AVROBIO Inc Stock

Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference for our next session. Looking forward to a hybrid presentation and fireside with Tectonic Therapeutics. And it's my pleasure to introduce Dr. Alise Reicin, President and CEO of Tectonic. Alise, it's a privilege to have you here. Thank you for joining me. I'll hand it over to you for the presentation.

Thank you for inviting me. In the next 10 to 15 minutes, I'm trying to give you a very high-level overview of what we're doing at Tectonic. Here is our forward-looking statement. And just to get started. Tectonic is focused for any of you that don't know, on the discovery and development of both agonist and antagonist biologics targeting GPCRs. We have a super experienced executive team. Between us, we've led teams that have resulted in over 20 first approvals drugs and many follow-up indications. Our focus to date has been on high unmet need areas with limited to no therapeutic options with multibillion-dollar market potential.

When we started the company, our goal was to have a robust product pipeline that enables optionality and good data-based decisions. And as of today, we have 2 programs in the clinic covering 3 indications as well as a strong emerging preclinical pipeline. First, we have TX45, our long-acting relaxin, which is in Phase II for pulmonary hypertension associated with preserved ejection fraction and heart failure. You'll hear me refer to that as PH-HFpEF going forward as well as we just initiated a study in pulmonary hypertension associated with interstitial lung disease, otherwise known as PH-ILD. TX2100, which just entered Phase I is a potential first-in-class APJ antagonist being developed for hereditary hemorrhagic telangiectasia, otherwise known as HHT. I'm going to use a lot of acronyms here, and it could be used for other bleeding disorders associated with dysregulated angiogenesis. We have really good clinical momentum, and we're well capitalized to advance the pipeline.

So in terms of pipeline-related catalysts, we expect to have results from our Phase II APEX Group II PH-HFpEF study in late 2026, maybe early 2027. And our Phase II study in PH-ILD was just initiated. As I noted, we're in Phase I with TX2100. We should have data from that by fourth quarter of this year, and we will be starting a Phase Ib in parallel with the Phase II very shortly thereafter.

So first, starting with our relaxin program. There are 5 groups of pulmonary hypertension. Most of the product development has been in Group 1 PAH. But the 2 that we're currently focused on are Group I, which is pulmonary hypertension associated with left heart failure. This is the largest group, probably with over 2 million patients in the U.S. alone. Group III is pulmonary hypertension that's associated with lung disease. And specifically, as I said, we're in the PH-ILD population.

The need in Group II PH is large and underserved. There's no approved therapy. And we estimate in the Group II PH-HFpEF population, so that's with preserved ejection fraction, there's about 1 million patients in the U.S. They have very long-term outcomes. The market is clinically segmentable, Group II PH has 2 subpopulations, IpcPH, and that's isolated post-capillary pulmonary hypertension and CpcPH combined pre and post pulmonary hypertension. Both are driven by elevated left -- pressures on the left side of the heart that backflow into the pulmonary circulation causing the pulmonary hypertension. And that's called the post-capillary component.

In the CpcPH subpopulation, in addition to that post-capillary component, there is a pre-capillary component that's caused by abnormal pulmonary vessels where you have muscularization and a narrowing of the lumen, which then causes an increase in pulmonary vascular resistance as the same amount of blood is tried to be driven through a smaller pipe. We think that, that sub -- while we think the drug could work in both IpcPH and CpcPH, the CpcPH population has a greater unmet need, and we think the benefit could be even greater in that population.

TX45 mechanism matches the biology. Relaxin results in pulmonary dilation, which should reduce pulmonary pressures and pulmonary vascular resistance. It also dilates the systemic circulation and improves diastolic relaxation. Both of those should improve left heart function. And lastly, its antifibrotic effects should both improve left heart function as well as the pulmonary circulation.

We have supporting clinical evidence, which I'll show you from our Phase Ib hemodynamic study in patients with PH-HFpEF, which showed that relaxin could improve both left heart function and pulmonary hemodynamics. And lastly, we think we've got an efficient plan. You'll see we've enriched for patients with CpcPH in our Phase II study, and we think that 6-minute walk will be an approvable endpoint in Phase III, which means we wouldn't have to do an outcome study.

