. Second, it is now indisputable that this class of drugs via inhalation has significant antifibrotic effects as we proved in the 2 TETON trials. ERGO, we very reasonably and scientifically expect Walti to show after further clinical trials that it is the best-in-class treatment for IPF and PPA.

The scientific reason lies in the chemical differences between the new ralinepag molecule and the old treprostinil molecule both of which are digitally mirrored in our client predictive computational biology model. ralinepag has 8 fewer hydrogen atoms than treprostinil but instead has a key nitrogen and a key chlorine item, that treprostinil lapse. These changes in molecular chemistry make all the difference in the world for pharmacodynamics and pharmacokinetics. Now treprostinil is a very, very good molecule, delivering very, very good results. but not our treprostinil, not Insmed, not liquidity as treprostinil none of these can ever be the super prostacyclin that is ralinepag. It is just not in their chemistry but it is in ralinepag chemistry. It is this change in chemistry that makes ralinepag a generational product for IPF. In summary, UT's long-standing multiple shot-on-goal strategy has now yielded its greatest reward, a proven once-daily NCE in PAH formulated to use a proven DPI drug device for the best in disease treatment of the largest indications to which we.

And as we march to this summit, we are rising through a series of great product stages that give us ever greater reach into the PAH and IPF community, namely, we are rising through Tyvaso for ILD and IPF, Tyvaso DPI for ILD and IPF open-label extension, Tyvaso SMI or trans for PAH, ILD and IPF and many more such combinations of products and diseases to treat, which are still in stealth mode in our Skunkworks division. Each incremental product indication platform that I just mentioned, each of these we are now aggressively developing for new and existing markets, and each of these brings UT ever closer to the ultimate goal depicted in the forecast chart released today.

Thanks for listening and digesting all of this great science and great clinical development work. And now I'll turn to Michael to describe how the demand for our existing products from doctors and patients is strong as ever. Mike?

That's a tough act to follow, but I'm going to do my best. Good morning, everyone. For the first quarter of 2026, we recorded $782 million in total revenue, Typical historical seasonality trends persisted in the first quarter, in addition to severe winter weather and pharmacy operations issues that slowed starts during the quarter, these have since been rectified, but it did impact our sales in the quarter, particularly in February.

As discussed on our last earnings call, we expect to return to sequential growth in the near term. Turning to Tyvaso. Total revenue for the first quarter was $458 million. While sales of nebulized Tyvaso lagged a little bit over the quarter, Tyvaso DPI contributed 9% year-over-year growth driven by an increase in patient demand. Looking at the competitive landscape, it's clear the market for inhaled prostacyclins is attractive and growing. We built and lead this market and expect our proven expertise to continue to win in the long term. We see this competitive dynamic as fuel for sharper execution across the organization, enhancing our strategic focus while operating with greater tactical intensity as we continue to shift momentum back in our favor. Speaking of momentum, we are seeing favorable trends in our underlying demand metrics. Coming out of the quarter, Tyvaso referrals or prescriptions, rates are at approximately the same level they were before [indiscernible] launched.

Patient shipments have grown for the last 5 months. Prescriber breadth and depth continued to grow, and we've seen a steady increase in patients graduating to higher doses of Tyvaso DPI with the launch of the 80-microgram single capsule and the 96-microgram and 112-microgram combination kits. Going forward, we're doubling down on what has always driven our success. Relentless innovation proven experience and patient obsessed. Additionally, the sales force investments we're making in anticipation of the ralinepag and IPF approvals will be deployed in the middle of this year to focus on expanding our reach and capturing more of the large addressable but yet uncaptured market in PH-ILD and expanding share in PAH with our existing commercial portfolio. We've built a durable high-performing commercial engine, and we're confident in our ability to expand our core business while driving the next wave of growth in [indiscernible] ralinepag and IPF.

To once again quickly recap, as Martin mentioned, both the [ TETON 1 and TETON 2 ] trials of nebulized Tyvaso and IPF were a resounding its success and exceeded our highest expectations. We look forward to filing a supplemental new drug application by the end of the summer and believe the highly compelling body of evidence across both the TETON studies could warrant an expedited approval through priority review to bring this therapy to those patients in need as quickly as possible.

If we receive a standard review time line, we would expect to launch by Q2 of next year. And in parallel, we have already embarked on preparations for a product launch. Following IPF approval, we'll work with payers to secure coverage for the new indication as soon as possible. We recognize the substantial market opportunity that lies ahead, and we're fully prepared to seize it. Coming back to advanced outcomes. The unprecedented top line results suggest ralinepag has the potential to revolutionize the treatment of pulmonary arterial hypertension as the first true once-a-day oral prostacyclin agonist.

We believe this advancement could fundamentally shift the treatment paradigm, potentially positioning prostacyclins for earlier relying usage in conjunction with ERAs and PD5. With a differentiated clinical profile, combined with its convenient once-daily dosing, we foresee a multibillion-dollar opportunity in the market for oral ralinepag where we expect to launch mid next year, assuming a smooth FDA approval on a standard review time line. In summary, our goals over the near to medium term are to drive further growth in Tyvaso, the most prescribed inhaled process cyclin and after anticipated FDA approvals for ralinepag to become the most prescribed process cycling for PAH and for nebulized as to become the most prescribed therapy for IPF.

To close, I want to recognize the intensity, discipline and patient first commitment. Our commercial and medical affairs teams bring every day. We remain confident that our business is positioned to deliver sustained double-digit long-term growth.

With that, I'll pass the call back over to Harry to start the Q&A session.

Thanks, Michael. Operator, if you want to assemble the roster and start with the first question. .

[Operator Instructions] Your first question comes from the line of Ash Verma of UBS.

Congrats on all the progress. Maybe just on the IPF regulatory filing and how you're positioning yourself in the market. I know you had previously mentioned that you would do a bidding study for the DPI. And where are we on that? And do you think that by the time that you launched the IPF, you would have the DPI format available? And just as a quick follow-up, I wanted to understand just your thoughts on the as Cade or random last launch metrics that are looking particularly strong. So do you think that is kind of like an indication of the pent-up demand in this market given there isn't much of good options available. And how does Tyvaso get positioned compared to Jade when you launch it?

All right. Thanks, Ash. [Operator Instructions]. Lee, if you want to take the DPI to IPF component and then maybe Michael can follow up on [indiscernible].

Yes. Thanks. So for -- we're actually working with FDA to come up with our bridge bridging strategy for IPF with the Tyvaso DPI, I think we've been discussing that before. We will likely do a healthy volunteer PK compatibility studies, comparability studies and as well as patient studies to demonstrate safety and efficacy. And as far as the sample size and duration of those studies, and we're still working with FDA to to come up with the clinical development plan.

[indiscernible] I think I'm going to address the question that had on [indiscernible] Yes. So yes, we -- I mean, obviously, we're following that very closely. I do think that's a good a good proxy or a good analog and does suggest that there is a lot of pent-up demand for new therapies and IPF given what's currently on the market. So I mean, I guess the short answer is, we agree with you, and that's really kind of how we're starting to think about potential launch curve. We're starting to have conversations with physicians now.

It's still a little bit on the early side because we were somewhat a barge in what we could talk about with the New England Journal publication. But now that that's behind us, we're able to have those conversations. And I think we're hearing from the physicians that there very impressed by the data. Very excited about bringing Tyvaso to market. I think we had an advisory board about a month or so ago where we had some of the -- like the top 15, I think, [indiscernible] [indiscernible] in the country, and we were asking a question around where are you going to use to as you use the first line you use it after Jazz kit? How do you think about this? And they all said it's going to be patient dependent. In some cases, they use so first. In some cases, they may start Cascade. But at the end of the day, it doesn't matter because they fully expect that this disease is going to look a lot like what we see in PAH, where it's combination therapy. So even if they're starting [indiscernible]. First, they're going to add Taibao very quickly thereafter. So yes, we think the potential is, as Martin said in the beginning, just enormous in IPF.

Your next question comes from the line of Roanna Ruiz of Leerink Partners.

So I was curious, how does your overall commercial strategy and peak sales and timing expectations change now that you're focusing on a few different levers like the triple combo pill for ralinepag DPI for ralinepag and also thinking about the SMI.

Thanks, Roanna, for the question. Good to hear your voice this morning. Michael, do you want to take that one?

Sure, Roanna. Yes, I think we'll provide some more granularity as we start to kind of build out our forecast. We start to have more conversations with physicians about the different products and where they expect to use them. But I think high level, what Martin said in her opening remarks is right. I mean, if we're we're turning towards $4 billion by next -- $4 billion run rate by next year. We think, certainly, with just ralinepag and the IPF indication regardless of the delivery device. That puts us on a path to more than double revenues over the next few years. That's what we're building for and aiming for. How that breaks out between the different indications, different devices. Like I said, I think we'll provide some more granularity on that as we get later in the year and build our models.

Your next question comes from the line of Jessica Fye of JPMorgan.

I wanted to focus on ralinepag DPI. Can you just confirm this product coming out of self mode. Is that the 1 [indiscernible] product you've been alluding to in prior quarters. When should we expect that Phase I healthy volunteer PK/PD data comparing that product to oral ralinepag? And what like you to decide for DPI over SMI for ralinepag's new formulation?

Thanks, Jess. Good to hear from you. Welcome back. We'll kick that over to Pat to answer on ralinepag DPI plans.

Thanks, [indiscernible], and thanks for the question. So first, let me say we are excited to work with the main time development team again. What we were able to do with -- together with Tyvaso DPI which was approved in less than 4 years from our engagement while contending with the pandemic was really nothing short of incredible, and we expect that even better on core with [indiscernible].

So as mentioned in the MannKind press release this morning, we began work on Rail about 6 months ago, and we've made great progress with the completion of formulation development, and this transition into manufacturing tox study supplies. We've had a very positive pre-IND engagement with FDA, and we'll shortly be moving into some minimal nonclinical testing, which will be quickly followed by an IND in a Phase I study, which we believe will be completed before the end of the year.

We believe the half-life of ralinepag, along with some other characteristics we are investigating are very promising for this to be a once-a-day product. And important to note that this will be without the addition of any release controlling materials, which need to be carefully studied for safety when used chronically. So I'll finish with, as they say in car racing, we are staying with hard tires and not making any pit stops.

Your next question comes from line of Joseph Thome of TD Cowen.

Maybe just to extend a little bit on the development program for maybe how quickly can this move? Is the availability of the data for oral ralinepag helpful at all maybe specifically for PAH, could you go right into registration? Just trying to think about time lines relative to some competitors in the space. .

Joe, thanks for the question this morning. I think we'll kick that back over to Pat again.

Yes, another great question. Of course, the advanced outcomes data was off the charts incredible. So that's very encouraging that route pie will be very effective to treat PAH ILD and IPI from PPF. So as far as the timing, I think long term, we're going to be able to move into AH fairly quickly relative to our world in pharma as we'll be pursuing that approval with the solid dose. And certainly, the solid dose has been a big contributor to our engagement with FDA and really the minimal amount of pre-IND work that we have to do for round pie.

So I anticipate we'll complete the initial Phase I study by the end of the year, and we'll rapidly be able to kick off studies for PAH efficacy as well as PH ILD, IPF and TPF. So each of those will progress at different paces. And -- but initially, PAH will be the first approval.

Your next question comes from the line of Lisa Walter of RBC Capital Markets.

On the [indiscernible] [indiscernible] BPI. Just wondering if you can share more color on the formulation. Should we think of this as a ralinepag prodrug or another formulation with the lung targeting ligand? Or are relatively little additional flourishes needed to make relanepag inhalable. Any color here would be helpful.

Thanks, Lisa, good to hear from you. Pat here at the star of the show today. .

All right. Thanks,. So we'll be leveraging MannKind's crystal carrier IP for ralinepag, very similar to what we have for [indiscernible]. It is not going to be a prodrug. Now perhaps we investigate other polymorphs of ralinepag in the future. But initially, it's going to be the ralinepag molecule that we investigated for solid dose. So again, very similar formulation to the current treprostinil in using MannKind's crystal carrier IP.

Your next question comes from the line of Olivia Brayer of Cantor.

Now that you are committing to developing a number of different formulations in IPF going forward, can you maybe just talk about which you think have the highest chances for success and how you're thinking about nebulized versus DPI versus SMI and then also Tyvaso versus ralinepag for IPF patients specifically. And just kind of following up on that from a regulatory strategy perspective, anything you can say yet in terms of what that strategy is for getting some of these next formulation to patients? I mean it sounds like a bridging study for DPI, but what about the SMI formulation? And then when could you realistically start those ralinepag studies in IPF and PPF.

Thanks, Olivia. Perhaps from a broader strategic standpoint, Michael can take that question and then maybe Leigh can follow up on the regulatory side.

Yes. I think from a strategic standpoint, our approach to IPF is very similar to what you've seen us over the last 30 years due in PAH, which is taking multiple shots on goal approach. And we started with [indiscernible] IV. We thought Remodulin subcu, could be a better version of Remodulin just in terms of dealing with the potential for infections.

And then we progressed to Tyvaso, we progressed to Orenitram. Now we're -- and then we looked at Tyvaso DPI, we look at -- and now [indiscernible]. And I think the point of all that is that I think what we've uncovered in PAH, and we think this is true in IPF is that patients are like now, right? They're not this homogenous group of people that rent all respond to the same drug delivery approach. And so there's a role for all of these products in PAH. And I think that's what we're going to see in IPF is we take multiple shots on goal. And I think we're very optimistic and confident in our ability to bring all of these products to market.

And we think they're all going to have a role, right? I think there's going to be some patients that for -- that are going to respond well to DPI. I mean you look over in PH-ILD. I mean, I think you still have a significant number of patients that are still on nebulizer even though you have of the DPI. So patients are -- they're unique. They all respond to different drugs and different delivery devices in different ways. And so the approach has always been multiple shots on goal. We give patients options give patients options in terms of the way they can receive the drug. And then from our standpoint, we're really kind of agnostic as to which one they choose as long as they're choosing one of our products. So strategically, that's how we think about these different devices and different NCEs and IPF. So Lee, I don't know if you want to -- or Pat, you guys want to talk about the regulatory path.

Yes. Actually, I just wanted to add on a little bit to -- a little bit of color to what you said and with the patients or people or snowflakes, just keep in mind that with -- so we have different -- the different sort of categories, we have the inhaled route versus the oral route now we know that oral for patients, especially if it's once a day, tends to be more convenient, but we also know that systemic vasodilators are generally -- count into indicated in patients with like PH-ILD or IPF, given the potential for worsening ventilation perfusion mismatch PQ mismatch.

And so that kind of separates that right there as to we imagine the inhaled would be more for this other population. And then as far as the powder versus some patients, it could be a convenience thing or cost. Some patients might be more sensitive to the powder versus the nebulizer. And so that's where that might fall out. And then as far as -- this is something we haven't really talked about too much. But even though treprostinil and ralinepag are both in the same class of drugs, they do bind Martin went through the chemistry of the actual molecular structure between the 2. And as such, they they bind their receptors differently.

Ralinepag is a really, really potent IP receptor agonist, whereas treprostinil binds multiple receptors, IP EP2 and DPI. And so there may be some differences with regard to efficacy there based on patient genetics. And so all of these things, again, just to reiterate that they really give us this really allows individual patients to get the absolute best treatment possible. And as far as the IP receptor goes, there's some recent data that recent preclinical data that IP receptor activation promotes Alber regeneration during long repair.

And so -- and this is if you want to really get into the molecules and the pathways versus this June p53 pathway. And so I mean, there's coming out more and more evidence for these things and these type -- this class of molecules versus different mechanisms of action in these indications, whether it's PAH or PLD or ILD or IPF or PPF or all of them. So anyway, I just wanted to add a little bit more there. And then maybe Pat would want to talk about the regulatory aspect.

Yes. I mean I think the regulatory strategy would proceed kind of as expected. So we'll have nebulized approved in and we'll conduct whatever and upon bridging study is necessary and then proceed directly with the filing from there. So I don't anticipate anything unusual.

Thank you, Pat, Lee, Michael, three really wonderful answers. Operator, I think one more question we have time for. .

Your last question comes from the line of Roger Song of Jefferies.

Congrats for the quarter. Maybe I think in the in the updates, you also have the PCPD Phase II about to start later this year. So curious about how should we think about the market opportunity? And then also what the product formulation potential sequence for that indication, given we haven't talked about a lot of the combination device in the drug.

Thanks, Roger. Leigh, perhaps you want to share a little bit of color on the PH-COPD study? .

Yes. So as far as the formulation, we're planning to use treprostinil SMA -- SMI, excuse me, for this -- and for PH COPD. And we're planning on doing it the study in a couple of phases. We obviously have our Phase I where that's already ongoing with the treprostinil SMI in healthy volunteers. And then we're planning a Phase II study with PH-COPD patients, and that will be followed by a Phase III PH-COPD study. And we have several learnings through -- over the years that are being considered here with regard to patient populations, and we're really looking forward to starting the studies with these sort of enriched patient population eligibility criteria.

Thank you, Leigh. Operator, you can go ahead and close the call.

Thank you for your participating in today's United Therapeutics Corporation earnings webcast. A rebroadcast of this webcast will be available for replay for 1 week by visiting the Events and Presentations section of the United Therapeutics Investor Relations website at ir.unither.com, that is ir.unither.com. This concludes today's conference call. You may now disconnect.

Thank you again for joining us at the Leerink Global Healthcare Conference. My name is Roanna Ruiz. I'm one of the senior biotech analysts here at Leerink. And it is my pleasure to introduce United Therapeutics here. And on the stage, I have with me Dr. Martine Rothblatt, who's really sort of led this company through a lot of different events and data and many, many things, milestones. So really glad to have you here.

Thank you, Roanna. I appreciate the opportunity to be here.

Yes. Great. And so I know there a lot of people know United Therapeutics. But just in case in terms of if investors are wanting to refresh on the story a little bit, I'll ask you a big picture question before I dive into the details. And just how are you thinking about the main pillars of the United Therapeutics story, both commercially and in the pipeline and your top goals for this year and beyond?

Sure. So the main pillars of the United Therapeutics story are 2 progressive fatal illnesses, pulmonary hypertension and pulmonary fibrosis, of which we have been able to report this year the best clinical trial results that have ever been reported in each of these separate diseases ever since the creation of the FDA.

Before I say more, let me just warn everybody that we are a publicly traded company, of course, and that I'm going to next say some things that are forecasts or projections into the future. And please consider all of these "forward-looking statements" as being conditioned by all of the information and risk factors described in our SEC, 10-K and 10-Qs.