Just real briefly, these are the results from the Phase Ib study in patients with PH-HFpEF. We took those patients. We put in a right heart cath. We measured hemodynamics at baseline. We gave them a single dose of relaxin and then we measured hemodynamics over the first 8 hours. And what you can see is we showed evidence of improvement of left heart function on the first row, you see there was almost a 19% reduction in the pulmonary capillary wedge pressure as a change from baseline. And then on the fourth row, you can see we also improved cardiac output by a little bit over 18%.

We also showed evidence of improved pulmonary hemodynamics. That increase in pulmonary vascular resistance that I referred to was brought down by over 30% in patients that had an abnormally high PVR. And we also, if you look further down, brought down mean pulmonary artery pressure by about 17%.

Our Phase II study, which is ongoing, is a 6-month study. Patients are brought in. We do a right heart cath at baseline. They then get randomized to either 300 milligrams Q4 of relaxin, 300 milligrams every 2 weeks of relaxin or placebo, a right heart cath is then done at the end of the study. The primary endpoint is change in pulmonary vascular resistance in the patients with a PVR greater than 3, and that's about 70% of the patient population. We'll be looking at other hemodynamics such as cardiac output, pulmonary capillary wedge pressure as well as 6-minute walk and secondary endpoints.

Switching quickly to PH-ILD. As I said, these are patients with Group II pulmonary hypertension, secondary to interstitial lung disease. These patients tend to have shortness of breath and cough. And when they get pulmonary hypertension on top of their ILD, their exercise and tolerance gets even lower, and they tend to have lower blood oxygen levels. Like other forms of pulmonary hypertension, you make the diagnosis on right heart cath, where you see an elevation in pulmonary pressures and pulmonary vascular resistance.

It's a very high unmet need population. The only approved -- there's about 60,000 patients in the U.S., and they have very high 3-year mortality. And currently, the only approved therapies are inhaled treprostinils, which can be difficult to tolerate because of cough and bronchospasm that can grow associated with that.

Preclinical models in pulmonary hypertension support exploration of PH-ILD. And furthermore, the data that just showed you in Group II pulmonary hypertension, where we reduced the pulmonary vascular resistance as well as the mean pulmonary artery pressure go along with the ability to potentially do that in this patient population. It's a devastating disease that has a significant commercial potential.

Just real briefly, the study, which just initiated is a 16-week open-label Phase II study, up to 25 patients. They'll have a baseline right heart cath and then another right heart cath after 16 weeks of therapy and the primary endpoint is safety and looking for a reduction in pulmonary vascular resistance.

And lastly, just switching to our TX2100 program. Hereditary hemorrhagic telangiectasia is the second most common genetic bleeding disorder. It's caused by mutations in the ALK1 pathway. It's a serious disease with major effects on quality of life and life expectancy and a multibillion-dollar potential market with no approved therapies. It's an orphan disease. And while off-label anti-angiogenic agents are used, such as the VEGF inhibitors, and they are efficacious, they're limited by their toxicity as well as a lack of durability.

Our approach to this is novel as APJ, the receptor for the peptide hormone Apelin is a selective and specific anti-angiogenic target. We don't have to prove that anti-angiogenesis works in this disease. That's already been done. Instead, we're going to improve on that because this approach is more tissue selective. It's really only expressed or mainly expressed in endothelial cells, and it's pathology biased, meaning that it's typically quiescent and only gets upregulated in the disease states. Further, we think there's the potential to expand into a broader group of bleeding disorders that are caused by dysregulated angiogenesis.

TX2100 is a potential first-in-class subcu administered APJ antagonist, again, with the goal of achieving the type of efficacy you see with other anti-angiogenic agents but with improved safety. And our POS is enhanced by the demonstration of efficacy in 2 separate preclinical models of HHT that have previously been shown to have clinical translation. We're currently in Phase I in Australia. And I told you that we had efficacy in 2 mouse models. In the interest of time, I'm just going to show you data from one of those. This is -- these are mouse models where the ALK1 pathway is inhibited to reproduce the disease, and they do reproduce the phenotype of the disease. The data on this slide is from the most severe of those, which is the adult ALK1 inducible knockout model, where you can see in the white is a normal mouse. Next to it in blue is the inducible knockout mouse. And then in orange is TX1351, which is a mouse surrogate for TX2100 in orange and the VEGF antibody is in gray.

And what you can see on the left-hand side on day 7 is you get a marked anemia in the knockout models that are rescued by both the anti-APJ and the VEGF. But if you take the model out to day 12, you still have persistent increase in hemoglobin in the anti-APJ animals but that's lost in the anti-VEGF animals, which may be showing us what happens in the clinic where there isn't durability of the effects in some patients. If you look at GI bleeding out to day 12, you can see that APJ inhibits the bleeding but the anti-VEGF does not.

And so as I said, our Phase I study is ongoing. And the toxicity profile preclinically enabled us to go into animals. We dosed nonhuman primates up to 100 mg per kg. There was no signal whatsoever on safety in that finding and that enabled us to go into normal healthy volunteers. When that study is over, we will quickly start a Phase Ib study in severe HHT patients in parallel with initiating a placebo-controlled dose-ranging study, proof-of-concept study, Phase II study in moderate to severe HHT patients.

And just lastly, as I said, we have 2 clinical candidates addressing untapped markets with significant market potential, expected data readouts from both our APEX study in either late 2026 or early 2027 and from our Phase I with TX2100, and we've got proven leadership and the capital, we think, to execute on this. And with that...

Good. Great. Thanks very much for the presentation, Alise. So we'll get into the fireside chat portion. So broadly speaking, at a high level, there's been updates from competitors recently, right? The Lilly discontinued last year. We saw some data in the fall. AstraZeneca had an update recently as well. So can you discuss your thoughts on some of that? Do you view it as noise? Or is there anything that could be learned from those updates? And what gives you confidence in TX45's design, dosing strategy, data target population?

So you've got 3 companies, and I think we all -- we've all gone about exploring relaxin in a slightly different way. I think a year from now, when we have data from everybody's programs, you will have learned a lot about what the right patient population is, what the right dose is. It's almost, I think, been a gift to the field that we've all done it in a slightly different way.

We'll start with Lilly and their program. They went into patients with preserved ejection fraction heart failure, not pulmonary hypertension with that. And more importantly, they went into patients who had to have been discharged from the hospital within the last 2 weeks, okay, for heart failure exacerbation. What causes a heart failure exacerbation? Sodium retention, fluid retention, you admit patients in the hospital who are fluid overloaded and you treat them with IV diuretics.

Turns out when you treat them with IV diuretics, you make those patients even more sodium retentive. What did they find in the Lilly study? They found an excess incidence of hospitalization for heart failure in the patients treated with relaxin. That's not good. And they saw evidence of about a 200 cc increase in plasma volume. Why did they see that? Well, relaxin, as I mentioned, is a systemic vasodilator. It dilates the vessels around the kidneys. And when the glomerulus sees less pressure, it thinks the patient is dehydrated and it holds on to sodium. That's not good for heart failure patients. Other vasodilators that are efficacious in heart failure do it. So it doesn't mean it can't have efficacy.

We think what happened in these patients is they took the most sensitive patients. The patients were already fluid overloaded. Typically, you haven't completely gotten rid of the fluid when you discharge them. And they were likely even more sodium retentive than they typically are because of the IV diuretics. And I think that -- and if you look at the doses they used, we think they were really on the upper end of the dosing. And I think dosing may be important.

So I can tell you in our study, obviously, because of the Lilly, we've been looking very carefully at blinded data. I think that you will get some sodium retention and some fluid retention. But looking at the blinded data, there's nothing that we've seen that suggests we're seeing what Lilly has. And our IDMC met in January, most recently, 40% of patient exposure. They had right heart cath data. They had safety data. They had plasma volume data, they had 6-minute walk data, and they didn't suggest any change.