So with that like front note, let me just mention that pulmonary hypertension, if it's untreated, the patients die within 5 years. Pulmonary fibrosis, similar situation. Pulmonary hypertension in the United States, around 50,000 patients; pulmonary fibrosis in the United States, probably twice as many people. And the results that we announced just in the past 3 months, so this conference is so timely were, first of all, the best ever clinical trial results for pulmonary fibrosis, which showed that we were able to improve patients' forced vital capacity, which is the overwhelmingly used endpoint in pulmonary fibrosis by a much greater amount than any other medicine ever approved by the FDA or the EMA. And physicians are now forecasting that because of this, our medicine called Tyvaso will be used as the primary medicine for the field of these upwards of 100,000 patients, which is so extraordinary and such a great privilege to be able to slow the progression of their disease and give everybody more years of life.

Then very similarly, just last week, we announced the results of our ADVANCE OUTCOMES clinical trial of a medicine that we call ralinepag. And this medicine is an amazing drug. We call it a super prostacyclin because it lasts -- one pill lasts all day long, and it has much greater potency for the pulmonary vasculature than any other medicine seen before in clinical trials. So at the end of our trial, which we announced just last week, we had shown that we had made a bigger improvement in slowing clinical worsening and a bigger improvement in clinical improvement than any other medicine taken orally in the whole time that the FDA has been approving medicines for pulmonary hypertension. So the leading doctors are forecasting that every pulmonary hypertension patient will be put on ralinepag. As mentioned, that's upwards of 50,000 patients. And we expect as soon as 2 years after launch that at least 15,000 of those patients will already be on it.

Yes. You sort of -- it's a good segue to my next question. I was thinking ahead with ralinepag for a second and some of the potential peak sales that you could reach with ralinepag and now that you have ADVANCE OUTCOMES data in hand, like what needs to happen? Or what are some of the levers that could get you to a higher peak sales and your excitement behind that?

Great question, Roanna. So there's a lot of factors in play here. First of all, is to have FDA approval, which we expect to have in the middle of next year, and we expect to file for approval in the middle of this year. So it will be launched very quickly. Next in place is to have a really great commercialization team that can go out to the pulmonary hypertension prescribers.

Fortunately, for United Therapeutics, we already have like 1, 2, 3, 4 medicines approved in pulmonary hypertension. So we are very well acquainted with the field. The field has an enormous respect for United Therapeutics. There is a special recognition for our company as a public benefit company that has a mantra to leave no patient behind. So if patients are unable to pay for their medicines, we always have a patient assistance program to provide them the medicines for free. So there's an enormous reservoir of great will for United Therapeutics. And as a result, I think we'll very quickly reach our first target of 15,000 patients within 24 months of approval. That correlates to approximately $3 billion in revenue.

Soon thereafter, we'll continue to march toward that peak revenue factor that you referred to. And that will involve going out to the large population of patients on dual oral background therapy, which is also known in the field as the AMBITION therapy. That's an ETRA, endothelin receptor antagonist and a PDE-5 such as Adcirca or tadalafil is its proper name. And there are about 30,000 to 40,000 patients on that dual background therapy. We have the first time to be able to say to doctors, if you just stay on background therapy, your patients are disease is going to get worse faster. But if you just add our super prostacyclin to that background therapy, it will slow their rate of worsening and many of them will actually get better. This is a very compelling proposition.

So I think very quickly, you're going to see us notching additional billions of dollars in peak revenue during the -- during the 2030s. And the ultimate story is that with something like 30,000 or 40,000 patients, we could literally have 20x the initial peak revenue. The initial launch revenue could be our peak revenue in the 2030s.

Yes. That's really interesting. And sort of thinking about the market and evolution here, I want to segue a little bit to PAH and PH-ILD with Tyvaso. And could you just level set a little bit about what you're seeing in terms of patient metrics for Tyvaso, with the nebulizer and the DPI. What's been exciting in terms of what you're hearing feedback from the field force and physician feedback as well?

Yes. So first, I want to correct one thing I just said. I said the peak revenues could be around 20x the launch revenues. I think the peak revenues would more likely be around 5x the launch revenues because the launch revenues are associated with about 15,000 patients in the U.S. and the peak revenues could reach 75,000 by considering both the U.S. patients and European and rest of world patients as well.

With regard to Tyvaso for pulmonary fibrosis, I think the revenue potential is even greater. And there, we think that in terms of launch revenues, we could probably be helping something like maybe 30,000 patients very rapidly. Those being the patients who are already taking some kind of medicine for pulmonary fibrosis or found themselves unable to tolerate medicine and went off it. With us, we can show the best clinical trial data ever shown that we can do better for those patients. So I think getting the 30,000 patients is something that will happen within 3 years of product launch, so very, very quickly.

And then from there, the peak revenues are really just amazing because pulmonary fibrosis exists in 2 flavors. There's what's called idiopathic pulmonary fibrosis, which as many of the audience knows, it kind of means we're like idiots about what causes it. And then there's another version called proliferative pulmonary fibrosis. which is, frankly speaking, about 10x more prevalent. There's many different types of it. So the peak revenues could actually be 10x our launch revenues in pulmonary fibrosis.

Got it. I'm glad you sort of segue to IPF, and there's a lot going on. In terms of thinking about the upcoming TETON 1 study readout, I mean, could you frame maybe for the audience, how -- what are your expectations from that data set in terms of reiterating what you saw potentially from TETON 2 and what would be a really exciting outcome?

Roanna, that's a great question. And all of our 1-on-1, that was the #1 question that was always asked. So we expect the TETON 1 results to lay very much right on top of the TETON 2 results. For the benefit of the audience, TETON 1 is the confirmatory registration pivotal trial for TETON 2, which was the first pivotal registration trial for the medicine Tyvaso in idiopathic pulmonary fibrosis. And TETON 2 is just named TETON 2 because it started after TETON 1, but enrolled all of its patients faster. So it got unblinded more quickly.

And the results, as we talked, were extraordinary, upwards of 100 milliliters of improvement in forced vital capacity, way above anything else. And we have looked very carefully to see, is there some reason that the TETON 1 results would be different from the TETON 2 results. And we can't find any reason. The inclusion criteria for patients in both trials were the same. The endpoints we're measuring are the same. These kind of indicators that tell you if the patients had any confounding diseases or other diseases beyond pulmonary fibrosis, all of the metrics shows that there were not any of those confounding factors. So from a standpoint of biostatistics, we expect the TETON 1 numbers to look just like the TETON 2 numbers.

Yes. And then in terms of thinking about the evolution of IPF and PPF and where you could layer into the treatment paradigm, how are you thinking about that?

I think that they would layer into the treatment paradigm in basically 3 different ways. So first of all, there are a number of patients who unfortunately are at the end of the life expectancy phase of pulmonary fibrosis. They have found themselves unable to tolerate the 2 generally prescribed background therapies, [ nintedanib ] and pirfenidone. And so they went off of those, and now they're getting even worse, and we see rescuing those patients with Tyvaso. So that's one group.

The second group are on these prevalent background therapies. And by the way, the reason I feel confident about that is in our clinical trial, 1/3 of the patients were on no background therapy or they had given up on the background therapy. So we've already proven that we work on top of nothing. Then the second group of patients are the roughly 30 or so thousand patients in the U.S. who are on background either pirfenidone and [ nintedanib ]. And while these drugs have an FDA label that shows some modest improvement in forced vital capacity, a much bigger portion of the label talks about the side effects, and they are very, very difficult to tolerate. So we will be able to go to the physicians treating those patients and say, you can go ahead and layer Tyvaso on top of these difficult to tolerate oral treatments.

And if you see the patient is getting better, then you can wean them off of the oral treatments and thereby kind of the patient gets 2 wins. They get win one of the power of Tyvaso moving them up to a 100-milliliter of oxygen FVC improvement. Win 2 is to get rid of a lot of the terrible side effects that they're suffering from pirfenidone and [ nintedanib ]. So I think that's a very compelling proposition, but what really seals the deal is 75% of the patients in our study were on those background therapies. So we've already proved that our drug works better and synergistically with those background therapies. So I think that will be a pretty easy prescribe for the physicians.

Finally, the third group is very recently, there have been a couple of new drugs approved in the IPF space. And while we did not test our medicines on top of the new drugs, our clinical trial results showed a far greater improvement in forced vital capacity, so it may be that the physicians want to migrate their patients from the drugs that performed less well in the pivotal trial to Tyvaso, which performed much better.

Yes. I hear you. That's really interesting. And speaking of other new updates from the company, you also unveiled TreSMI or the new soft mist inhaler. So I couldn't help but want to ask like how are you positioning this product? You haven't released a lot of data, but you did mention a 90% reduction in cough. So how should the investors in the audience think about that commentary, the data you have so far and what you're building towards with the soft mist inhaler?

Sure. So we were very excited to announce TreSMI because it's the first product that came out of the United Therapeutics, what we call our Skunk Works, where we develop like amazing new products that are much better than all of the products out there already. So TreSMI was the first one. And we are going to file for approval this year, 2026 and expect to launch it next year in 2027.

We wanted to give the market some indication that there was a sea change coming in the field of inhalation therapy. Up until this date, first, there was a generation of just big bulky nebulizers being used for inhalation therapy. And then there was a next generation of dry powder inhalers. The dry powder inhalers have turned out to be much more convenient for the patients, but much more difficult to tolerate with a lot of patients suffering cough because it's so dry. It is just what the name says. When we were able to invent this soft mist inhaler and do our first study in humans, we saw that, wow, it's 90% fewer of these people are coughing at all, like no cough compared to the patients, the other kind of patients.

So this was to us a sea change in inhalation therapy. We wanted to get that out to everybody. Even though we ourselves have a wonderful dry powder inhaler, and it's helping preserve the lives of over 6,000 patients. It's growing by double-digit amounts year-over-year. I think it will continue to grow by double-digit amounts. But once the soft mist inhaler is approved by the FDA, hopefully next year, I think the -- very quickly, within 2 years, the majority of people who do any kind of inhalation therapy will be breathing the soft mist inhaler.

That's great. And thinking ahead, with TETON 1 data coming up and IPF potentially pursuing that indication and bring it together with the soft mist inhaler, how are you thinking about the soft mist inhaler potentially moving into other pulmonary indications?

So excellent question, Roanna, once again. What we're trying to do is to segue things in the lowest risk way. So our first goal will be to file for Tyvaso to be approved in IPF without the soft mist inhaler. Then the next stage would be to file for Tyvaso soft mist inhaler or TreSMI to also be approved in SMI in IPF. And it's a kind of a very natural transition because nebulizers, despite their bulkiness and despite the need to have like a prolonged breathing period, they are easier to tolerate in terms of cough than dry powder. So we think it will be a much easier regulatory ramp into IPF to make the next product that goes into their -- the TreSMI product.

And TreSMI is not the only new thing you started talking about. So if you're able to share, I was curious if you could talk about the once-daily inhaler that you mentioned. You also mentioned a PRN inhaler and also a possible combo with ralinepag.

I think maybe you've been snooping around our Skunk Works. You know all the products in the Skunk Works. So yes, the next product queued up from the Skunk Works in our Stealth group is the once-daily inhalation treatment for pulmonary hypertension. And we intend to provide a full visibility into that product right after we file the ralinepag NDA in this summer, as I mentioned before, which would be the pill. So -- and then also at the same time, we'll file the Tyvaso product for IPF. So both of those filings will go in.

The target date is June, June, July, something like that, will go into the FDA. And we hope to have both of those products approved in time for our 30th anniversary, which is actually June of '27. So that gives the FDA more than their usual period of time, and hopefully, we'll get it approved a little bit earlier. But that will be a tremendous thing to celebrate along with the 30th anniversary. Of course, because 30 years is 3 decades, we want to have a third product to celebrate the launch of, which would be the TreSMI product, the soft mist inhaler.

But we also have these additional Stealth projects coming out, like, first of all, the once-a-day inhaler. So right after we do those filings in mid-summer, we'll announce more details on the once-daily inhaler. However, I can say that we have a very detailed and fine-tuned Gantt chart for its progress. And by everything that we see, we would expect to launch that product in 2028. So it will be really just kind of right after the corner of these current products.

Another really cool product coming out of that is a product that is for PRN use. Of course, as you know, my daughter has pulmonary hypertension, and I live in a community of pulmonary hypertension. And I see very, very frequently that people need something that I would just functionally describe as a rescue inhaler. They want to go to the store, they're running out of energy or they're at the store and they're running out of energy. And this is the common problem with pulmonary hypertension, you just run out of energy. And so the ability to have a PRN inhaler that you could use as needed that had a fast onset, but maybe not a long duration, so it's not to compound with your systemic once-daily type of treatment is another product we're really excited about in our Stealth Works group that you mentioned.

A third product is a combo oral pill that would combine the kind of medicines that we proved that we were synergistic with in the ADVANCE OUTCOMES study because as I may have mentioned, 80% of the patients in that study were on dual background therapy, both an ETRA and a PDE-5 inhibitor. So we have actually recently figured out a unique way to combine all 3 medicines, ralinepag and those 2, all in an easy-to-swallow pill. And it took some little smarts. But I think our core competency of UT is in drug formulation. So that's another thing that is in our Skunk Works that we'll be announcing the release of very soon.

Great. Looking forward to it.

Thank you, Roanna.

A lot of development going on. So that's also a good pivot to another topic I wanted to hit, the organ manufacturing/xenotransplantation area of your work. And I know you have about 2 active xeno-kidney INDs and you're quickly moving into first in human. Could you talk about some of the early clinical signals that you're watching for from these studies in future studies?

Yes. So the main point we look for is just normal kidney function and lack of signs of rejection. And fortunately, we already have 2 patients enrolled in the clinical trial that the FDA has approved. The second patient is nearing 12 weeks, and both of the patients walk around their neighborhoods. They're doing great. They're so grateful and thankful to be off of dialysis. So there's every single indicator of all the lights are green on the dashboard to go forward into the second FDA-approved tranche, which is 4 more patients, all at one time without waiting serially one after another.

So we'll now do the next 4 patients will be enrolled, and that will be all completed by the beginning of the summer. We'll have 4 -- so then there would be 6 xeno-kidney patients walking around. And again, what we're looking for is normal kidney function at the end of 12 weeks. That's what the FDA required. Once we get the 12 weeks from the fourth of those next 4, then we'll submit all the first 6 patient data to the FDA, which we plan to do in the third quarter of this year. And they will then give us an answer in terms of they had told us initially when they cleared the IND that to gain approval, you'll have to do up to 50 patients, but they didn't give us like an exact number. So based on these 6 patients, we're going to get like an exact number from them of how many patients.

We have some reason to hope it could be as few as 30, but if it's 50, it's no problem, we'll do that, too. And whether it's 30 to 50, whatever it is, we'll then enroll those at centers coast to coast throughout the country. We already have such strong interest from like Washington University, the Mayo Clinic, other great hospitals. Northwestern is another one. So there'll be more -- all of these centers I've like named dropped have all already agreed to be in on that next cohort of patients. And I think it will be no more than 2027 to enroll the rest of it, whether it's 30 or 50, it wouldn't matter. We have the production capability for those xenografts from our xenograft production facility, the Honorable Tommy Thompson, Louis Sullivan xenograft production facility in Christiansburg, Virginia.

And the last patient from that study, let's say, they are transplanted as late as December of '27, the FDA said we have to watch for the last patient up to 24 weeks, so 6 months. That would be the middle of '28. And then assuming that all goes well, we would file a BLA for the first-ever xeno product, which is like super exciting. We would do that in the second half of ' 28 and hope to have approval in '29. I did say at the last earnings call that we would expect approval -- a reasonable expectation is 2030 because after 3 decades, I've learned to always provide some wiggle room on biotechnology. It always takes its own little twists and turns.

Totally fair. I hear you. And then a little more detailed question I've gotten from some investors. How are you strategically differentiating like UThymoKidney versus UKidney in terms of could they coexist or how these products will be used in different patients? What are you thinking about that?

It's an amazing question. It's one of the things that I find so fascinating about United Therapeutics, it makes it like such an amazing place to work. So the UThymoKidney is a -- just to bring everybody to the same platform is when the genetically engineered pig is less than 4 weeks old, it's thymus, which is the source of all of the T cells in all of our bodies, and it's the source of the cells that differentiate ourselves from anything else. So the little tiny thymus of a 4-week-old piglet is auto transplanted by expert surgeon into a little niche in the kidney of the pig, which is called the kidney capsid.

And there, it grows for the next couple of months in the pig as the kidney is growing, as the pig is growing, the thymus is growing. But instead of where it usually is, it's growing inside the kidney. And it's fortunate that in this kidney capsid, there is a very rich vascularization of that space. So that's important for T cells because they have to get out to every part of your body. You've got T cells in every part of your body. Then when it's time to do the transplant into the patient, which is about 12 weeks, maybe 16 weeks, then the patient is getting not just a kidney, but they're getting a thymus and a kidney. And the purpose of the thymus is to teach the body's immune system, the recipient's body's immune system that this kidney is part of you. You should welcome this kidney as part of you because that's the job of the thymus to define self versus not self.

There is a little bit of question right now in terms of whether or not we should thymectomize the recipient, take out their thymus or not. I'm not a fan myself of [ thymectomizing ] the recipient for 2 reasons. First of all, believe it or not, after you're 2 years old, your thymus becomes involuted and it does almost nothing. It's like -- becomes like an appendix after you're 2 years old. And by the way, more and more people, they don't want their appendix out because you could take antibiotics if you have appendicitis or something like that, or [indiscernible] out. So that's one reason. I wouldn't want to take the thymus out.

The other reason is the thymus is a little bit of a difficult reach to place -- a difficult place to reach behind the heart. And it's just -- I wouldn't want to do a more complicated surgery that wasn't necessary. And we did do in our brain dead heart beating donor models, we did not [ thymectomize ] them, and we showed that the involuted natural thymus of the human and the genetically engineered thymokidney of the donor that they can coexist and the immunology looked 100% coexistent. So I'm kind of voting that we leave the thymus in. But the first of those patients, the first of those final kidney patients will be transplanted within the next 3 months. In fact, those piglets have all been born inside the DPF, which are actually the first ever donor pigs 100% born within a pathogen-free facility. That's what I mean by DPF, a place where it's protected against any pathogens.