And you also didn't hear that about the AZ program. Now AZ, the subcu is a much more similar patient population to us. And I have to tell you, they gave so little inflammation. I don't know exactly what happened in that, but I can tell you they had a much more heterogeneous patient population. They had HFpEF and HFrEF, so reduced ejection fraction and preserved ejection fraction. Their PVR was their primary endpoint, and yet they included patients with normal PVR. You're not going to get a reduction in those patients. So it may have diluted the signal. I think we've got to wait for the data. The good news is they explored a very large dose range, even doses that I would have predicted would not be efficacious. And I think once we see that data, there'll be a lot to learn from it.

Got it. Okay. So I guess just a follow-up on the Lilly disclosure. So I guess it's possible to overshoot with the relaxin mechanism.

I think it is. And the Lilly data taught us that. I don't know before the Lilly if we would have expected that necessarily.

Got it. And -- so do you think there's the same -- relative to that population, do you think there's the same increased risk of pulmonary congestion in stable HFpEF patients? Or do you think it should be much lower?

I think it will be lower. That's my hypothesis.

Okay. And again -- is there -- how is that being managed in the ongoing Phase II?

Well, even before we saw the Lilly data, we were encouraging our investigators to make sure patients were euvolemic before coming into the study. If you're going to treat pulmonary hypertension in the setting of heart failure, they always encourage you to make sure fluid status is taken care of. We want patients on stable standard of care medicines. Part of the reason that you could get this increase in congestion is if renin levels go up. And many of these patients are on ACE inhibitors and MRAs, which should blunt that. And we've been encouraging the investigators just to make sure they're monitoring their patients for fluid, which is what you're supposed to do when you take care of a heart failure patient.

And how is enrollment progressing in the Phase II?

Enrollment has been going well. If you look on clinicaltrials.gov, we're supposed to complete the study actually in about November, which would put us really at the end of the year. And so we may go into 2027. We're sort of in the last several months of recruitment.

Okay. And I guess, should we expect updates? Will you tell us when enrollment is completed so we can do that math? Or how should we...

Yes. We will. We will.

All right. And in terms of the Phase Ib data that you showed, really exciting kind of first-in-class clinical data providing validation for the mechanism. How should we think about the ability for that to translate into a longer time frame of treatment? What evidence you have that suggests it will be durable?

So actually, in that study and a similar study we did in HFrEF, where it was just a single dose, we didn't echo out to day 30. And somewhat surprisingly, we actually, in both studies showed very reproducible evidence of maintenance of effect on a surrogate for pulmonary vascular resistance, which you can look at Echo called TAPSE/sPAP as well as evidence of improved right ventricular function. So it was showing some sense of durability out to day 30. If you look at the Lilly study, systemic vascular resistance goes down with relaxin, and they saw that was maintained out to 6 months.

So that's telling you you're getting durability of effect. And if you look at 2 recent publications from AZ looking at a reduced ejection fraction model of heart failure in nonhuman primates, if anything, you saw effects on heart function go up over time over a 6-month period.

Great. And as we think about the primary and secondary endpoints of the Phase II, what do you need to show on those endpoints to claim success?

I think for PVR, it's somewhere around a 15% to 20% reduction in PVR. We'll want to show evidence that we're seeing improvement in left heart function. And while we're not powered for 6-minute walk, I want to see a numeric trend on 6-minute walk.

What -- is there any kind of -- to follow up on the trend comment, is there any sort of minimal improvement in 6-minute walk test that you think is necessary?

You probably -- the KOLs are very clear that a 20-meter increase is what's clinically relevant in this patient population. I think if we saw 15 to 20, that would be one.

Great. And how soon could you start the pivotal trial after data potentially if it's successful, which hopefully is?

I'm going to keep that as I'm torturing my team as soon as possible. I'm not ready to give -- but let's put it this way. I would hope that we could beat the median timelines in the industry.

Great. And the primary statistical analysis is focused on CpcPH patients, right? So can you elaborate on why you did that? What portion of total enrollment that is in the study? And also what you expect to see in IpcPH?

I think you could get efficacy in both CpcPH and IpcPH very clearly because it bring wedge pressure down and improved cardiac output, you could see an increase. Our hypothesis was if you brought down the pulmonary vascular resistance and improved, you'd see a greater increase. That's basically what the hypothesis was.

Okay. And so if you see positive data in IPC in the Phase III, would you envision a mixed population kind of like the Phase II or 2 separate studies?