Yes. Sounds great. That's super interesting. And then last question, I know we have a minute left. I know you've alluded to discussions with large pharmas before in terms of largely driven by the interest in the AI-enabled digital lung model. So I was curious, could you talk a bit more about what's so unique about this platform?

Great question, Roanna. So we began working on the AI-enabled digital lung model actually 7 years ago as part of our program to 3D print a human lung and then cellularize it with autologous cells from the intended patient that would be reprogrammed into iPSCs and then further differentiated into airway and blood side cells. So in doing that program, we needed to speed things up by having a digital lung that we could recellularize completely digitally in computer model and cyberspace. That was successful and has -- we are now like on the verge of going into the brain dead human heart beating brain dead models with our 3D printed autologously cellularized lungs.

In the process of doing that, we were able to then develop this model to test business development concepts that were brought to us in terms of you want to in-license this PAH drug, you want to in-license this IPF drug. And so we began running those models and the answers that we got from the AI-enabled digital lung model, every time it matched with what these third parties ended up resulting in their trials. Unfortunately, those trials weren't successful, but the digital lung model told us that, and we saved billions of dollars not buying those companies.

So then we began running all of our own models to try to shadow match what we would find out in the in vivo unblinding. And it turned out to be highly, highly successful. In fact, like in the IPF model, I described how we got closer to the in vivo results than any of the other in vivo actual trials got to our results. So it was really amazing. So this is of great interest to some of the great pharmaceutical companies in the world that are developing new pulmonary hypertension treatments. I've mentioned that I see tremendous synergy with WINREVAIR and ralinepag. So that's something that complete can be completely vetted out and proven in our AI model.

There are other companies working on other great drugs for pulmonary fibrosis that can also be vetted in our AI model. And it's one thing to save a lot of money on doing a trial that you don't want to do or maybe doing it with a little bit different endpoints, then you don't have time to run all the Phase II trials to show all those endpoints. But what excites me most is the time save you want to. I am literally blown away that we can run 100 trials with countless thousands of virtual patients that match all of the inclusion criteria factors of our trials in 48 hours, and it takes us years to run those trials in real life.

So we're now in the process actually of briefing the FDA on our model. And I'm very hopeful that soon, we'll be able to file our model results as collateral supportive evidence to try to pave the way for, I think, a brighter future when drugs can be developed much more quickly and even more safely because of our ability to replicate countless polygenetic morphisms that people have than you would ever find in a clinical trial population.

Yes. It's super exciting. I can keep going. But...

It's amazing. Cool.

I think we're at time. So thank you, again, Martine for joining us.

[Audio Gap] get started. So thank you, everyone, for joining us in the room and online at TD Cowen's 46th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen. And it is my pleasure to have with me today a couple of members of the United Therapeutics team. We have President and COO, Mike Benkowitz; and CFO, James Edgemond. So thank you very much for being here today.

We usually kick these off with just sort of an overall state of the business, what's been sort of the highlights of recent progress and what should investors be looking for, for the rest of 2026. And then obviously, we'll dive into specific programs and your exciting new data.

Thanks, Joe. Thanks for inviting us to attend the conference this year. Yes, I think as we look at really over the next 18 months, I think the key takeaways are we have a growing existing commercial business, reported double-digit annual growth last year, expect that to continue as we move into -- moving forward.

And then if you think about where we are or will be over the next 18 months, we released our ralinepag data today, which I know we're going to talk about, but we're poised to launch the best drug in PAH. We're poised to launch the best drug, which is Tyvaso in IPF. And then as we announced on our earnings call last week, we think we'll have the best and most well-tolerated drug delivery device for inhaled therapies across multiple indications. And so that just really, I think, positions us really nice for significant growth as we move out to the rest of the decade.

Great. And maybe we'll start with the ralinepag data that you announced this morning. Obviously, we saw the 55% reduction in headline. Maybe if you could just kind of recap the data. What are the highlights of the release this morning? And obviously, Uptravi was always used as sort of a comparison, but how should we think about these 2 trials?

Yes. So we were, frankly, pleasantly surprised with how robust the data was. I think one of the things that came through, if you happen to listen to our call this morning, came through multiple times was the idea of how contemporary this patient population was. We had over 80% or around 80% of the patients on dual background therapy, which was what we see in clinical practice. You mentioned the 55% reduction in risk of clinical worsening, which we think is very significant. You had patients that were on ralinepag had a delay of disease progression 3x better than what you saw on placebo with the dual therapy. You had about a 50% chance of actually seeing clinical improvement, which is something we haven't really seen in pulmonary hypertension.

The other thing that I thought was really important was the durability, the benefit we saw going out to at least 4 years, which is something that's, I think, pretty impressive and great for patients. And then lastly, seems to be well tolerated. So just from our standpoint, we think it's a home run, and we're looking forward to working with the FDA to get it approved and then out into the market to help patients.

And maybe how do you expect this to be incorporated into the treatment paradigm? Obviously, it does have the more convenient dosing than both Uptravi and Orenitram with the differences in the activity that we just saw. I guess, is this going to be sort of the first prostacyclin oral, the first branded oral? How do we think about how this is going to fold in?

Yes. So we had Dr. [indiscernible], who was our top enroller in the U.S. on our call this morning. And I think he summarized it really well, which is it's going to be a frontline -- first-line prostacyclin after AMBITION and very soon after AMBITION. So he talked about the idea that he would start patients in AMBITION or if we had patients on AMBITION really as quickly as within a month at ralinepag. And so we think this has the potential and will be the new standard of care for pulmonary arterial hypertension.

And when you think about what that value is, and we'll see if you answer it. But I guess, how big of a drug do you think this could be? Obviously, Uptravi has done very well. Orenitram has done very well. It's around $500 million-ish, I guess, a year expected. Kind of where do you think this will fall?

We think this has an opportunity to be a blockbuster and our biggest product in pulmonary hypertension. If you think about the landscape right now, you've got about 30,000 patients not currently on a prostacyclin therapy, right? So just right there, and again, as Dr. [indiscernible] said, those patients should all -- really all be on ralinepag.

So you've got a pretty big addressable capturable market. And so as we kind of look at what the opportunities are launching hopefully middle of next year, we think by 2030, we could be upwards of around $2 billion with just ralinepag.

Great. And maybe to talk a little bit about the PAH market in general and how that's been changing over the past couple of years. I guess, first, anything else that we left off on ralinepag that you wanted to emphasize given the newness?

Just the last point, I guess, I should have -- when we think about pricing because that question has come up a lot, I think we think about pricing to be pretty comparable to existing prostacyclin therapies.

Great. And maybe on the PAH business, how have you seen this change? We've obviously had the introduction of sotatercept. We've had the introduction of Liquidia's Yutrepia. I guess how has the Tyvaso and the prostacyclin market for you or branded drugs changed since the launch of either of these? And then maybe we'll get into your unveiling from last week as well.

Sure. I think if you kind of go back over the last couple of years, I think we've had nice double-digit growth. That's continued. As we said on the call last week, we expect that to continue going forward. Haven't really seen much of an impact, I think, from sotatercept in terms of utilization of our therapies. In fact, when you dig into their trial data, you actually see there appears to be some sort of synergistic effect between prostacyclin and sotatercept. The patients that were on both of those drugs had really favorable results in their trial data. And so largely, we're seeing sotatercept used as it was in the trial and no real impact to any of our prostacyclin products.

Liquidia launched their product last year, we talked at the time and have over the last couple of quarters. I think given some of the statements and claims they were making, it's not surprising that physicians wanted to try a new agent or try a new product. So we did go through this trialing period. I think over -- really over the last couple of months, I think what we've seen is that the physicians are starting to figure out what's real and what's not with respect to their product. I would say while we saw an initial dip in referrals after their launch, really by the end of the summer, that started to trend back up.

As we reported on the call last week, our referrals or our prescriptions for the last 3 of the last 4 months for DPI are at prelaunch, pre-Liquidia launch levels. Nebulizer referrals for the last month are now back up at pre-Liquidia launch levels. And then really in the last 4 to 5 weeks, we've seen the starts pull through. I described last week that we do typically see some seasonality in the fourth quarter with respect to starts, and we saw that. And so while the referrals were coming in at a healthy clip, the starts were a little bit slow to follow. But in the last 3 to 4 weeks, we've seen that log jam break and the starts are now really over the last few weeks back where we were last spring.

Great. And then obviously, on the call last week, unveiled the soft mist inhaler. Maybe before we get into how that's going to fold into the treatment paradigm, what sort of data do you have in-house to support the competitive profile or differentiation versus maybe your dry powder inhalers? And when will we see some of that data?

Sure. So we started working on this about 2 years ago. We conducted our first healthy volunteer study cohort second half of last year. And that data looked really good. And I think Martin reported last week that we saw a 90% reduction in cough, which is the #1 side effect with dry powder inhalers. And so very encouraged by that data. And we still have to do some more studies in healthy volunteers to prove out PK bioequivalence. So that work is ongoing right now, and we expect to file for FDA for approval by the end of the year.

Great. And those bioequivalence and stability studies that you need for approval, I guess, does anything need to be done in PAH patients? Or can you get that done with healthy volunteers?

The FDA has told us thus far that all we need is healthy volunteers.

Great. And if this is approved, how do you expect the Tyvaso-based business to be impacted? Would everyone kind of flip to the softness inhaler? And I guess same for Liquidia when you think about just the overall impact to DPIs, what proportion do you think is going to be on nebulized Tyvaso, Tyvaso DPI and the TresMi?

Yes. So what I would expect is that nebulized Tyvaso probably goes somewhere close to 0. Nothing ever really goes to 0. But I think the difference -- the softness inhaler and the nebulizer are very close in terms of drug delivery. And I think patients -- and doctors are certainly going to prefer 1 breath 4 times a day than doing anywhere from 9 to 15 breaths 4 times a day, not to mention the fact that the SMI is a much smaller device. So not quite as small as the DPI, but certainly smaller than the nebulizer. So I think SMI trumps a nebulizer.

I do think it's probably going to be preferred over the DPI as well. I think there will still be a market for DPI, but I think it is going to be the preferred option for inhaled delivery.

And maybe...

Just MannKind put up the chart in their presentation about I guess the only approved softness type inhaler was Spiriva. And I guess that was basically 50% penetration over it's time. What's different, the same? How you think about that as an analogy, both the technology and/or the market of [indiscernible].

Yes. I think it's -- we'll prove this out when we do the healthy volunteer study is going to be -- I think it's going to be the side effect profile, right? So I think when we do this next trial, we look at the data, and we do see a striking difference in cough. I think that's really going to be what turns things.

And then the next thing to fold in is, obviously, with Insmed, the potential once-daily administration therapies, Martine has indicated that UT themselves are also advancing a once-daily inhaled therapy. How do you think that will compare to TresMi? And kind of when can we expect an update from your once-daily drug?

Yes. So we'll have more to say on the once-daily drug later this year. I think what we've said pretty consistently is we want to get through these filings for IPF and for ralinepag and then we'll start to talk about the once-daily inhaled therapy. Assuming that works, and we're very confident that it will work, I think that once daily will trump 4 times a day. I mean just pretty simple.

And maybe if we go to IPF now because that's the next data set to read out. Obviously, you saw really strong data from TETON 2, TETON 1 is coming out now. I guess when we look at the background and baseline characteristics between TETON 2 and TETON outside of the geographical differences, I guess, any reason why this study wouldn't replicate? And kind of what are your expectations for the top line release?

We don't think so. I mean, as you mentioned, the baseline characteristics between the 2 studies are very similar. The trial design is the same. So we -- I guess there's always a wildcard in there, but we remain, I think, very, very confident that we will have a positive readout along the lines of what we saw for TETON 2.

And what do you anticipate sharing in the top line release? Because obviously, with the 2 studies, there's also the opportunity to maybe show some additional data on subsets or mortality or things like that. What would make sense for the top line? And maybe what would be you save for ATS or something else like that?

Yes. I think the baseline assumption is what we did for TETON 2, right? So you'll probably see that level of data in the top line. And then we'll follow on later at a medical conference with additional data.

And then how long after the data could you file the sNDA? I know the company was anticipating meeting with the FDA for potential accelerated filing paths or review paths. I guess when could we hear the outcomes of those discussions? And how fast do you think this could get on the market?

So our internal plan is to file by the middle of the summer with the FDA. We continue to have discussions and explore options for an accelerated approval, but I don't have any updates for you at this point.

And I guess, how large of an opportunity do you think IPF is for Tyvaso? And where do you see it fitting in? Obviously, it showed that 50-milliliter decline no matter if you were on no background, OFEV, Esbriet. I guess where do you think physicians are going to use it based on your discussions? And how big of a growth opportunity is this?

Sure. So I think if you look at the IPF market in the U.S., it's roughly 100,000 patients, maybe a little bit more than that actually. So you're talking about a patient population that's twice the size of PAH. So really, I think -- and still an area of unmet need despite the fact that there's, I guess, 3 drugs in the market.

So I think in terms of utilization, we just hosted an advisory board with 15 of the top KOLs in the country a few weeks ago. And I think their general sense of things is that, one, this becomes a polypharmacy market. And they think that the dominant drugs will be neurendomalast and Tyvaso. And so you'll see patients on a combination therapy of those 2 drugs.

Sequencing of that, I think, is going to be a little bit patient dependent, but I think the other point they made is it probably doesn't matter because if I start on one, I'm going to add the second pretty quickly thereafter.

And would the softness inhaler also benefit from an approval in IPF? Or how would you potentially incorporate that to this label?

So we've not had discussions with the FDA yet on SMI and IPF. We'll start those conversations again after we get the filings in, in the summertime.

And are you seeing any off-label benefit from the data you presented so far, either in patients with PH IPF? Or do you think this is something once we have the U.S. data in hand could happen? Or do we really kind of need a label for IPF to see that?

Yes. So just to be clear, PH IPF really is PH-ILD. So that's on label. I would say we -- I think the academicians are familiar with the data. Those that like maybe are not yet because we've been pretty much embargoed until we issue -- get a publication out, which is hopefully coming here before not too long. And then at least our medical affairs teams will be able to go out and start talking about the data in greater detail.

What I think we could see in the U.S. is more aggressive screening of patients with PH-ILD because in some ways, you're going to treat the PH-ILD, you're also going to get a benefit from the IPF by doing that. So I do think that we could start to see some more aggressive screening for PH-ILD between now and approval.

I think getting off-label -- seeing a material off-label use in IPF is going to be really difficult because right now, in order for the payers to approve the drug, you have to have a right heart cath to confirm pulmonary hypertension.

And if you do get an eventual label, hopefully, in IPF, would that also be a tailwind to PH-ILD because maybe you wouldn't need a right heart cath to confirm disease, maybe you could do an echo. How would that -- do you think that's going to be a tailwind to the PH-ILD opportunity for that reason?

I think it will be -- I think we'll see a tailwind for PH-ILD. It's going to depend on the subset because ILD is a really broad patient population. So our initial indication in IPF is going to be a subset of that. So I think clearly, if the patients have IPF, you'll be able to start them on Tyvaso without a right heart cath. If they aren't diagnosed with IPF as a subset, you probably will still need to do a right heart cath in order to get it approved.

Okay. Great. And obviously, since the TETON 2 study was run in Europe, I guess, what are your discussions and plans kind of ex U.S. for Tyvaso? And I know Martine has kind of alluded to potential global partnerships on the last 2 calls. How do we think about that?

So we designed the trials to support approval in Europe. That's part of one of the reasons we ran 2 trials. So we're continuing to -- right now, we're focused on the U.S. approval, getting that filing in and getting it approved. I think after that, we'll start to take a look at opportunities in Europe.

I think one of the things that we're obviously mindful of is some of the most favored nation policies that are coming out of the Trump administration and how that could potentially impact pricing in the U.S. So we're very interested in exploring approval outside the U.S., but still some work to be done there.

And maybe can you give us an update on the progress of the PPF study? I think the company has indicated this could be an additional 60,000 patient opportunity in the U.S. Is that still the case? And when can we see data from that trial?

Sure. So we started that trial, I think it was last year. We're about 50% enrolled. And so that's been enrolling -- that trial has been enrolling at a really nice clip. So we're really enthusiastic and optimistic about the success of that trial.

The patient population, I think 60,000 is conservative, to be honest. I think depending on who you talk to, say it could be as much as 200,000, but somewhere in that range. But again, just another really kind of virgin market for us with no great therapies. I mean there's 1 or 2 that are out there, but I think it's still an area of unmet need. And so we're excited about the potential that Tyvaso can bring to those patients.

And maybe rounding out the Tyvaso conversation, maybe how penetrated are you right now, you think, into the PH-ILD market? And obviously, we indicated some of the issues with the right heart catheterization. I guess, how much of that can be the team just really educating and pushing sites to do more right heart caths? Or what sort of peak penetration do you think you can get to?

Yes. I think we're probably at around 15% to 20% right now. And I think coming back to your question about the tailwind potentially from IPF, that's where I think this can really help us out in PH-ILD because I still think the majority of patients are being referred to PAH clinics. The PH-ILD patients are being referred to PAH clinics. I mean we are increasing the number of treaters in ILD.

I think as those physicians start to get more experience using Tyvaso with their IPF patients, they're going to be more inclined to start, again, more aggressively screening and treating the PH-ILD patients that don't -- that aren't a subset -- in the IPF subset.

Okay. Great. And maybe before we get to xenotransplantation, we'll circle back maybe on some -- obviously, with ralinepag, you brought that into -- through business development, a lot of the opportunities we're touching on for the first 20-plus minutes here, you're going to have some pretty good cash flows generated over the coming years. I guess, are you interested in BD? Kind of how are you thinking about how to use maybe some of these funds?

Sure. I'm going to let my colleague here, James...

Thank you. Yes. So BD is something that is always on our radar screen. But we -- as we've talked about, what we try and be as good financial stewards of investors' money. But the areas where we tend to focus on are pulmonary, cardiopulmonary, even oncology, we've talked about. So as part of, Joe, our capital allocation priorities that I know we talked about, just as a quick review for those listening. We first focus on internal research and development and also our facilities. It's kind of our first priority. We always want to make sure we have enough capital to make sure we can execute against the programs and R&D programs we've talked about, including things like ralinepag today.

The second thing is corporate development. So as I talked about, we do look at opportunities often. We also don't feel we have the need to rush out to bring in an asset. And we've talked about AVA Outcomes in ralinepag today. the TETON trials in IPF. And so we have a lot of conviction in our internal programs and to bring something in and displace what's on our plate is something that we evaluate very carefully. So we do evaluate opportunities often. We don't feel the need to rush out.

And then the third item is return of capital to investors. As we put in our 10-K that we just filed last week, we did wrap up the most recent $1 billion share repurchase that we felt went very well. And I think going forward, what people can expect is us to continue to evaluate this waterfall of capital allocation priorities, including, I think, where you started with corporate development.

And the last thing I would say on corporate development is we have a tremendous amount of resources internally from Michael's commercial teams to clinical development teams to manufacturing. and regulatory. So when we look at opportunities, we want to make sure, first, there's scientific validity to an opportunity, and then we kind of match it up against our internal resources that we do have a lot of confidence in. And again, you're seeing some of that play out in the recent clinical trial unblindings.

So overall, we just want to be good stewards of capital. And I think people can expect going forward the same capital allocation priorities.

Great. And maybe we'll move over to xenotransplantation. If you could just kind of hit on the first study that's entering the clinic now in the kidneys. What's the current status of the program? How many transplanted patients would you like to have data on before maybe releasing that to publicly?

Sure. So we started our 10-gene xeno kidney trial in the fall of last year. We've now enrolled 2 patients. And the way the FDA has asked us to do the trial is enroll -- transplant the first patient, wait 12 weeks, do the second patient, wait 12 weeks, and then we can do patients 3 through 6. And then after we have data on 6 patients, we'll go back to the FDA, share that information with them. And then per the trial, they said that the full trial is up to 50 patients. But I think after looking at the data for the first 6, they'll tell us what that number is. So it could be something less than 50.

So because it's a clinical trial, privacy concerns with the patients, we're not going to provide regular updates on the patients and how they're doing. I think the next update you can expect from us is after we get those 6 patients enrolled and have that discussion with the FDA.

Great. And what is derisking for these patients? Obviously, you can get immediate rejection, which obviously you've shown these patients can be followed for quite some time. And then maybe there's this sort of next acute stage and then there's kind of chronic acceptance of the tissue. I guess how long is long enough to know that this organ is making a difference for these patients?

Yes. I think 6 months for the trial.

Okay. Great. And how large of an opportunity do you think this could be when you look at the number of patients this could address? And maybe what's your current footprint on the xeno side of things?

Sure. So the -- I mean, the opportunity is massive. You have about 0.5 million patients with end-stage renal disease that aren't even eligible for -- to be on the transplant list. So massive opportunity. Just as a reminder, the eligibility criteria for our trial are patients that aren't eligible to be on the transplant list or are expected -- or on the list aren't expected to get a transplant within -- or have been on for 5 years, right? They've been on for 5 years or not on the transplant list. So I think the opportunity is there.

In terms of our footprint, we have one, what we call a designated pathogen-free facility that we opened last year in Virginia. And that's what we're using to source the organs for a clinical trial. Once we're commercial, we'll also be able to source organs for commercialization. And then we will open 2 more designated pathogen-free facilities this year. And then as we see how the trial goes, our strategy is continue to open up more facilities across -- strategically across the country to get the facilities near the transplant centers that we think are going to be performing these surgeries.

And maybe on that last point, can you talk a little bit about the reception that you've seen so far to sites wanting to participate in the study? And are they seeing this as sort of a bridge to allo transplant or more of a hopefully permanent cure for some patients?

Yes. I think the receptivity has been really good. Now so far, we're just doing transplants at one site, but we will -- I think once we get past the first 6, we'll open it up. And so I think there's certainly a lot of interest in participating in the trial. So that's not an issue. And I think based on our early conversations and ongoing conversations with the transplant surgeons, I think they see it as a potential cure. So not just a bridge, but a potential cure.

Great. And maybe we'll circle back to some announcements that you made last week as well. You indicated that you're going to take Tyvaso into PH COPD again. I guess, can you just remind us what happened the first time with PH COPD? It was kind of during COVID, I feel like there were some issues. I guess, what got you reinterested in pursuing PH COPD?

Yes. The issue -- this is called the PERFENT trial that we ran. As you said, a lot of the trial occurred during COVID. I think there are a number of issues with the trial in terms of patient selection, endpoints, dealing with COVID because a lot of the measurements were being -- of benefit were being done at home. So it was just -- it was really a challenging trial for us. And I think we learned a lot from that trial. I think we also believe that the drug works in the right subset of PH COPD patients. And so just by virtue of getting smarter about from what we learned from the prior trial, we think we've got a path to get an approval -- to have a positive study and get an approval.

Great. And maybe in the last minute here, we'll talk about Remodulin. It's held in really well kind of over the years, and the company has done well at kind of innovating new devices to kind of stay competitive there. I guess how should we think about Remodulin moving forward? Is this a stable kind of part of a PAH regimen? Or are some of these newer agents going to disrupt that? How do we watch that?

I think there's always going to be a role for parenteral, right? I think particularly as you start to look at the functional Class IV patients, the really late-stage severe patients, I think that Remodulin is going to continue to be the go-to drug for doctors in that group of patients.

Now I think what you may see is there's opportunities to -- if you can stabilize patients on Remodulin, transition them over to, say, Orenitram, we've got a couple of studies that have shown that you're able to do that. I imagine we'll be doing a Remodulin to ralinepag study now to show that you can take a stable patient on Remodulin or a severe patient on Remodulin and then transition them over to ralinepag. But I think there's always going to be some role for Remodulin in PAH.

Awesome. And with that, I think we're just about out of time. So thank you very much for the time.

Good morning, everyone, and welcome to the United Therapeutics Corporation Phase III ADVANCE OUTCOMES Clinical Trial Results Conference Call. My name is Jamie, and I will be your conference operator today. [Operator Instructions] Please also note today's event is being recorded. At this time, I'd like to turn the floor over to Mr. Harry Silvers, Investor Relations Manager at United Therapeutics.

Thank you, Jamie. Good day, everyone. It is my pleasure to welcome you to the United Therapeutics Corporation Phase III ADVANCE OUTCOMES Clinical Trial Results Conference Call. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties. We assume no obligation to update forward-looking statements.

Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products. These remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for the products is available on our website.

Accompanying me on today's call are Dr. Martine Rothblatt, Chairperson and Chief Executive Officer; Michael Benkowitz, President and Chief Operating Officer; Dr. Leigh Peterson, Executive Vice President of Product Development and Xenotransplantation; Dr. Derek Solum, our Senior Director of Product Development and Lead for the Global Advanced Outcomes Program; and Dr. Daniel Lachant, Associate Professor of Medicine at University of Rochester Medicine and one of the principal investigators on the ADVANCE Outcomes study.

Now I will turn the webcast over to Martine to begin our overview. Martine?

Thank you, Harry, and good morning, everyone. There are days for which you work your entire life, and this is that day for me and dozens of my teammates at United Therapeutics. Today is the day we announced that we proved our unique pill, ralinepag, a new chemical entity, is more than 3x likely to avoid disease progression events from pulmonary hypertension as compared to taking the standard of care background double therapy of an ETRA and a PDE-5 inhibitor.

When like me, you have a daughter with pulmonary hypertension, slashing the likelihood of disease progression is everything. This is a remarkable result, not matched in any trial of a prostacyclin or a pill that I'm aware of. This is why I call ralinepag a super prostacyclin. It is just once-a-day orally. It has greater potency, meaning receptor binding than any other prostacyclin, and it is uniquely durable in its clinical trial results that argue for frontline treatment promptly upon patient diagnosis.

It has best-in-class pharmacokinetics with the longest half-life and most stable plasma concentrations. This is what powers its once-daily dosing. No other prostacyclin or pill of any kind has ever met its clinical worsening endpoint in PAH with a hazard ratio nearly as good as the 0.5 that we unblinded today. 0.45, wow. Our clinical trial met its primary endpoint with a p-value of less than 0.0001. In addition, in our secondary endpoints, we showed a statistically significant clinical improvement compared to background therapy. And as soon as week 28, indeed, our treated group was 47% more likely to improve. Again, just speaking as a parent, this is huge.

Because ralinepag is so favorably differentiated from other prostacyclin-based pills, -- based on these pivotal trial results, I believe, if approved by the FDA, doctors will prescribe and payers will reimburse ralinepag not only in lieu of such pills, but as frontline therapy. The trial we unblinded today shows that ralinepag works in every type of subgroup that we analyzed. This gives me great confidence that it will become prescribed for tens of thousands of patients, more patients than all of our current drugs combined.

The data we are sharing today supports all patients on single or double background therapy, at least 30,000 in the U.S. alone being prescribed ralinepag as well. This is transformative for PAH, transformative for the lives of all the patients, their families and their health care teams and transformative for all of us at United Therapeutics.

Today would be the best day in the life of any biotech company. Yet I want to remind everyone that just last quarter, we unblinded our TETON trial, showing that our Tyvaso medicine had the best clinical trial results for pulmonary fibrosis of any drug ever approved by the FDA. I don't think a biotech company could be in a better position than are we. Our best-in-class news is flying information, marking the skies with solid statistical proof that in our diseases, no one has better science, technology and execution capability.

This is the day we have been working for since we began working at United Therapeutics. This is the goal we've been striving for over the past decade, proving that we have a unique proprietary pill that is well tolerated and that has proven beyond a shadow of a doubt that it is effective in multiple ways, even on top of dual background therapy. This is a wow moment for the field.

I'm now going to turn the call over to the scientist who proved this wow, our company's lead ultra-marathoner and 100-miler outcomes clinical trial leader, Dr. Derek Solum. Derek?

Thanks, Martine. It's a real privilege to be here today and to get to share these exciting results. As Martine noted, this is a project we have been working on for many, many years. And so it's great to see the fruits of our labor and to be able to share these exciting results with you. I'm going to spend just a little bit of time sort of level setting so everybody kind of remembers what the study is about because it has been a few minutes.

And so as you can see on the slide, the primary endpoint for this study is a time to first adjudicated clinical worsening event. The study was straightforward and that it was randomized 1:1. So one participant received active ralinepag for every participant that received placebo. We powered the study to find 180 adjudicated events before we could close it and the study was powered with 80% to determine a 0.65 hazard ratio in the study.

We also wanted to look at a number of important secondary endpoints that speak to the disease state and to the study results and that -- those secondary endpoints are listed on the slide. And predominantly, it's a change from baseline to week 28 in the usual suspects, the NT-proBNP, 6-minute walk distance, functional class, et cetera. We also added a very important endpoint, the clinical improvement endpoint to the study because we feel that not only do we want to demonstrate that you can delay participants disease from getting worse, but we wanted to show that it got better. And so we added this endpoint into the study.

And then there's a number of others that are listed on the slide, and I won't go into a lot of details here. But suffice it to say, we were looking at a lot of ways to determine whether or not ralinepag really demonstrated a clinically meaningful change in people who were in the study. So if we can go to the next slide. I want to kind of get a detail around what the clinical worsening definition is because it's a little complicated. It's a composite definition, and you can see in the bullets on the slide, that, that composite composed of all-cause mortality, nonelective hospital admission, and that needed to be at least 24 hours and it needed to be due to PAH.

You could have also met the definition by initiating parenteral or inhaled prostacyclin therapy. We have a disease definition, disease progression definition, which is a composite in and of itself, including a 6-minute walk distance drop of 15%, worsening of functional class or initiation of additional escalation of PAH therapy. We also added an unsatisfactory long-term clinical response criteria because for a study that goes on this long, we wanted to make sure that anybody who maintained functional Class III or IV had any drop in their 6-minute walk distance after 28 weeks of treatment would meet that definition because we really, like I said before, wanted to not just show that we could delay people from getting worse, but really getting better.

So anybody who was not improving -- we wanted to be able to allow them to move to the open-label extension study. And I emphasize that, but anybody who met the definition could move to the open-label extension to receive active ralinepag. We also moved everybody else at study closure to the open-label extension study as well. So this is the kind of key point to the study design. Now here if you go to the next slide, please.

The baseline demographics are pretty important in this study because what it really speaks to is the fact that this is a contemporary real-world study. You can see that the age at study entry is predominantly in the 50s. It predominantly affected females. And those are not huge surprises other than we're seeing participants a little bit older. You can see the time since diagnosis that overall was about 4.5 years. The specific ethnicities and races is not a real surprise, but it does speak to who we are seeing in the clinic. And so you can kind of see the breakdown there.

More importantly, if we go to the next slide, continuing the baseline demographics is I want you to kind of key in on the background therapy. And you can see that importantly, 80% of the people in the ADVANCE OUTCOMES study were on dual background therapy, predominantly in ERA and a PDE-5. 20% of those were on monotherapy. So again, ever since the publication and the AMBITION results, the community has adapted their change to start people on dual combination therapy. And so that is most of the people who were enrolled in the study were on TO background therapy. So they're a heavily pretreated population. And if you look at the baseline 6-minute walk distance, you can see that on average, participants were walking about 440 meters.

So they're meeting that low-risk criteria threshold. So this is an early disease state population. And we did stratify the study in eligibility, and you can see that one of those stratification factors was above and below 400 meters. And again, you can see that predominantly, people were walking over 400 meters.

Lastly, you can see if we look at who functional class, that the vast majority of participants were in the functional Class II category with a few functional Class III, about 1/3 of those. We did allow people who are functional Class IV, but we only had one participant who was enrolled with that criteria. So again, overall, the take-home message is that this is contemporary. This is real world. and it is the type of participants that we're seeing in the community. I also don't have a slide, but I do want to emphasize that we did want this to be real world. And so our eligibility criteria are aligned with current ERS/ESC guidelines, and we've taken into consideration the recommendations from the World Symposium. So our hemodynamic eligibility criteria meet those.

So it's really important to see that this study does really enroll the people who we're seeing in the community now. And now, Harry, if you don't mind going to the next slide, this is my favorite slide that has been sort of burned into my retinas recently. And you can see this is the Kaplan-Meier graph that shows the separation. The blue line is ralinepag, red line is placebo. And you can see that separation happens very early and then the separation between the treatment and the placebo groups is robust. It continues and it is very durable.

This Kaplan-Meier graph goes to 4 years speaking to the durability of the treatment effect. Importantly, you can see, and this was shown on the intro slide that the significance, we are so incredibly confident because this is a highly statistically significant difference with a hazard ratio of 0.45, demonstrating a 55% reduction in the risk of achieving a clinical worsening event. We couldn't be happier with these results, and it's taken us a long time to get there. But the durability and treatment effect in this heavily pretreated population really speaks volumes to how well this molecule works.

Now kind of carrying on, Harry, to the next slide, you can see the breakdown of the primary endpoint. And I gave you the definition a little bit earlier. And what you can see here is that the driver of the clinical worsening definition was disease progression. And you can see there is a threefold decrease in the number of people who had disease progression in the active treatment group. We also saw benefits of the initiation of inhaled or infused therapies and that unsatisfactory long-term clinical responders. We've done sensitivity analysis where we removed the unsatisfactory responders in this population, and we find that the numbers really don't change. It's a 0.49 hazard ratio and significance is still just as good.

We weren't surprised to see that there were not many hospitalizations or death because I want to emphasize that this is an intermediate low-risk population, heavily pretreated. So the fact that we have such low mortality across the study is really no surprise and in fact, a good thing really. Here, if you go to the next one, I want to just continue to drill down on that, the impressive results in the disease progression. Here, you can see the Kaplan-Meier graph. And again, very, very early in the treatment. Within a few weeks, you see separation between the treatment group and the placebo group, and that separation does not change. In fact, it just continues to grow. And we're really just pleased with this 4-year period that we're demonstrating here. Again, hazard ratio showing a 75% reduction in risk that is highly statistically significant. Very, very great results that we're very happy to see.

Now moving forward again, Harry, I want to just emphasize the importance of what the study results mean, and that's using this forest plot with a lot of subgroup analyses. And you can see that in the middle is the break between where we favor ralinepag on the left and placebo on the right. And I just can't emphasize enough that it doesn't matter what treatment subgroup you are in. Ralinepag still shows a highly significant difference. It doesn't matter if you're walking 400 meters or more. It doesn't matter if you are in the CTD etiology or if you have the other etiologies.

It doesn't matter if you're one background therapy or two. If you're young or old or if you're male or female, every single subgroup analysis strongly favors treatment with ralinepag, and we're just so happy to see this. Again, moving forward to more subgroup analyses, we can see that -- again, it doesn't matter if you're functional Class II, III or IV or if you're on an ERA or PDE-5 or both for that matter. We don't have a dose limit in this study, but we find that also doesn't matter that you could be on a less than 600-microgram dose or you could be over, and it still shows very significant. And it doesn't matter if you're in Brazil or France or in Singapore, all of the results geographically demonstrate that there's a nice significant benefit to being treated with ralinepag.

One more group here, if you don't mind, Harry, is to look at some of the baseline hemodynamics, and we can see that regardless of where your hemodynamics lie if your mean pressures or your PVR, we still see great benefits. And it also doesn't matter what your NT-proBNP is or how long you've had the disease. So we just emphasize that we should be adding this early in order to delay the disease from progressing. The last little group you see on this slide is the baseline risk category. So this is the low-risk category. So if you -- which breaks down into the walk, the functional class and NT-proBNP and you could either have none of those low-risk criteria or all 3, and we still show benefits just across the board, so impressive.

Moving forward just a little bit, I do want to just touch on the side effect component because we have a very robust pharmacovigilance group who's been working on this project from the beginning. And because this is a new chemical entity for us, we wanted to make sure that we didn't miss anything. And you can see that there is no surprises here. And so the adverse events that we see are the usual suspect for prostacyclins headache diarrhea, nausea, myalgia and some jaw pain. But again, not a surprise in the percentages, more in the ralinepag-treated group, but also the number is not too overwhelming. And also for a study that went on for 7 years, it's not a surprise to see these sort of numbers. So no surprises from a safety standpoint, which is great as a clinical trial. That's always one of the first things we want to make sure and just such outstanding efficacy results.

So with that in mind, I just want to dive here, if you go back to the summary slide really quick, just to really emphasize how significant the results are here that we benefited the delay in disease progression. We also have a lot of key secondary endpoints that we'll be disseminating in the coming weeks and also the safety profile is as we expect.

So with that in mind, I actually want to turn it over to a colleague and friend, Dr. Dan Lachant, who is an Associate Professor of Medicine at the University of Rochester. Dan has been on the study from the very beginning. He's the highest enroller in the United States, and he has as much experience with the molecule and with being in the study as anybody. So with that in mind, Dan?