I would envision we'd obviously have to speak to the FDA but I envision them both in one study.

Okay. And just more broadly with respect to the competitive landscape, in Group II PH. Curious to get your thoughts on Merck's sotatercept, of course, relative to TX45 and like the Tenax approach and just in general for others...

Listen, I think the fact that Merck had a positive study is a win for the field. I think there's plenty of room for more than one mechanism. They're in a more -- in a much -- in a smaller patient population, and they want to keep it small. They've said they want to keep their pricing the same, and they want to keep orphan status. So they're in a PVR greater than 4 population, an ejection fraction greater than 50% population. And we're expecting to see strong data based on what we're hearing. So I think that's exciting. And I hope we'll learn something about core -- are there correlations and what are the best correlations between hemodynamics and 6-minute walk. And I think there'll be learnings for the field.

Tenax, I think, is interesting. Their hypothesis is that if you bring down right atrial pressure and wedge pressure that you'll have an effect on 6-minute walk. By the way, relaxin does the same. We bring down wedge. We bring down right atrial pressure. We'll have to see.

And switching gears a little bit to HFrEF. You mentioned the data that was pretty darn consistent with HFpEF. What are plans for HFrEF moving forward?

I want to see what HFrEF looks like in the AZ data sets. I think that and seeing our own Phase II and then we can make a decision. And I think if there is compelling data there, we could go straight to a Phase II/III and is one possibility that we could do in HFrEF.

Fair enough. And PH-ILD, you've guided to initiating a Phase II trial there. Maybe just -- you touched on it a little bit in the presentation but maybe you could just elaborate on that, that opportunity and why you've prioritized it over even HFrEF.

So it's a large unmet need. Almost all of the drug development that's going on in that area is inhaled. And inhaled can be difficult for these patients. We think there is room for a systemic approach that could come in there, and that could be a little bit differentiated as well. Our Phase Ib data in HFpEF really suggested you could have a large impact on PVR. And then the preclinical data and the fact that there is an antifibrotic element went along with that as well. The other thing is if fluid congestion is an issue, these patients will be less susceptible to any sort of fluid retention.

That's interesting. Last couple of minutes, we have to turn to 2100. My apologies for not spending more time on it. But you had a very interesting KOL webcast the other day that I encourage everyone to listen to, really hammered home the unmet need there, really quite horrible what some of these patients are dealing with and APJ seems like a very exciting target to go after. So can you elaborate on the development plan there, the Phase I healthy volunteer data later this year and what you hope to see from that?

Yes. So the Phase I, actually, we think it was because we had such a good preclinical safety package that we could go into healthy volunteers. And it means you can get dose escalation and get PK. It will mainly be PK and safety. Mechanism has never been in humans. So getting some initial safety data, I think we'll do some derisking for the program as a whole. And then we've got -- I'm going to put it in a surrogate for receptor occupancy that should help us additionally choose doses going forward. And then as quickly as we can, we'll get a Phase Ib started in severe HHT patients where we can look not only at epistaxis but we can look at hematologic support, i.e., the need for iron and blood transfusions as well as hemoglobin levels.

What sort of reduction in epistaxis would be meaningful in this population?

I can't give you a good answer to that yet because nobody knows the best way to measure epistaxis yet. The most commonly used measure so far has been an epistaxis severity score, ESS, which is a look back a month. That is not going to be the best way to do this. And on that scale, a 0.7 improvement is considered clinically meaningful. We're going to be also exploring a daily diary. I think that is the way the field is going to go. And part of what we're going to have to do in that is define what a clinically relevant improvement in that is. So I think people have to -- in this field, this Phase II, there's going to be learnings to define the best way to measure epistaxis going forward. It's looking from other groups that are doing this that it's some sort of duration and intensity, and that will be something that clearly we'll be exploring.

Great. So we're up on time but to wrap up, I'll ask you what you believe is the most underappreciated aspect of the Tectonic story by investors right now.

Probably right now, it's still -- no one really knew about the HHT program, and I think it's just starting to get appreciated by investors. And I think it's an important program for us.

Fair enough. Alise, thank you so much for your time.

Thank you.