Perfect. Thank you, Derek. So as a physician who treats pulmonary arterial hypertension, I share Martine's enthusiasm, and I'm just so very excited for these results and to be here today to talk about ralinepag. First off, I just want to thank all the patients who participated in the study, all the sites in United Therapeutics for conducting and completing this pivotal study through the COVID-19 pandemic, a very challenging time, and they came out on top with home run results.

So someone who uses a significant amount of oral and parenteral prostacyclin therapy in pulmonary hypertension, these results once again are just amazing. Based on my experience in the study, the results track with what I observed clinically. To have a once-a-day titratable prostacyclin receptor agonist with comparable or improved tolerability relative to our other oral therapies currently approved and show such an impressive reduction in clinical worsening and what's been said multiple times, a contemporarily treated cohort patients, nearly 100% on background therapy, 80% on dual combination therapy, primarily functional Class II, high baseline 6-minute walk distance. It's just -- that's what blows me away and gets me excited about this data. No other oral prostacyclin has shown such impressive results like this.

Selexipag, which showed a reduction in clinical worsening and they had a much higher risk cohort of patients, so it's easier to show that kind of a benefit and only 1/3 were on dual combination therapy. So it's really hard to extrapolate those results forward. And then subsequent trials of selexipag in the setting of dual background therapy didn't show any benefit over placebo. Oral treprostinil showed a reduction in clinical worsening, but that was more in monotherapy patients and after recent diagnosis.

So in this well-treated functional cohort with an average duration, once again, it's been said, of 4 years, ralinepag was able to reduce the risk of clinical worsening with curves diverging around week 8 to 16 and remaining separated throughout the remainder of the study. Importantly, it also showed improvement in 6-minute walk distance during a clinical worsening study, something that's very difficult to do, something that wasn't seen with the other oral prostacyclins. And even in a 6-month study, having such a high baseline to begin with makes it even more impressive that ralinepag was able to show that.

As Derek just went over, all the subgroup analyses are internally consistent with the primary findings, which is great to see that everybody benefits from the drug. Like Derek said, it doesn't matter the type of PAH. It doesn't matter where you start. It doesn't matter what your PVR is. Everybody found benefit from ralinepag. And once again, the patients are representative of non-parenterally treated patients in a traditional pulmonary hypertension clinic. If you're on background therapy, you're typically functional Class II and these etiologies of PAH is what we see in our clinic. And it just makes the results more translatable and easier to explain to patients, which is great.

And with the frequent study visits and proactive evaluation to pick up changes in the patients in the study, I'm not surprised about the clinical worsening outcomes just being clinical worsening disease progression and unsatisfactory response and that hospitalization and mortality aren't hit. And that's just because we're so attuned and good at picking up changes sooner that we don't let patients progress to that part. So I'm not surprised that there was no changes with those or no difference between the 2.

The side effects reported are also what would be expected based on the mechanism of action and similar to what we see with other prostacyclin therapies. As Derek said, we enrolled 14 patients at our site. We were able to manage side effects in all of them. No patient dropped out because of untreated side effects or inability to tolerate ralinepag, which just speaks volumes about the once-daily pharmacokinetics and tolerability -- even early on in the COVID-19 pandemic, patients who had started the study were willing to drive 10-hour round trips to continue in.

We had patients flying back from different parts of the country to complete study visits because they didn't want to give up this drug. They felt that the benefit they were experiencing was just worth it for them. And one thing is ralinepag may be showing us that prostacyclin side effects, although the pharmacokinetics definitely are better, they may be more manageable if patients actually feel clinical benefit to go along with it. So instead of just preventing clinical worsening, when patients feel improvement in their exercise capacity, side effects become more mild and easier to tolerate.

And there's been over 1,000 years of patient observation on ralinepag so far, and there have been no new unexpected side effects attributable to ralinepag. And ralinepag also has the benefit of not needing frequent lab draws to monitor blood counts or anything else. So the titration also makes it easier on patients and providers to make adjustments. Based on the current data, ralinepag has the potential to be used in many different clinical scenarios following approval, early on after initiation of combination therapy, even frontline therapy in some patients and stable patients on background therapy to prevent clinical worsening or help improve functional capacity further. The data supports its use in all those different areas.

Future studies still need to help better understand transition options for select patients who are well treated on parenteral Remodulin, potential strategies for using parenteral Remodulin to achieve higher doses of ralinepag quickly similar to strategies evaluated in the EXPEDITE study and even more exciting as a replacement for other oral prostacyclin therapies that are more burdensome in administration and have significantly more side effects, which greatly impact quality of life.

So this is just an exciting time for patients with pulmonary arterial hypertension as the number of therapeutic options continue to expand. Ralinepag does have the potential to become a preferred oral prostacyclin therapy early on. It's durable and has clinically meaningful reduction and something we all care about. The flexible titration makes it so that you can find a dose for every patient that provides benefit. And importantly, its side effect profile is just so much more favorable compared to what's currently available. And this allows it to potentially become a broader access to the prostacyclin pathway in all patients with PAH.

And now I'll turn the call back over to Martine to close.

Thank you so much, Dr. Lachant. And those -- that was like the best 360-degree coverage of everything from the trial and the treatment realities that exist today in the next few years. So again, as a parent of a patient and one who knows many, you're blessing to the field. Thank you so much, Dr. Lachant. Operator, you can now open up the call to any questions.

[Operator Instructions] Our first question today comes from Andreas Argyrides from Oppenheimer.

Congrats on these impressive results. How are you thinking about the opportunity for patients to switch from to a once daily from a twice daily given the strength of these results? And how big do you think ralinepag can really be? Again, congrats on these results.

Thank you for the question, Andreas. Derek has really the most experience with all of the dynamics of the different oral medications for treating pulmonary hypertension. So Derek, could you answer that question?

Sure, Martine. Thanks, Andreas, for the call. So I think any time you can reduce the pill burden for this patient population, I think you have a great opportunity. Like I said, the population is heavily treated. They already take a lot of medications. And I think just from a compliance that if you can reduce their pill burden, improve the patient compliance, ultimately, that's going to really speak to the durability and effect. So I think that it's -- that in itself is a big factor outside of the fact of the pharmacokinetics and the treatment effect here. And I think that was the primary point of the question.

Thanks, Derek. Andreas, another thing that I would add, again, being very close to the patients, when there is a new pill that comes out that demonstrates these sort of results in reduction of disease progression and somebody is on another pill that has not demonstrated these results, as Dr. Lachant explained, it's, I think, very highly incumbent upon the health care team to go ahead and make the switch that you're referring to. Certainly, if you put yourself in the shoes of a patient, you would ask for ralinepag.

Our next question comes from Roanna Ruiz from Leerink Partners.

I was curious, how should we think about prescriber uptake of ralinepag in PAH given how some other newer agents like sotatercept are layering into the treatment paradigm and possibly moving into earlier line use as well?

Thanks, Roanna. Since we have a great, great prescriber on the call, I'd like to ask Dr. Lachant to kindly answer that question.

Yes, that's a great question. So based on my experience with the study, based on the data that was just presented today and based on the ease of use, the way I see this playing out for a new diagnosis patient is they started on initial upon combination. And once they get situated on a steady dose, I plan on layering ralinepag next. I think it's a well-tolerated once-a-day pill. And the patient pill burden and blood draw, it just makes it easier and then other therapies would potentially be added on after that.

Our next question comes from Olivia Brayer from Cantor.

Congrats again on these results. Can you give us any details at this point around adverse event profile just in terms of severity for some of those events? And I think I heard that there were no discontinuations due to AEs. Can you just confirm if that's the case? And Martine, I just wanted to ask you kind of more broadly, as you think about the PAH market, where ralinepag really fits into your overall commercial strategy, just especially in light of last week's softness inhaler disclosure.

Sure. So for all of the first questions you asked about AE, Derek would be, I think, the best person to talk about that. Derek?

Yes, absolutely. Okay. So no, it's not true that nobody discontinued due to AEs. We did have discontinuations overall in the study was allowed 11%, less than 10% in the active group. So much better than the other pivotal trials in the space. The AE profile is very consistent with other prostacyclins, and I showed that kind of at the end with headache, nausea and myalgias are kind of the lead AEs. So ultimately, I think that the profile matches the long half-life and allows us to kind of titrate into a treatment effect that avoids the severe AEs. We've collected a lot of data around that, and we'll be disseminating that in the future around -- in the granularity around the age. But like I said, there was no safety signals that were unsurprising here.

Thanks, Derek. Olivia, with regard to the amazing product we announced last week of Tresmi, the way to think about pulmonary hypertension, at least the way we think about it is inhaled is a very different kind of situation from the rest of PAH. And inhaled is primarily focused on the ILD population, where there's been a legacy of data contraindicating systemic treatments. So we see that the Tresmi product is perfect for the ILD population where it can reduce by up to 90%. The main side effect causing people using DPIs to discontinue or even not to really start. We think that the SMIs can cover that entire space.

There are -- there is a portion of the non-ILD population that does use inhaled therapy. But now that it's available to have just a once-a-day pill, it would be kind of like I mean, there will always be some people using every type of therapy. But I think from the patient's perspective, the prescribers' perspective, it will be much better just to take one pill once a day than to go ahead and deal with a multiple times a day inhalation.

I should also mention at this point, Olivia, that in our Skunk Works division, where we develop new products like the SMI that we announced, we are also working on a once-a-day combination pill that would combine the ETRA PDE-5 as well as ralinepag. So just in a single dosage, the patient can get all of that. And that will be more formally announced as we move a little bit deeper into the year.

Our next question comes from Roger Song from Jefferies.

Congrats for the data as well. My question may be related to the access and then reimbursement ramp. So how should we think about this data mostly in the intermediate risk seems more suitable for earlier stage of disease? And then how should we think about this will be used as a first line versus the selexipag maybe go to a generic in the near term? And then also related to the hospitalization death impact, understanding this is a little bit lower risk population and how this profile will impact the payer decision?

Well, there's a lot of questions there, and there's so many people on the line. We're only going to really take a subset of all of them. I'd like to ask Dr. Lachant to respond as best you could to the array of questions basically relating to how you expect to use ralinepag in your practice.

Yes. So ralinepag and it's kind of like how we think of statin therapy is when you're preventing clinical worsening, you're preventing somebody from experiencing something they don't know would have happened. So because of that, it's better to start it earlier when they're well. So once again, prostacyclin pathway is a pillar in pulmonary arterial hypertension. So having an easy well-tolerated medication that can target that pathway, even if you start out at lower doses and titrate up over 6 months, I feel like it will provide great benefit to patients. So for me, the way I'm going to start looking at this once it gets FDA approval is offer it to patients 1 month after diagnosis saying this is something that's going to pay dividends in the future. I don't care about 1, 3 years. I'm caring about 10, 15, 20 years down the road. So -- and if the best way to maximize this is to start early, that's what I'm going to offer to patients.

Thank you, Dr. Lachant. I'll just add like one more comment with regard to your question, Jason, about selexipag going generic. I think it's completely irrelevant. This is like -- this data is much better than the data that came out of the GRIPHON study. And we saw exactly the same situation when sildenafil went generic. We were selling branded Cialis Tadalafil, and we called it Adcirca. And when it was, again, much simpler for the patients to take once a day instead of multiple times a day, amazing data. And the vast majority of the prescriptions went to Adcirca. And sildenafil going generic was an irrelevant data point. And I think the same situation will be the case with selexipag. It will simply become irrelevant in terms of the prescribing patterns of physicians in this field.

Our next question comes from Lisa Walter from RBC.

On the results today. Just curious, maybe a question for Dr. Lachant, if he's still on the line. Wondering if you can expand how you would use ralinepag in your patients in your practice today if the drug was ultimately approved. Would you start this in new patients? Would you switch over existing patients from other treatments? Any color here would be helpful.

Thanks. Dr. Lachant?

Yes, great question. So, yes, I would certainly start it in all my new patients 1 month after just getting the other therapies on board just to minimize side effects as you're starting a drug, you don't want to blast necessarily right away and just get things cooled down. To your question about transitioning, as Martine said, and I agree 100%, just like we figured out how to transition patients from selexipag to Orenitram, I would start doing that early in patients who are well compensated lower doses of oral prostacyclins. I would offer ralinepag as a potential option for them.

And then as further data comes out and we figure out how to transition from stable Remodulin and things like that, -- my personal experience, we had one person who was on ralinepag who had to go on Remodulin because of clinical worsening. And the doses that person achieved was astronomically high without any Remodulin side effects. And to be honest, I don't think the person improved after we put them on Remodulin. So I'm not sure we really did them a favor. We followed what we thought was the best decision, but I don't know if it was the best for the patient. And ralinepag just has a very potent receptor profile. And because of that, you get benefit that almost all patients, like Martine said, not every patient, but a lot of patients will be able to benefit from.

Our next question comes from Jason Gerberry from Bank of America.

On the data. Wondering, I think you guys in a prior call mentioned running studies with prostacyclins in combination with Winrevair in early patients. Given kind of how you framed SMI versus ralinepag, is it fair to think that any future combination studies with Winrevair would be with ralinepag and not SMI? And your comment about only a small portion of, I think, inhaled sales coming from non-ILD settings. I think in the past, there was something like a 50-50 kind of revenue split or understanding of PAH versus PH-ILD. So just wondering how 2025, if you can kind of give us an update on how that revenue split looked.

So because we're going to focus this call on ralinepag, I'm going to skip over the revenue split question, which was kind of a little bit convoluted anyway. So just going right to the combination with Winrevair, yes, in fact, our discussions with its sponsor have focused on ralinepag as being the most logical agent to combine it with.

Our next question comes from Terence Flynn from Morgan Stanley.

On the data. One for Dr. Lachant. I was just wondering if you look at your potential ralinepag use on the forward, if you think you'll use it in a similar number of patients or more patients than your current number of patients on Uptravi and Orenitram combined. So just trying to understand if you see this expanding the oral market or ultimately, over time, if you're going to have a similar number of patients on oral prostacyclins.

I think this is greatly going to expand the oral prostacyclin market. There are many patients who we kind of talk about saying, oh, this first would be great for an oral prostacyclin -- but because of their milder disease status, we just say the quality of life impact sometimes isn't worth it. And so in some fraction, I can't give it to you maybe 15%, 20% of patients where we're like an oral prostacyclin would be good, but we just can't justify it. This is exactly where ralinepag will fill that market and expand who can actually get treatment through the prostacyclin pathway.

Perfect. Thank you so much, Dr. Lachant. All right. Well, I think that wraps up all the questions in the queue here. And by way of summary, I want to thank Derek and his team, Dr. Lachant and all of the other investigators. This is some really extraordinary science that we've been able to share with everybody today. And it's -- it's especially amazing for me because so often in business, timing is everything. And here, as was elucidated in the call, selexipag did their trial at a time when there was one background therapy, predominantly a PDE-5 inhibitor and the era of dual background therapies was kind of just over the horizon.

So they were not really able to enroll very much in the trial in the dual background therapies. And as Dr. Lachant explained, as the years rolled on, it was later shown that it really was not that effective in the dual background therapy arena. Whereas today, dual background therapy is all but universal and the timing of this advanced outcomes therapy was just like a great surfer catching a great wave.

We caught the dual background therapy wave perfectly with the timing of the enrollment of ralinepag. And as a result, we have a best-in-class result, extraordinary efficacy, hazard ratio not seen in any other drugs and all of this on top of the real reality that is in pulmonary hypertension today and very likely to be the reality of background therapy for the next decade to come.

So I just want to thank everybody for all of their contribution to the study. Of course, I'm huge gratitude to all of the patients from throughout the world Derek has traveled in an insane number of miles around the world enrolling the study. Just to give you a couple of anecdotes, there is a patient who has been on ralinepag now for 12 years, doing very well, and that patient is in the Ukraine.

So the patient was a Phase II patient who rolled over on to open-label therapy. Derek and his team have been adamant about making sure that every patient on open label and of course, in the trial itself gets their therapy no matter what. So through the war in Ukraine, this patient has been delivered their medicine and 12 years, still doing very well. Similar situation for patients in [ Israel ] through the course there, as Derek mentioned, through COVID. It's just an amazing, amazing execution of a trial, and I cannot give higher kudos to the physicians, the patients, all of the clinical trial team. We had well over 100 unitarians, United Therapeutics employees are dedicating themselves to this for years and years and years.

Thank you, everybody, for listening. And operator, you can now wrap up the call.

Thank you for participating in today's webcast. A rebroadcast of this webcast will be available for replay for 1 year by visiting the Events and Presentations section of the United Therapeutics Investor Relations website at ir.unither.com. Again, that is ir.unither.com. Thank you for joining. You may now disconnect your lines.

Good morning, everyone, and welcome to the United Therapeutics Corporation Fourth Quarter 2025 Corporate Update Conference Call. My name is Jamie, and I will be your conference operator today. [Operator Instructions] Please also note today's event is being recorded.

At this time, I'd like to turn the webcast over to Harry Silvers, Investor Relations Manager at United Therapeutics.

Thank you, Jamie.

Good morning. It is my pleasure to welcome you to the United Therapeutics Corporation Fourth Quarter 2025 Corporate Update Webcast. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties. We assume no obligation to update forward-looking statements. Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products. These remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for the products is available on our website.

Accompanying me on today's call are Dr. Martine Rothblatt, our Chairperson and Chief Executive Officer; Michael Benkowitz, our President and Chief Operating Officer; James Edgemond, our Chief Financial Officer and Treasurer; Dr. Leigh Peterson, our Executive Vice President of Product Development and Xenotransplantation; and Pat Poisson, our Executive Vice President of Strategic Development.

Note that Michael Benkowitz, James Edgemond and I will participate in a fireside chat and one-on-one meetings at the TD Cowen 46th Annual Healthcare Conference in Boston on March 2. Additionally, Martine Rothblatt, James and I will be at the Leerink Global Healthcare Conference in Miami on March 9 for a fireside chat and one-on-one meetings. Finally, James and I will also participate in one-on-one meetings at the UBS Biotech Summit in Miami on March 10. Our scientific, commercial and medical affairs teams will be present at the 21st Annual John Vane Memorial Symposia in London, March 13 and 14, and at the International Society for Heart & Lung Transplantation in Toronto, April 22 to 25.

Now I will turn the webcast over to Martine for an overview of our development pipeline and business activities.

Martine?

Thank you, Harry. Good morning, everyone. Today, I'm going to share with you news that transforms the fields of pulmonary hypertension and IPF. This news is our unsheathing of a category killer product called [ Tresmi. ] This product is a revolutionary proprietary drug device formulation of treprostinil into a soft mist inhaler. It will reduce the #1 side effect of dry powder inhalers, which is coughing by up to 90% based on the human studies we've done so far. And we intend to file for its approval in PAH and ILD this year and commercially launch it next year. The days of people discontinuing their PAH or ILD therapy due to cough will be over. Anyone would rather have soft mist than dry powder.

Also transformative for our markets will be the unblinding of our outcome study next week. We are optimistic that this unblinding will usher in a new era of once-a-day treatments for pulmonary hypertension. The reason we can promise once-a-day treatment is because the new medicine is a super prostacyclin. It is a super prostacyclin because it lasts much longer and binds molecules much more efficiently than all other approved forms of prostacyclin. Hence, between our super prostacyclin once-daily pill and our cough less soft mist inhaler, or SMI, we have solved the two biggest problems in our diseases, cough and dose frequency.

Also very exciting is our unblinding next month of our second pivotal trial of Tyvaso for IPF. You'll recall from last quarter that our first pivotal trial showed Tyvaso to be much better than any other IPF drug the FDA has ever approved. With confirmation of those results next month, we'll quickly file for approval and commercially launch into IPF not later than June of 2027.

In summary, for 2027, we should have three disease transformative paradigm-shattering commercial launches: one, a once-daily super prostacyclin for PAH; two, a category crushing [ Tresmi ] coughless inhaler for ILD; and three, a better than everything new treatment for IPF.

Hell, yes, we are pumped.

Now let me review some of the other major management areas that I track as CEO. We are religious about revenue growth at UT. And Mike Benkowitz...

Good morning, everyone.

2025 marked another year of record-breaking revenue, driven by double-digit percent revenue growth from Tyvaso and Orenitram, leading to [ 11% ] total revenue growth over full year 2024 and surpassing $3 billion in total revenue for the first time in our history. For the fourth quarter, we recorded $790 million in total revenue, representing 7% growth from the fourth quarter of 2024. We have pointed out in the past and continue to remind investors of our historical seasonal revenue trends where the first quarter and fourth quarter tend to be lighter ordering quarters, while the second quarter and third quarter tend to be heavier ordering quarters.

As such, sales in the short term can vary depending on the timing and magnitude of orders from our specialty pharmaceutical distributors and may not precisely reflect patient demand or changes in patient census. Turning to Tyvaso. Total revenue for the fourth quarter was $464 million, a 12% increase over the previous year, underpinned by robust 24% year-over-year growth in Tyvaso DPI. This impressive trajectory reflects our strategic positioning in a large and growing addressable but uncaptured market in PAH and PH-ILD, where we are steadily increasing our share of voice and expect to continue delivering double-digit growth. Through mid-February of this year, our rate of referrals for total Tyvaso was at its highest level in two years.

Notably, the referral rate in 3 of the last 4 months was at or above where we were heading into a competitive launch early summer of last year. This continued strength in the underlying fundamentals reflects the disciplined execution of our teams who continue to reinforce our message. And we expect this momentum to continue throughout the year as the many attributes of Tyvaso DPI position the device for sustainable long-term growth. We are constantly striving to enhance our Tyvaso DPI platform, which we believe will help us solidify and grow our position as the preferred inhaled prostacyclin therapy. We recently introduced 80-microgram cartridges, which enable delivery of the equivalent of 15 nebulized treprostinil breaths in a single DPI breath as well as 96 and 112-microgram combination kits.

This advancement strengthens Tyvaso DPI's differentiation in the pulmonary hypertension market by improving convenience and expanding dosing flexibility, which we believe can support broader adoption and longer-term growth while streamlining access and affordability for patients with more advanced dosing needs. Moreover, we believe the consistency of flow rate and delivery with our DPI device and its low inspiratory flow requirements further differentiates our platform. Turning to Orenitram and Remodulin. Last month at the Pulmonary Vascular Research Institute Annual Congress in Dublin, our medical affairs teams presented data from the ongoing [ ARTISAN ] study, examining the effect of early and rapid treprostinil therapy on mean pulmonary arterial pressure, or mPAP, and the reduction to improve right ventricular function in PAH.

Preliminary data suggests that early initiation of high-dose treprostinil therapy represents a feasible strategy for reducing mPAP and improving right ventricular structure and function. These data further reinforce the significant benefits that can be achieved from Orenitram and Remodulin, which remain backbones to treprostinil-based therapy in treating pulmonary hypertension and are strong foundational pieces to our commercial business.

To close, we are proud of the exceptional drive and relentless focus of our teams who remain deeply committed to making a real difference for the patients we serve. Building on the strength of this past year, we expect this foundation will continue to support durable double-digit growth and ongoing success over the long term.

With that, I'll turn things back to Martine to run the Q&A.

Michael, thanks so much for that great review of our religious dedication to strong revenue growth...

Operator, maybe we could go to the first question in the queue.

[Operator Instructions] Our first question today comes from Ash Verma from UBS.

So just on TETON 1 data coming up, I wanted to understand your level of confidence here in a positive study for IPF. I know you're very confident ahead of the TETON 2 study, but just in terms of how you're thinking about for this second study, I would love to get your thoughts. And then secondly, it seems like this question keeps coming up, just the impact from Yutrepia. I know previously, you talked about that this is -- there was a give it a try dynamic. But just what are you seeing latest in terms of the patient adds for DPI or nebulizer and if there is any impact from the competitor?

Yes. I'll go ahead. This is Leigh Peterson, and I will go ahead and answer the first question about expectations for TETON 1 and yes, just to reinforce that we are extremely encouraged by the TETON 2 results. And we're really optimistic that we can show a treatment effect in the TETON 1 study as well, particularly since we did see such a robust effect in TETON 2 and that the TETON 1 and TETON 2 study population are relatively similar with regards to the baseline characteristics. So we're confident that the TETON 2 results will translate to a second successful study.

Operator, it seems like we lost Martine and Michael.

We have Martine rejoining. Martine, this is the conference operator. You joined into the live conference. Your line just dropped here recently. We rejoined you back in. Your line is live.

Okay. I'm sorry, everybody, the conference operator messed up the conference call. And I think, Mike, were you able to get your entire presentation through before you got dropped?

I think so. I'm not sure if anybody heard me.

Okay. Well, why don't we start back up? We'll go over 9:30. And why don't we start back up around the time I think that was dropped. And then Mike, if you don't mind redoing your presentation after I continue. Is that okay?

Yes, Martine, I think I just -- we just confirmed that everybody heard my presentation.

Okay. Good. Well, I'll pick up from when I was dropped then. So everyone has just heard Mike's presentation. And I think it confirms what we've been saying to everybody is our commitment to double-digit revenue growth. I'm going to continue from the point that I got dropped by the call to say, in addition to all of the fantastic success that Mike and his team have delivered in terms of revenues that we at UT are also fanatical about new product development because we never like to rest on laurels.

And Dr. Peterson, who is also on this call, is doing a superb job of product development, including the amazing new super prostacyclin and IPF medicines that I mentioned at the start. Before I dive into these new products, let me just take a moment due to the conference call error earlier, just to double check with Harry and Michael that my remarks are coming through.

Are they coming through?

Yes, we got you, Martine.

Okay. Sorry for the interruption, but like trust but verify kind of thing.

All right. So other areas that I focus on in addition to new product development are Investor Relations and business development. With regard to business development, we are now in fruitful discussions with three great pharmaceutical companies. And this is really driven by their keen interest in the proven predictive power of our AI-enabled digital lung model. Our model can run hundreds of accurate in silico Phase III trials in way less time than it takes for a single in vivo trial.

No one else has this advanced and lung-specific computational biology technology. It is great to know that the outcome of a pulmonary trial can be known before spending hundreds of millions of dollars to run it, not to mention the many years saved or gained. Transplantation is another major management focus for me, and it too is firing on all thrusters. I'm just going to -- before I go into transplantation, just let me take a moment to check again with Harry and Mike and make sure the line remains active.

Yes, we have you.

Okay. Great. The first thruster is Xeno, which has now two patients transplanted and doing well in our FDA-approved phase less clinical trial. We are on schedule to fully enroll the full 6-patient cohort by this summer. Then we'll enroll the full balance of the trial needed for registration as decided by the FDA in 2027. At this rate, we should have a commercial Xeno product on the market in 2030. The second transplant thruster is Miromatrix.

We've now fully enrolled and successfully completed the first manufactured liver clinical trial ever. We expect FDA guidance on how to take this liver failure recovery product and also our mirokidney implanted product to regulatory approval during the course of this year. Instead of me going through all of our multiple other transplant thrusters such as, for example, 3D bioprinting of kidneys and lungs, let me simply say that I felt honored to be chosen by Forbes team of experts and AIs as the eighth most innovative person in America. I feel an obligation to live up to that, and there is no company in the world manufacturing as many transplantable organs in as many different ways with as many or for that matter, any in human clinical trials as my teams at United Therapeutics.

This is life-saving innovation with very, very large. A final area of major management focus for me is our strategic clinical development group, also known as our Skunkworks or Stealth division. It is in this group that the revolutionary new [ Tresmi ] product was birthed as described at the start of the call. This is the product that will totally transform our markets by all but eliminating treprostinil's #1 reason for patient discontinuation, harsh coughing. We are unsheathing this product today because it will be filed this year for commercial launch next year. The immense power of this product is summarized in its name. Few will want to continue inhaling a dry powder when instead they can breathe a soft mist.

Other products that you'll soon see emerging from our Skunkworks division include: one, a once-daily inhaler two, PRN inhalers; three, even better pills than the once-daily ralinepag; and four, more IPF and PAH products than I can really discuss in a mass call like this because they are deeper in stealth mode. But all of these products have long IP. In summary, UT is committed to using relentless innovation and our AI-enabled digital lung model to keep producing the best, most convenient, most effective and safest products in the PAH and IPF space.

Operator, you can now open up the line for additional questions.

Our first question once again will be from Ash Verma from UBS.

Great. Sorry about what happened earlier. Just on like the TETON 1 data coming up, I wanted to get an understanding of the level of confidence you have in the IPF study outcome versus how you're feeling about TETON 2. And secondly, just wanted to get the latest on impact from Yutrepia if you're starting to see any type of patient add or competitive dynamic on the DPI or the nebulizer.

Okay. Thank you, Ash. Thanks for the question. So the first part of your question about TETON 1, we will have answered by Dr. Leigh Peterson. She is in charge of product development and in charge of the team that's running the TETON trials. And then after she finishes answering your question, then the second part of your question will be answered by Mike Benkowitz relating to marketplace dynamics between us and Yutrepia.

Dr. Peterson, could you please start?

Yes, sure. So I don't know if you all heard me the first time I said this, but I'll add a little bit more detail this time. So just to reiterate, we're extremely enthusiastic about the TETON 2 results. And we have great confidence that these results are going to be translated to a second successful study, in particular, TETON 1. The baseline characteristics of both studies are similar, relatively similar. So the possibility of the translation is really high. And again, the robust results that we saw in TETON 2 also give us confidence.

I mean, we not only saw a very good, very positive statistically significant basically primary endpoint with regard to FVC, we saw the -- as everyone know, we saw an improvement in absolute forced vital capacity of 95.6 milliliters. And we also saw significant improvements in our secondary endpoints. And so again, given these really good results, we expect similar results from TETON-1.

Perfect, Dr. Peterson. Thank you so much. Mike, I'm not sure how much they heard of the earlier discussion. So if you could just respond to Ash's question as you think.

Yes. So Ash, I think you were asking about just kind of the competitive dynamics between us and Liquidia. So what I'd say is Tyvaso remains the well-entrenched market leader for inhaled therapy in pulmonary hypertension. The health care providers consistently affirm UT's leadership position in this space. As we said, there was initial curiosity to evaluate a new market entrant, but the doctors are recognizing that the advantages of Tyvaso DPI is easy and importantly, consistent delivery in just one breath is important. Our primary market research insights and underlying demand trends support this. What we're hearing and seeing is that the belief in Liquidia's unsubstantiated claims of higher dosing, less cough, better lung deposition, lower effort is definitely weighing.

Our referrals have been at pre-Liquidia launch level -- at pre-Liquidia launch levels in 3 of the last 4 months. Our prescriber breadth and depth and patient retention is at or better to where it was before Liquidia launched. Now what we have seen is the patient starts have lagged these trends a little bit. I think that's primarily due to the typical Q4 seasonality we see as well as just kind of the cross-country severe weather we experienced in January; however, that log jam really seems to have broken in February based on what we've seen in the last 3 to 4 weeks. And I would say if these trends continue, you'd expect to see us return to sequential revenue growth no later than Q2.

Our next question comes from Roanna Ruiz from Leerink Partners.

So I thought it was a really interesting update on the soft mist inhaler product. And I was curious if you could talk a bit more about the human-based studies you've done so far and what additional features you've been optimizing for this product? And how you think physicians will react in terms of prescribing it if it's fully available and commercialized?

Yes. Thanks for your question. I think physicians will be super happy about it. It is -- as it says right in the name, it's soft mist versus dry powder. So I think physicians will be happy about it because patients will be happy about it. I think it will be equivalently effective. So why not have something that works just as good, but is easier for the patient to tolerate. We have just brought this out of stealth mode today on this call.

So this is totally really exciting news. And so many of the details we are not going to share openly. But I did want everybody to know that it was going to be filed for approval this year and then launch next year. So given the proximity of all of that, it was important to -- for us to unsheathe the product, but the -- all of the various competitive advantages of this product will remain undisclosed until we end up seeing the FDA approval.

Our next question comes from Roger Song from Jefferies.

Great. Congrats for the progress and exciting to see those three launches. Maybe the team, so I think you confirmed the double-digit growth this year. I think, Martine, you mentioned the $4 billion run rate by 2027 -- the end of 2027. Can you also comment on that kind of soft guidance? And also given those three new product launches next year, so how much contribution from those launches will contribute to the long-term growth, including the $4 billion run rate?

Yes, it's a really insightful question. So first of all, we can clearly double down on our commitment to hit that $4 billion revenue run rate next year. So it will be in the back half of the year. But if you just take our double-digit revenue growth and you roll it forward from the levels that we are at right now, you'll see that we would be hitting that $1 billion a quarter by the tail end of next year. So we're doubling down on that. It does not require the contribution of these three new product launches.

So all of that is, you could say, gravy, whip cream, whatever is your favorite metaphor. But definitely, these three product launches are going to bend the curve upwards in terms of our revenue levels beyond the $4 billion annualized rate because we were growing double digit with the great products that we currently have, the Tyvaso DPI, Orenitram, Remodulin, all of these -- Unituxin, all of these products. So above and beyond that, we've now got three more products, and these aren't just like me-too products. These are [ truly ] category crusher products. I mean the first one that can like slash way down the cough, a cough less inhaler, that's amazing.

A once-a-day super prostacyclin, that's amazing. And an IPF treatment that's better than anything the FDA has ever approved for IPF since the beginning of IPF. It does not get better than that. So like I said, we're super pumped. And I think the $4 billion revenue run rate, it's just to be the point at which the revenue curve bends even more sharply upwards.

Our next question comes from Joseph Thome from TD Cowen and Company.

Congrats on the progress. Maybe given your excitement for ralinepag, what are the most important outcomes that we should be looking at when we see those data? Is it on PVR, 6-minute walk, time to worsening event? Kind of what do you think will resonate most with physicians in addition to the dosing benefit to drive adoption there?

Yes. That's -- we love these kind of scientific questions. Dr. Peterson, the Head of Product Development, she has lived this trial for 7 years because this trial like started before COVID and persevered through COVID. So I don't think anybody knows the whole panorama of positive therapeutic benefits from this super prostacyclin than she does. So Leigh, if you could give kind of your stream of consciousness of what we can expect from this super prostacyclin and what do you think physicians will appreciate?

Yes. Sure. Happy to. So obviously, what Martine said is the most important with regard to this being a very, very potent drug. It binds the receptors, the IP receptor very tightly and has a really long half-life. And so this translates to the once-a-day dosing and potentially more tolerability. So that's definitely a bonus. But also, we're looking to -- I mean, we're looking to see the statistically significant and clinical meaningful benefit on top of that in clinical worsening versus placebo.

And as you all know from our other studies as well as this one, clinical worsening is defined with specific parameters and seeing a benefit in the number of hospitalizations as well as mortality would be a super effect to see in this product. So as Martine says, we are unblinding next week, and we are really, really looking forward to that and happy to put those results out there.

Thank you so much, Leigh. Really appreciate it. Operator, I'm getting inputs that other people are being dropped on the call, so we can close the call at this time.

Ladies and gentlemen, at this time, we will close today's conference call. We thank you for participating in today's United Therapeutics Corporation earnings webcast. A rebroadcast of this webcast will be available for replay for one week by visiting the Events and Presentations section of the United Therapeutics Investor Relations website at ir.unither.com.

We thank you for joining. You may now disconnect your lines.

Great. Good afternoon, everyone. My name is Jess Fye, large-cap biotech analyst at JPMorgan, and we're continuing the 44th Annual JPMorgan Healthcare Conference today with United Therapeutics.

I'm joined up here by the company's Chair and CEO, Dr. Martine Rothblatt, who's going to give a presentation on the business, then we're going to go into some Q&A. If you're in the room and you want to ask a question, just raise your hand, and then I'll bring you a microphone. [Operator Instructions]

So with that, let me turn it over to Martine.

Thank you, Jess. Thanks, Jess, and thanks, everybody at JPMorgan for coming to the presentation. I'm going to show quite a few slides today and say a lot of words. But I think if you leave here with just 2 words, you will understand United Therapeutics completely. And those 2 words are IPF, that's 1 word. IPF. And the second word is super-prostacyclin, that too is just 1 word, hyphenated super-prostacyclin. And I think if you just come away with those 2 words, you will understand the amazing potential that United Therapeutics has.

Now what do those 2 words mean? IPF is an acronym for idiopathic pulmonary fibrosis. And this is a fatal condition that robs patients of their ability to breathe. This IPF indication has been known to medicine for many, many decades. And in all that time, there have just been 2 medicines widely approved for that condition. One new medicine just recently approved in a couple of jurisdictions. And none of those 3 medicines has made any truly significant impact on the progression of pulmonary fibrosis.