Good day, and welcome to the TX45 Phase Ib Part B PH-HFrEF data conference call. [Operator Instructions] As a reminder, this call may be recorded.

I would now like to turn the call over to Dr. Alise Reicin. Please go ahead.

Thank you. Good afternoon, and thank you for joining us. Today, we'll be reviewing the top line results from Part B of our Phase Ib clinical trial, which evaluated the safety and hemodynamic effects associated with a single dose of TX45 in patients with pulmonary hypertension associated with reduced ejection fraction heart failure, and we'll be referring to this as PH-HFrEF . Next slide, please.

Attached is our disclaimer information regarding forward-looking statements that will be made today. Next slide.

This 14-patient clinical trial was designed to evaluate the safety and tolerability of TX45 in patients with PH-HFrEF and to explore the hemodynamic effects of TX45 in this patient population. I've been asked over the -- several times over the last few months, what do I hope to see in this trial? And the goal was to observe hemodynamic effects that were directionally similar to what was seen in Part A of this clinical trial in patients with PH-HFpEF with evidence of improvement in both left heart function and pulmonary hemodynamics. And I can say unequivocally that the results met that goal. Similar to what we saw in PH-HFpEF patients in Part A, TX45 was well tolerated and demonstrated improvements in all hemodynamic measurements that we evaluated.

The data from Part B of this trial support further clinical investigation of TX45 in PH-HFrEF patients, pending data from our ongoing APEX Phase II clinical trial in PH-HFpEF patients. And as a reminder, APEX is a 24-week clinical trial to evaluate the safety and efficacy of TX45 in PH-HFpEF. This study is highly enriched for CPC patients with a PVR greater than or equal to 3 Wood units. In fact, we're aiming that 70% of the population have a PVR greater than 3. And the primary endpoint of mean change from baseline in PVR in this PVR greater than 3 population is -- that's the primary endpoint. 6-minute walk distance will be a secondary endpoint.

And with that, I'm going to now turn the presentation over to Marcie Ruddy, Tectonic's Chief Medical Officer, who would describe the rationale for us doing Part B of the clinical trial as well as the results.

Thanks, Alise. Next slide. So what was the rationale for exploring TX45 in PH-HFrEF patients? First, TX45 is a long-acting relaxin. This mechanism appears ideal to address the disease pathology in both types of heart failure associated with pulmonary hypertension, given its vasodilatory, lusotropic, antifibrotic and reverse remodeling effects.

Second, we were encouraged to explore TX45 in PH-HFrEF , actually saw that meaningful hemodynamic improvements in PH-HFpEF were consistent with what would be expected from the relaxin mechanism. Similar to PH-HFpEF, there is a significant need for new treatments for these patients. In both types of heart failure, patients have worse exercise capacity and increased mortality if they develop pulmonary hypertension compared to those who do not. This is especially true for those with combined pre- and post-capillary pulmonary hypertension or CpcPH and a pulmonary vascular resistance, or, PVR greater than or equal to 3 Wood units.

Lastly, expansion into PH-HFpEF represents a significant potential market expansion. There are approximately 1.1 million people in the U.S. with this condition, of which approximately 300,000 have CpcPH with a PVR greater than or equal to 3. Next slide, please.

So although the left ventricular pathology for these 2 types of heart failure is different, the development of pulmonary hypertension and its consequences are similar. PH-HFrEF is defined by an ejection fraction less than or equal to 40%. It is most commonly due to myocardial wall infarction, often referred to as a heart attack. This results in a dilated weakened ventricle with a decreased ability to pump blood during systole. In contrast, PH-HFpEF, the ejection fraction is normal or near normal. It is typically seen in patients with a history of significant hypertension, diabetes and/or obesity. These patients have a thickened, less distensible left ventricle, which has difficulty relaxing for maximal filling during diastole.

In both forms of pulmonary hypertension, the impaired function of the left ventricle leads to elevated left atrial filling pressures, which is manifested as elevated pulmonary capillary wedge pressure. In some patients, these elevated pressures backflow into the pulmonary circulation, leading to elevated pulmonary artery pressures that is then pulmonary hypertension. As this condition persists, patients develop elevations in pulmonary vascular resistance or CpcPH, they develop decreased cardiac output, particularly with exercise and then eventually can develop right heart failure. Next slide.