In fact, several years ago, when I tried to purchase for United Therapeutics, the company promoting 1 of those 2 -- 1 of those medicines, a company's called [ NImmune ]. Our Scientific Advisory Board unanimously told me not to purchase the medicine because in their experience, it had such a de minimis effect on their patients with pulmonary fibrosis that company ended up being able to make a pretty good chunk of revenues with that product, but the Scientific Advisory Board's opinion, which was full of KOL pulmonologists was what it was.

The other word is super-prostacyclin. So what does that mean? Prostacyclin is an endogenous molecule, meaning it's a molecule that's made based on coding in your DNA and is absolutely essential to life. It keeps all of a person's blood vessels patent and open and free of sticky platelets and among other things, some of which science is just beginning to learn. So some like 30 or so years ago, Nobel Prize was granted to the Chairman of our Scientific Advisory Board, Sir John Vane for discovering the mechanisms of action behind prostacyclin and other drugs that act on downstream of phospholipids.

And then that same Sir John Vane in his laboratories at Burl's welcome, was able to develop a stable analog, meaning an artificial kind of tweaked version of that prostacyclin molecule. And that molecule ultimately became the bedrock of United Therapeutics. And we have turned that molecule into a number of life-saving medicines for patients. They go by the names of Remodulin, Tyvaso, Orenitram and other companies as well have developed this treprostinil molecule into good medicines for patients.

There have also been other variants of the prostacyclin molecule or the prostacyclin pathway that have been developed by other companies. And these have also been shown to be a benefit to patients with pulmonary hypertension. However, all of these various analogs at the endogenous molecule and certainly the endogenous molecule itself, have severe therapeutic pharmacokinetic and pharmodynamic limitations that don't allow them to reach the full potential of being able to give the patients the full measure of health that would be possible from modulating the prostacyclin pathway.

We at United Therapeutics have developed a next-generation prostacyclin molecule called ralinepag, which is what I call a super-prostacyclin because it has the best and far away the only truly long-lasting pharmacokinetic life. It has the most potent pharmacodynamic effect on the prostacyclin receptor pathways. And even though we will just unblind the Phase III trial within the next 3 months, it has also shown an open-label extension data from patients from that trial a physiologic effect which is above and beyond anything that we have seen with any other -- of all of these 30 years of molecules in prostacyclin.

So IPF, click. Super prostacyclin, click. You got the United Therapeutic story for the next several years. The -- we have been able to reach this threshold of developing what I believe will become quickly recognized as the best product for IPF or pulmonary fibrosis as a result of a trial that we unblinded just -- I guess, it was about 3 months ago now called the TETON 2 trial. And this trial of inhaled Tyvaso, one of our medicines in patients with IPF both patients with IPF who are on these don't work so good therapies that I mentioned earlier or on no background therapy at all had such a dramatic improvement in their forced vital capacity, which is the widely accepted measure of how well patients with pulmonary fibrosis are doing that every single physician we have spoken to key opinion leaders, everybody has said, this is a game changer in pulmonary fibrosis and feel extremely confident that this will become the most prescribed medicine in IPF.

Now just a word about IPF. Over all of these years that you see on this chart, we have received not $1 of revenue, no growth in patients, nothing from IPF. Yet it is an indication with just in the United States alone, a prevalence of about 100,000 patients, and most of them unfortunately die in just a handful of years. So I believe that we will quickly make this kind of revenue course that you see on this chart completely irrelevant by ramping Tyvaso into this completely virgin 100,000 patient population where the data shows, it is above and beyond, far better than any other medicines currently approved in that indication.

The other interesting thing to look at this chart over these past many years, you see this continued growth. All of this is with the first generation somewhat problematic prostacyclins, prostacyclin analogs, prostacyclin receptor antagonists that have been out there in the market. This is the kind of revenues the therapeutics have been able to do.

All of this past revenue growth, I think, is truly irrelevant because the vast majority of all of these patients as well as all of the patients who are not in our medicines are going to migrate over to the super prostacyclin, which is much simpler to take just 1 pill a day, much more effective in the prostacyclin receptor pathway. And as I mentioned, has already shown physiologic benefits which are better than anything else we've ever seen before.

Now we will unblind that trial, as mentioned just in the next 3 months. So you're not going to have to wait very long to see it. And assuming that the data are positive, which I'll show you a little inkling in a moment what those data might look like, then you will see us filing for approval this summer, hopefully, approval from the FDA next year. And then this type of 20-year history that's shown on the chart here would really just be the starting point for a takeoff in revenues that would be 2, 3, maybe even 4x the level that you see here in this chart.

We at United Therapeutics have done so much to make the most out of what we have. Here's an example of how difficult the current generations of prostacyclins are. They are so hard to manage that this patient here has to take the prostacyclin by an infused delivery 24 hours a day, 365 days a year with no interruption.

With this new super prostacyclin that we'll be introducing, this entire delivery system can be replaced with just 1 pill once a day and greater affinity within the prostacyclin receptors that line the pulmonary vasculature and airways in the lung. So it's going to be a game changer. And when people talk about like what made the United Therapeutics of 2026 to the 2030s, so much different than what happened before. They're going to say 1 word is going to be the super-prostacyclin, ralinepag and the other word will be they have become the go-to drug in IPF.

United Therapeutics, even though we are focused on these 2 words and the 2 words I want you to keep in mind, it's not that we don't also concentrate on other indications. And this is where I think a lot of our business development growth will be coming. We always have kind of a philosophy to do our best to leave no patient behind. In this chart, you see the logos of a couple of our products that are addressed to orphan populations.

The one on the right is the one I'll speak to for a moment here while we talk about business development. This drug is approved by the FDA and by the regulatory authorities in other jurisdictions for the treatment of neuroblastoma. Neuroblastoma is an almost universally fatal pediatric cancer of the nervous system. But after Unituxin was approved and for those patients to whom it was given, half of the patients completely banquet their neuroblastoma and have gone on to live a normal life with no recurrence of their cancer even 5 and more years after the cancer was first diagnosed, a true cure for these patients with neuroblastoma.

So we've now built up this indication into a position of leadership among pediatric oncology centers. And when people ask me, Martine, I understand about IPF, you're going to cross that I understand about the super-prostacyclin and you're going to be a go-to drug. What are you doing in new business development, this orphan oncology area is one of the key areas that we're looking at for new business development to try to leverage our success with neuroblastoma into other pediatric and orphan cancers.

Now the Tyvaso drug, which proved itself to be so remarkably successful in IPF. And it's very interesting that we had run our Phase III trial in a very detailed computational biology model, an AI model of the human lung that we've spent the past 5 years developing at United Therapeutics. We call it the CLIMB model, CLIMB being an acronym for Computational Laboratory for In Silico Molecular Biology. In other words, instead of running trials in vivo, you can run them in silico if you accurately model all the aspects of the in vivo entity, which we have with regard to the lung.

And when we did an unblinding of our in silico model of pulmonary fibrosis with the Tyvaso drug that you see here. We came up with a measure of its efficacy in terms of its improvement in forced vital capacity, again, the main measure, that was within 30 milliliters of oxygen of the actual in vivo pivotal trial that we later unblinded. But what's really fascinating is the unblinded data was about 60 milliliters of oxygen better than the other competitive drugs that are out there in the market.

So our -- this is to say that our in silico models are pretty damn good. And even if the FDA had approved something based on the in silico model, which I think will start happening within the next decade or so, it would have been far better than the drugs that are already out there. But nevertheless, we did prove it in the in vivo model. By the way, for those geeks of you who are in the audience, it took us 3 years to conduct the in vivo model in hundreds of patients with pulmonary hypertension. We ran 54 pivotal trials of the in silico model in just 48 hours. So imagine the future when you can run so many clinical trials in such a fast period of time and get such accurate results as we got for pulmonary fibrosis.

This chart shows a next-generation Tyvaso device that we do with UT. One of our core competencies at UT is something that we call drug device combination products. And this is where we combine a drug with a device to make the drug do something much better than it could do without the device. And it also adds a lot of proprietary IP to the drug which allows us to reinvest and develop yet better drug device combinations.

I'm looking over here at one of the head of the United Therapeutics [ Contworks ], where Pat Poisson has about a dozen different advanced devices like this. He's a genius and his team in is a genius at turning our molecules into effectively brand-new pharmacokinetic and even pharmacodynamic properties of drugs based on their passage through these unique types of delivery devices. So that's something that is, right now, in fact, it's our best-selling drug in the United States for pulmonary hypertension. And I think you're going to see this in IPF as well.

In terms of pulmonary hypertension, I think it is going to be overtaken by the super prostacyclin ralinepag that I referred to earlier in terms of our best-selling drug. But it's -- we never mind lapping ourselves to create better health care for patients. I think that's what it's all about.

Here, you see an example of why Tyvaso DPI worked so well compared to other type of devices, it reaches much further into the distal portions of the lung. And for those of you who are well versed in pulmonary biology, you probably know that the lung is a branching structure, so it's like 2, 4, 8, 16, 32 and you know very quickly, you get up into the millions of tiny, tiny arterials. And it's in those are far distal portions, meaning the tiny, tiny ones that may be like 10 millimeters in diameter micrometers and diameter -- sorry, about 10 micrometers in diameter that the pulmonary hypertension takes hold. So you need a drug that can get down to the far distal portions which the Tyvaso DPI does -- that device does it far better than any other product out there. And no doubt, that's why it's far and away the best selling DPI type of device.

Now I mentioned to you that when you take Tyvaso into pulmonary fibrosis, you get dramatically better results than have ever been seen before. And here, you see the data from the -- what I promised you take a peek at from TETON 2. This is the unblinded data from the TETON 2 trial, which was completed in the fourth quarter of last year. And you can see that the patients on drug did far better [ point triple 01P ] value than the patients who are on placebo. And we are now completing a confirmatory study. In fact, it's fully enrolled. And it will be unblinded in the first half of this year. So sometime in the next 2, 3, 4, 5 months.

And we expect that trial that's called the TETON 1 trial. We expect that trial to pretty much like overlay with this data. Our -- certainly, our computational model implies with overlay with this data. And that will be amazing because then we'll submit it for approval, I think the FDA will be very, very excited to grant an approval. And finally, for the 100,000 patients literally suffering the death from pulmonary fibrosis there will be like a life raft -- a lifeboat that they could jump on to, which will be Tyvaso. And it should definitely at minimum, greatly improve their quality of life, improve their oxygen saturation, which will logically improve their longevity of life as well.

So super, super excited about this, and we have every reason to expect that we should be able to garner onto this drug literally tens of thousands of brand new patients within the 2, 3, 4 years after it's launched. And we have been building up our inventory of Tyvaso inhalers so that we have an adequate supply of drugs and devices to take -- stay on top of literally a hockey stick launch into the IPF indication.

I also promised you a deep peak at the super-prostacyclin, ralinepag. Here you see some data this trial, again, is still blinded. We won't see the unblinded data until the next 2 or 3 months from now. So it's very exciting. 2 major news events in the same year. Neither of them terribly risky, very largely derisked by now. But here, you see that the ralinepag in the open-label extension study. All of this little data might not be visible to everybody in the back of the room.

But basically, what it shows is that in the -- for the people who left the drug in the open-label extension phase and then went on to the drug itself, their improvement in their 6-minute walk continued dramatically and was maintained out to 2 years here with an improvement level of just about 40 meters of 6-minute walk distance, which you almost never see in any of the first-generation prostacyclin drugs. So this is the beauty of our pharmaceutical industries. We can do these next-generation drugs and have like kind of step function improvements in the exercise performance and the physiological health of the patients we treat.

So again, this kind of open-label extension data very largely derisk this product. And we believe that it will become the most prescribed medicine for pulmonary hypertension. Right now, there's about 50,000 patients in the U.S. in the U.S. with some form or another of a drug prescribed for their pulmonary hypertension. Most often, a drug called a PD-5 inhibitor. For those of you who are familiar with that class of drugs. They go by -- for an ED either called Cialis or Viagra and PAH. They're known that it's like Revatio or Cialis. We ourselves have had an amazing partnership with Lilly over about 15 years now. Lilly chose us above all of the other companies working on pulmonary hypertension to entrust Cialis to us. and have been exceedingly pleased with the results -- so we partnership with Lilly.

And under our stewardship, that drug became the most prescribed drug for pulmonary hypertension. Now our drugs, which are also very good and great drugs and have been fantastic for UT, as you saw in the revenue steps at the beginning of my talk. Our drugs have reached about 15,000 patients, which, let's say, is around 1/3 of all the U.S. patients with pulmonary hypertension.

Ralinepag, mark my words, we are going to go past 15,000, okay? We're going to become the most prescribed drug of this category for pulmonary hypertension, and that will just be humongous because if you combine this potency you have a super-prostacyclin with the known functionality and safety profile of a PD-5 inhibitor like Cialis, everybody accepts that is safe and a ETRA, which is another type of generic drug which is out there. You have a triple threat. You are addressing like the 3 predominant pathways of pulmonary hypertension.

And the most potent of those will be in our momentarium, ralinepag. And then you can even overlay on top of those other drugs which have been shown to be synergistic like TGF inhibitors such as sotatercept. And there is already very, very exciting data available that shows the synergy of sotatercept to whom I might give huge kudos to Merck for their superb work on developing that drug for pulmonary hypertension and so happy to see patients who are on both that and prostacyclins doing even better than they would do on either 1 alone.

It's also been somewhat in the news that United Therapeutics is trying to solve the problem for patients with pulmonary fibrosis, IPF or pulmonary hypertension, PAH, for whom all of these drugs do not work. There are always some patients that progress through. We have shown if the patient is treated at the right way in the right expert center and they get their numbers down into a safe zone. They could get into kind of a stable equilibrium and go for decades without a need for a transplant. But not every patient that's going to like fall into that treatment channel, if you will. And for those patients whose pulmonary pressures, get out of control or whose pulmonary fibrosis gets out of control, a lung transplant is the only pathway.

So we began looking at several years ago at Xeno transplantation as a way to provide an unlimited number of lungs for these patients. What we found out is because the lungs have the largest colonization by immune cells especially primary immune system cells such as macrophages and these are the innate immune system, which just jump on anything right away, that we did not have success with signal transplantation in immune cells.

But since we wanted to make the best use of every pig that we had to sacrifice that we genetically engineered to be used in humans. So we tried the kidneys in the hearts. And sometimes, it's like you got to do the experiment, you see the amazing results. kidneys and hearts worked great, even though the lungs didn't because of their disproportionate overload of immune cells. So we went ahead and developed our Xeno transplantation platform for xeno-kidneys, xenohearts. The FDA has now approved 2 of our clinical trials for xeno-kidneys. First patients already enrolled. Very modest requirements from the FDA just something like 3, 4 dozen patients, max is all you need for FDA approval. And as I mentioned, we're already on that clinical trial pathway.

So I feel pretty confident that before the end of this decade, we'll be able to complete that clinical trial, submit the data to the FDA and obtain approval for creating an unlimited supply of transplantable kids and kidneys and hearts from these single transplantation models. We've, in fact, already built 2 commercial and 1 clinical xenotransplantation facilities, one in Houston, Texas. One in Minnesota, 1 in Virginia. So these 3 xenotransplantation production centers will be able to collectively provide well over 1,000 xenographs a year. to patients upon FDA approval. I'll note that we also are on the cusp of submitting INDs for 2 more xeno transplant studies in the xenoheart, and the, [ xenoheart ].

And so very probably within the first half of this year, knock on wood, the FDA will increase the number of approved INDs that we have in xeno from 2 to 4. And for those of you who've been following the feel quite amazing for a long time, it's quite amazing to imagine that here in 2026, there'd be 4 FDA-approved INDs for xenotransplantation, truly amazing. But for the -- we didn't forget the people with the lung problems. It's not their fault that our lungs are all full of macrophages, probably a very good thing that they are. So we decided the best solution for them would be to not insult the immune system and instead give them a salaried lung that is matched to their own DNA or at least to their own HLA type.

So we do that with -- we manufacture the lung shape and we do that in a number of different ways. And then we cover that lung shape with iPSC-derived cells or HLA master bank derived cells that cover the airways of the lung and the vasculature of the lung and then we keep them breathing in the bioreactor, test them like one would do an ex vivo lung perfusion. So that's even a whole another organ transplantation pathway that should be at the stage of FDA approval, either at the end of this decade or the beginning of the next one.

So all told, I think you remember the 2 words that I told you summarize UT, mostly because I know most of you are financialists and you care about the numbers. So the numbers are going to be overwhelming IPF and super-prostacyclin. So you remember those 2 words. But we do a lot more. We do exciting BD in oncology and exciting clinical development and transplantation. And I've reached the time on my clock when I need to open up the floor for questions.

So thanks for your patient listening. And between myself, our President and Chief Operating Officer, Michael Benkowitz; and our Chief Financial Officer, James Edgemond, we'll be happy to answer all of the questions that you have. I urge you to answer -- to ask questions because if you don't Jess's going to ask all the questions. And her questions are much more difficult. So please ask questions.

[indiscernible] is that your IP or [indiscernible].

So very good question. So the answer is both. The specific inhaler that I showed in that image is from a third-party contractor called MannKind. And they developed that inhaler for delivering insulin for diabetics, and we reengineered it to work with Tyvaso. So that 1 is from a third-party contractor.

We have actually almost finished building our own manufacturing plant for that inhaler, which will open up, begin producing stability batches for commercial launch by the end of this year, and then we'll commercially launch those products out of that company internal source next year. In addition to that, we have other devices that I mentioned in our skunkworks that are developed internally to UT, and there's not a lot that I could say with them about them right now because they are in stealth mode. I have on earnings call mentioned that I would share a lot of the details of the next-generation drug devices.

After we file the NDAs for the super-prostacyclin for IPF, those NDAs will go in, in this summer. So if you watch this space by the third quarter of this year, you'll get more insight into the completely proprietary next-generation inhalers similar to the one I showed you.

Next question. There's a roving mic there, if you want your question to be heard from everywhere. Going once, going twice, going Jess.

All right. So we do have a question on the iPad here on the portal. So what is the latest thinking on whether you'll need 2 trials in IPF given the potential FDA flexibility on not needing 2 trials in some cases, could you file with TETON 2 alone?

So, we're going to file with both of them because we're very, very close to having the TETON 1 data. The guidance that we've received from the FDA, which has been superior throughout this special recognition would go to the pulmonary division at the FDA. So just because like some parts of the FDA might do things 1 way in different divisions of the FDA do things a different way due to the greater complexities involved.

They've guided us to do 2 studies in this indication. I would say they actually guided us extremely wisely. They guided us to include both patients on the background therapies that don't work very well and they know they don't work very well. As well as patients that are -- have given up on those background therapies.