So the trial design of Part B was similar to Part A. Patients with PH-HFrEF were screened by history and echocardiograms to meet our entry criteria and then they were admitted to the trial. The day 1 procedures are outlined in the center of this slide. After a right heart cath was inserted, baseline hemodynamics were obtained. Patients were then given an IV infusion of TX45. The TX45 doses administered are described in the top blue box in the schematic. To assess the tolerability of TX45 in this population, the first patient received a 0.3 milligram per kilogram dose, the second 1 milligram per kilogram. The rest of the cohort was dosed at 3 milligrams per kilogram, a dose that was expected to have an efficacious trough exposure through day 29 post dose. Hemodynamic measurements were then obtained repeatedly over the next 8 hours post infusion and results were pooled and compared with baseline measurements. Next slide, please.

So to orient you to some of the hemodynamic measures we will be discussing, I have a short primer here on this slide for your reference. I've already talked about pulmonary capillary wedge pressure as a measure of left atrial pressure, and this is a key marker of the pressures on the left side of the heart. PVR or pulmonary vascular resistance measures the resistance to blood flow in the pulmonary artery. This is a calculated measurement that subtracts the pulmonary capillary wedge pressure from the mean pulmonary artery pressure divided by cardiac output. Total pulmonary resistance, or TPR, measures the afterload that the right ventricle needs to pump against. Elevated right ventricular afterload has been linked to poor outcomes in patients with pulmonary hypertension, including Group II PH. Cardiac output is the amount of blood that the heart pumps over time and stroke volume is the amount of blood ejected from the ventricle per beat. Next slide, please.

So in this trial, the baseline characteristics and concomitant medications were consistent with the PH-HFrEF population enriched for CpcPH. Patients had an average left ventricular ejection fraction of 34% and elevated NT-proBNP of over 3,000 picograms per ml. The patients had expected comorbidities of hypertension, atrial fibrillation and coronary artery disease. 57% of these patients had New York Heart Association Class III. These patients had symptoms with minimal exertion. Only 2 patients in Part B had a PVR less than 2 Wood units, 5 had a PVR between 2 and 3 Wood units and 7 had a PVR greater than or equal to 3. Patients were well treated for their heart failure. This is reflected in the high percentage of patients on each key category of HFrEF standard of care. Next slide, please.

So the baseline hemodynamics were also consistent with the diagnosis of PH-HFrEF, means baseline pulmonary capillary wedge pressure was elevated at 31 millimeters of mercury. The PVR of 3.26 Wood units is consistent with the majority of this cohort having CpcPH. The total pulmonary resistance, a measure of right ventricular afterload, was elevated as was the mean pulmonary artery pressure. Notably, the right atrial pressure was also increased, suggesting that these patients also had elevations in right ventricular preload. Next slide, please.

In this clinical trial, TX45 was well tolerated. There were no serious or severe adverse events, discontinuations, infusion-related or drug-related adverse events. The only treatment-emergent adverse event was mild-to-moderate procedure-related back pain, which resolved after completion of the right heart catheterization procedure. There were no clinically significant changes in vital signs, ECG or lab values. In some patients, we observed transient asymptomatic decreases in systolic blood pressure of approximately 5 to 10 millimeters of mercury over the first 24 hours. We saw a similar effect in Part A, and this has also been previously reported for the relaxin mechanism. There were no signs or symptoms of congestion or worsening heart failure, and there were no TEAEs of fatigue. Next slide, please.

In this trial, TX45 resulted in improved left heart function and pulmonary hemodynamics. This slide represents the data as the mean change and the mean percent change from baseline, along with 95% confidence intervals. The values highlighted in green are those values for which the confidence intervals do not include 0, meaning changes are consistent with a nominal p-value of less than 0.05. Notably, the wedge pressure in this population decreased by greater than 6 millimeters of mercury, which translated into an impressive 29% decrease from baseline. Many studies have shown that lowering wedge pressure alone improves exercise capacity in both patients with heart failure as well as heart failure associated with pulmonary hypertension. There was a meaningful approximately 20% reduction in PVR in the PVR greater than or equal to 3 Wood unit populations.