Actually, there's probably more people that have given up on those background therapies then use them because they have a very bad side effect profile associated with them. So the FDA wanted to make sure that we have data both on naive patients as well as those on background therapy, which is reflected in the IPF pivotal data that I showed you previously.

So we thought about it, and we said it's just going to be like 3 months until we unblind the study. Let's just go ahead and do things right. One of our -- we have a few outages at UT. I try to keep them not too many, but one of the main adages is that there's always time to do things right. And I think the right way is to lead in the strongest possible way with 2 well-controlled pivotal studies, both demonstrating like amazing results for Tyvaso in IPF. And so that's what we're going to do.

And what are your expectations for the results in TETON 1 relative to TETON 2, particularly when you think about the availability of Tyvaso in the TETON 1 territories.

Yes. We think that the -- our results in TETON 1, just for everybody to get on the same page. So it's exactly the same trial, exactly the same protocol for TETON 1 and TETON 2. TETON 1 is done in the U.S. and TETON 2 was done outside the U.S. TETON 1 started first, that's why it was called TETON 1. TETON 2 started second. For TETON 2, we had the advantage of a CRO. I -- at the moment, I forgot this particular CRO's name, but they had just finished. They had exactly just finished doing an IPF study that unfortunately didn't turn out well for the sponsor.

And so they had like dozens and dozens of IPS centers that are all ready up and rearing and they had patients that had to get off their previous therapy. So they were able to enroll very, very quickly. And that's why they beat TETON 1 for a few months. It is true that there are -- that Tyvaso is not generally available in Europe.

Whereas idea is generally available in the U.S. So the people sometimes have asked, well, are you worried that the patients who did so well in Europe in TETON 2 that some of those patients actually did not really have real IPF. They actually had pulmonary hypertension and that would be -- and they didn't have anything to avail themselves of. So that little definitely bumped your statistics, whereas in the U.S., a patient with pulmonary hypertension would supposedly be able to definitely access Tyvaso so that you would have a "pure IPF alone" population in the U.S. versus in Europe.

But in fact, there's absolutely nothing to back that up in all of the data. We have the background characteristics of both the TETON 1, and the TETON 2 population are exactly the same. We have various indirect indicators that can tell us whether or not there's any pulmonary fibrosis. Any pulmonary hypertension in the TETON 2 population, which there was not.

So we feel 100% confident that the background is strictly comparable. And given the like hyper-strong statistics from TETON 2, we expect to have an overlap result with TETON 1.

Yes, sir. I'll wait. They'll bring you a mic. There's like a home audience that wants to hear your questions.

So it's very exciting that you're going to be scaling up of these xenotransplantation facilities. How are you thinking about quality control there, particularly with the risk of porcine endogenous viruses, which obviously at scale is quite a big risk if you get that wrong.

Yes. It's a very challenging undertaking to scale up a xeno product, okay? I would say like one-on-ones earlier today, and I said, a xenograft is basically a product from hell with angel wings. So it's a product from hell because it is a very large biologic. It ain't no monoclonal antibody, okay? It's like just this massive biologic product that has -- it's nothing that the industry has ever manufactured before.

So you have to give a humongous amount of attention to quality assurance and quality control processes and the whole GMP type of process. On the other hand, it's a product with angel wings because it is literally life-saving. Every one of those kidneys that we make is a life-saving product or a heart.

So it's not a product you want to be afraid of because it's a challenge. And we've gone to the nth degree to make sure that we manage all the QA/QC aspects of it. Just to brag for a moment, not that past is prologue, but UT has been making biologic products for over 10 years in terms of the monoclonal antibodies. We've not had 1 single [ 483 ] from the FDA. We've been inspected numerous times, and we've been making small molecules even longer and no problem with any FDA inspections.

So we have a large QA/QC group Roughly speaking, we have about 1 QA/QC person, for example, and not just that anybody is anybody, I mean, we they're highly trained and all that kind of thing for about every 2 to 3 people in manufacturing. So it's a very high overhead. We have built facilities that are designed to ensure that every product goes through superior QA/QC.

I will say all of the product pigs are actually birthed inside of a designated pathogen-free facility, so it's not easy. It's extremely difficult. And what we've decided to do is even though the need for these kidneys is very, very large. We've decided to take a modular approach in building these facilities so that we always are like 5 steps ahead of any QA/QC scale-up issue that we might run into.

So we build these facilities to handle a few hundred organs each one. I mentioned there's 3, so that gives us like 1,000 a year. And we own the land adjacent to these facilities, so then we can modularly add additional facilities each 1 of a scale that we can manage, scale up with full attention to QA/QC.

Last questions? No more?

[indiscernible] Can you talk about the significance of what that 60 ml delta, what it means relative to the current standard of care?

Yes. I would say it's more than double what you could see in the current standard of care. So it's quite significant patient with, I think, really, really appreciate it.

Great. Well, we're out of time, so we will stop there. Thank you.

Welcome, everyone, to Jefferies London Healthcare Conference 2025. My name is Roger Song, one of the senior analysts cover SMid-cap biotech in the U.S. It is my pleasure to have the fireside chat with our next company, United Therapeutics, James and Harry. Welcome, gentlemen.

Thank you.

Thank you for having us and hosting United Therapeutics. And Harry and I have had some really good meetings this morning. So we look for some more this afternoon.

Excellent to hear. Awesome.

So we have a lot to cover and United Therapeutics have a very exciting news recently as well on top of the very solid business. So maybe we start with this current commercial business.

So James, can you give us some overview on all your kind of projection in terms of the growth trajectory, what we have been seeing and then what we're about to see in the coming months and years for the current commercial?

Yes. Thank you very much, Roger. It's a good question. So just coming off our Q3 report where we posted total overall revenue growth, but continue to have significant growth in total Tyvaso and Tyvaso DPI. And these are going to be the growth drivers going forward with us. And a lot of the uptake in Tyvaso in the quarter and going forward is going to continue to be around PH-ILD, so the uptake in that indication as well as overall Tyvaso DPI.

And these would be the major growth drivers for us going forward. We continue to believe we're going to have this growth because of the product profile of Tyvaso and really our understanding in longevity in the pulmonary space. So we continue to believe we're going to have growth there. And one of the aspects when you think about growth on Tyvaso DPI, and we're going to talk about this, I think, a little bit more in some of your questions, but we feel really good about the product profile.

So for Tyvaso DPI, there's no dosing limitation with Tyvaso DPI for us going forward. From a prescriber perspective and a patient perspective, we've had a couple of good years of positive feedback and uptake. From a payer incentive perspective, we don't feel we're disadvantaged in terms of -- in the payers -- or from the payers in the market. And then from a product profile perspective, we feel we have a superior product that has ease of use. And for example, 4 times a day 1 breath and talking about -- or considering some of the new cartridge strengths that we have, we think this is an advantage for us going forward.

So overall, Roger, on a going-forward basis, we think we've delivered strong revenue growth, and we expect to have revenue growth...

Excellent. Yes, we know recently, you have a couple of new approvals in the PH-ILD space. I know investor has been a little bit kind of cautious on the growth trajectory or the durability of the business, but so far, it seems looking pretty solid.

So can you just give us any anecdotes? The number is good, right? So -- but we always one looking for some lead indicator. So have you -- can you give us some anecdotes in terms of the feedback from the field, physician, how they think about the new patient or the existing patient, how they prioritize Tyvaso versus the other mechanism or the other drugs?

And Roger, I'm going to have Harry take this one. We're going to go back and forth today.

Sounds good.

Yes, Roger. So I'm assuming you're talking about Yutrepia here. Leading into their launch, they were trying to differentiate themselves, albeit using treprostinil is the same active ingredient, slightly different device, but they try to differentiate themselves on things like dosing and tolerability and many of these things we reputed as recently as our first quarter earnings call, but James just talked about no max dose.

Tyvaso is convenient. Tyvaso tolerability is well understood. So as they try to do these things, we think real-world experience kind of catches up and these things will kind of play out in the real world. And look, we talked about on our third earnings call -- our most recent earnings call, sure, when a new product comes to market, physicians are going to want to give it a try.

It's something that you typically see in almost any new drug launch in any category, and that's historically been the case for PAH as more therapies have come to market, patients are going to -- or doctors are going to want to give them a try. But despite this dynamic, what we've seen as we ramped up throughout the third quarter and into October that the referrals and start trends are kind of trending back towards us in our favor basically to where they were prelaunch of Yutrepia.

So while it's out there and while physicians have given it a try, I think in the real-world experience, the sort of factors that make us believe that we have the best positioned device play out. And you're starting to see that come back in the underlying dynamics.

Yes. And then it's interesting because since Yutrepia launch, it's trending towards a pretty positive way as well, but your business is also pretty durable. And then WINREVAIR, so the Merck drug, also they are doing pretty okay. So to me, it seems it's not zero-sum game and then rather maybe with more education, with more attention and then you will have more patients on those novel drug and nephrotoxicity. Is that the sentiment you're also getting?

It is, Roger. Thank you. What you see just as an analogy and going back to just the PAH space. So when Martine started the company years ago, there was only a few therapies on the market, and there was roughly 3,000 to 5,000 patients. But now you look at the PAH market, and there's some estimates, 50,000 treated patients, but there's something like over 15 therapies in the market.

So what you've seen over time is you've seen new therapies come to market more voice in the market, better diagnosis, and you've seen that addressable patient population expand. I think it's no different here.

You're going to have another voice around Yutrepia in the market, which could expand the market, Merck's product WINREVAIR. And so when you have more voice in the market, better diagnosis, you can expand the available patient population. And that could be the case that's going on right now with our products.

So you've seen us have a very good quarter in light of having a competitor come to market in the May time frame. And we expect that trend in terms of the growth of the addressable patient population to continue. And so that's part of our continued growth story going forward.

Excellent. Okay. And then we also want to state the elephant in the room in terms of the ongoing litigation with the Yutrepia. So obviously, you don't need to comment any legal kind of consequence here. But just internally or externally facing investor, what's your scenario analysis for this outcome out of this litigation? And then what will be potential impact, if at all, to your commercial? We just talk about the growth trajectory.

I think it's been well forecasted all these potential outcomes. And at this point, it's in the judge's hands. We're not going to sit here and try and speculate or figure out what he's going to say. We're waiting on the decision just like everybody else.

And whatever the outcome is, it's in his hands for him to decide. But nonetheless, if it's an adverse ruling against us, we're going to continue to operate. They've been on the market for a full quarter, and we continue to grow 22%, 23% growth for Tyvaso DPI in the third quarter of this year.

So look, we've shown that we can continue to grow even with them being on the market. And if that's the outcome of the ruling, we're still confident in our ability to grow.

Okay. Great. So regardless of the outcome of the litigation, just assuming they have another inhaled treprostinil in the market. So you're confident about the Tyvaso continued growth trajectory?

We are, Roger. I think in light of the Judge Andrew's ruling is we feel very confident in our commercial portfolio, we feel very confident in some of the early clinical trials that are currently ongoing with TETON as well as ADVANCE OUTCOMES. So from a commercial perspective, there's a lot of conviction in what we're doing and a lot of belief, and that's what we're going to continue to do to keep our heads down and focus.

And then further, and we'll probably get into this a little bit later, there's a longer-term opportunity here with respect to some of the organ manufacturing act. So from an enterprise perspective, from a current commercial perspective, near-term pipeline and long-term pipeline, we feel very comfortable on the trajectory of the business.

Absolutely. Yes. We're definitely going to talk about IPF, Tan and then also the transplant a little bit. But let's just wrapping up the commercial business for now. I think in recent quarter, I think that's the first time I've ever seen -- ever heard is you talk about the $4 billion run rate by 2027.

Can you just elaborate on what's the component of the business? You have a multiple product on the market. And also you are about to get approval potentially for IPF. Is that part of the projection or that's mostly coming from the base business?

Sure. It's a good question, one we've gotten this morning as well. So what we talked about on the most recent earnings call is that we would have a quarterly revenue run rate by the end of 2027 of $1 billion. And a couple of points related to the majority of that growth is going to come from the existing commercial business because that's what is approved and is currently being marketed by our sales and marketing teams.

If you follow along the kind of estimated time lines when you think about the TETON trials for idiopathic pulmonary fibrosis and the advanced outcomes trial for ralinepag, approval for those would roughly be in the 2027 time frame. And so any revenue contribution that would come from those 2 products would be certainly additive, but they would be later towards that calendar year 2027.

So it would certainly be additive, but the bulk of the $1 billion run rate is going to come from the expansion and growth of the current business, current commercial products on a going-forward basis. So that's kind of our target and our goal is to have $0.25 billion run rate by the end of 2027?

Got it. Just -- and I'll set the stage for the investors as well. I think it's above the -- at least the sell side consensus when I look at the projection for 2027. So that probably if you can achieve that or people start to believe or building the expectation, you can achieve that, this is upside for the current business.

It is. And that's what we are focused on, as Martine clearly outlined on the last earnings call.

Awesome. All righty. Okay. So we should talk about very big upside driver from the IPF with the recent very impressive GLO 2 data. And I think with the more detailed data, you will start to believe this is a real drug and then either as a monotherapy or the combination with the standard of care. So how users thinking about this opportunity? And then -- and maybe just let us know what's the next step for the IPF.

Yes, sure. So just to quickly recap for those in the room, 96-milliliter benefit, placebo-adjusted difference on FVC. We hit statistical significance on most secondary endpoints in the study and well-known safety and tolerability profile of Tyvaso. So we were really happy with the outcome from TETON 2, and we do recognize that it's a very large opportunity. What we are hearing from physicians is mirroring our own excitement for the opportunity and the availability of another therapy to add to the treatment armamentarium for IPF.

And look, I think your last question was the commercial opportunity. 100,000 patients in the U.S. And just based on the existing therapies in the market, it's a multibillion-dollar opportunity that we're looking at here. Whether it shakes out based on the end label when we combine the 2 studies or when we have the 2 studies, I think that will really determine what the overall market opportunity is, but you're looking at a very sizable market no matter how you slice the pie.

Got it. And then one of the key discussion points for the -- after the TETON 2 top line detailed data is how this will translate into TETON 1 data. That's TETON 2 is ex U.S., Canada and then TETON 1 is the U.S. and Canada. So we did some deep analysis as well, so looking at the baseline, looking at the different kind of baseline treatment and then the practice.

So what is your conviction this will translate into TETON 1? And then honestly, when I see the TETON 2 data, the effects are so big, I believe you still have a chance to pull those together to enhance the filing package. So just tell us about the TETON 1 translation and also the filing strategy with those 2 trials.

Sure. So I'll take part of it and then Harry can add some, too, because there's a lot to the question. So I think overall, the results of the TETON 2 clinical study in IPF were really successful even from all the way down to a P value perspective. So we do have a lot of conviction as that translates over to TETON 1, which is your clinical trial for IPF in the United States and Canada. When you look at the baseline characteristics of the patient populations, they're very similar, and we have a poster, I think a poster out on that.

So we wanted to share that with investors to see. So overall, there's a lot of conviction, Roger, that this would really translate from TETON 2 over to TETON 1. And then there's also the opportunity to pool the data as well overall. And what am I missing in your question? Was there another?

Yes, I think that's the translation. And then the filing, you say you can pull the study. So what -- under what condition you think you will pull the study -- to study or is it necessary for the filing package?

Yes. So I'm not as smart unless you have any background on pulling the data.

I think if it provides us an opportunity to maybe hit statistical significance on some of those secondaries that we didn't hit on in the TETON 2 trial that could potentially help the overall label, it's a possibility. And like you said, if perhaps the data aren't as strong in TETON 1 versus TETON 2, you can pull it together and potentially get a statistically significant benefit. But again, based on everything that we can see, we're highly optimistic.

Yes. I was going to say, Roger, the conviction level that we have just on each individual trial is pretty high. So we feel really good about kind of the overall results. And TETON 1, which we will -- and we do still expect to unblind in the first half of 2026. And I think you had a question on there about regulatory strategy and filing, and I'm sorry, I missed it earlier. One of the aspects that we've talked about is we are going to meet with the FDA by the end of calendar year 2025.

One is we want to start the dialogue or really continue the dialogue with them regarding these 2 trials. We do need both trials at this point for approval of Tyvaso in use in IPF. And that was the agreement that we did have with the FDA early on. So that's why we're continuing to do these trials, one international, one domestic because we also want to explore opportunities for Tyvaso ex U.S. So that's one of the reasons why we did the ex-U.S. trial.

So we are meeting with the FDA or the regulatory teams are meeting with the FDA prior to the end of the year, and they're looking for any opportunity to continue the dialogue and to see if there are opportunities to accelerate any of the aspects around getting Tyvaso to market sooner for these patients because at the end of the day, the real motivating factor for us is there's a patient population that we believe we have a really beneficial therapy for them, and we want to make sure we can take it to the market as quickly as possible. But we also want to make sure we do it in a way that gives us the best opportunity for approval and the best label possible.

And so that's why we're trying to be very methodical. And we say at UT, we always have time to do it right, and we're going to do it right, but we're going to try and accelerate it as well for the benefit of the patients.

Absolutely. Okay. Great. I think IPF is, as Harry mentioned, is 100-plus thousand patients. So no matter how you look at the pipeline, look at the market size and it can be multibillion at least. And then we know we have a 2 standard of care. So it's not best drug and they're still getting towards like a $4 billion market.

We agree with all the above. It's a very large opportunity for us. And I think what will be interesting is -- and I talked about this earlier, is what the ultimate label would be because if you think about the clinical trial, there were certain aspects, and Dr. Nathan talked about this at the unblinding in terms of quality of life attributes.

No study has had a benefit that we have seen in terms of patient quality of life. So there's many attributes in the study in terms of how we want to take advantage of that, whether it's through the FDA approval process and from a marketing perspective.

Excellent. I know we have a lot to cover. We already talked about the base business. We talk about IPF as a major next kind of leg for the growth. But we still have a couple more, right? So first, maybe on the PPF side, so I think that's still the Tyvaso TETON PPF. So with this IPF data, so what's the level of conviction you now in terms of like success for PPF translate from IPF, if any?

Yes. Thanks, Roger. Look, we're equally as excited about PPF. When you think about the disease progression and the underlying fibrosis relative to IPF, it's more or less the same. So based on what we've seen thus far in the TETON trials, we're confident that -- confident and optimistic that we can see a similar outcome in PPF.