In a previous hemodynamic study in patients with PH-HFrEF treated with Sildenafil, a 20% reduction in PVR was associated with a 29-meter increase in 6-minute walk. In the PVR greater than 2 population, the mean percent reduction was 10.3%. As footnoted in the slide, the lower percentage change from baseline in this subgroup was driven by 1 outlier as evidenced by the difference between the mean percent change of minus 10.3% and the median percent change of minus 18.3%.

For the other hemodynamic measures, there was less variability and the mean and median assessments were similar. Importantly, we observed an increase in cardiac output of approximately 17%, and there was a marked decrease of approximately 29% in total pulmonary resistance, consistent with a meaningful effect in right ventricular afterload reduction. We were encouraged by this because, as I just mentioned, elevated right ventricular afterload is associated with increased mortality and poor outcomes. The mean pulmonary artery pressure decreased by 19% and the right atrial pressure decreased by 29%, suggesting an important reduction in right ventricular preload.

Taken together, the concordance of these hemodynamic effects suggest that TX45 meaningfully improves left ventricular function and pulmonary hemodynamics, both of which are necessary for an effective treatment in PH-HFrEF. Next slide.

So we included echo assessments in this trial to capture persistent effects of the single dose of TX45 out to day 29 post dose. We did this because the constraints of our clinical trial design did not allow us to conduct a second right heart catheterization at that time point. These data demonstrate sustained improvement in markers of left ventricular function, pulmonary hemodynamics and right ventricular function. In the first panel on the left side, the echocardiographic data demonstrated change from baseline in left ventricular ejection fraction from 34% at baseline to 40.3% at day 29, representing an improvement in LVEF of approximately 19%.

The middle panel demonstrates the improvement in TAPSE over SPAP. This is an echo measure that is considered an inversely correlated surrogate for PVR, meaning that if PVR is reduced, we would expect to see TAPSE over SPAP increase. We observed a change from baseline from 0.3 to 0.4, representing an increase of approximately 36% at day 29. This finding provides further confidence that TX45 had a meaningful effect in PVR in this population.

In the far right panel, the treatment with TX45 increased right ventricular fractional area of change, a measure of right ventricular ejection fraction. We saw a change from 29% at baseline to 35% at day 29. This change represents an improvement of approximately 20%. These echo data are very encouraging as they suggest that the hemodynamic improvements seen on day 1 as measured by right heart cath are persistent through day 29 after a single dose of TX45. Next slide.

In summary, these data met our goals. Our Part B data presented today again demonstrate that single doses of TX45 are well tolerated. TX45 demonstrated hemodynamic improvements in both left heart function and in the pulmonary vasculature in PH-HFrEF. This is noted by improvements in pulmonary capillary wedge pressure, cardiac output and left ventricular ejection fraction by echo, which demonstrate the improvement in left heart function and reductions in pulmonary vascular resistance, total pulmonary resistance and mean pulmonary artery pressure, along with the increase in TAPSE over SPAP by echo, which demonstrates improved pulmonary hemodynamics.

The echocardiographic data suggests persistence of the TX45 effects out to 29 days post dose. These data are consistent with what we observed in our PH-HFpEF cohort in Part A. So we are always asked about how these data would translate into changes in 6-minute walk distance. It is difficult to give an exact answer to this question as there have been no approved therapies for pulmonary hypertension associated with heart failure. However, the magnitude of the reduction in wedge pressure and PVR demonstrated in our PH-HFpEF and HFrEF cohorts have been associated with meaningful changes in exercise tolerance in previous clinical trials in the PH heart failure population.

TX45 demonstrated improvements in total pulmonary resistance, a measure of right ventricular afterload. Reductions in right ventricular afterload have been shown to be associated with improved outcomes and a reduction in mortality in patients with pulmonary hypertension due to left heart failure. We are encouraged by these data in PH-HFrEF, and we believe they support further clinical investigation in this population, pending results from our ongoing 24-week APEX Phase II trial in PH-HFpEF.

I will now hand it back to Alise. Next slide.

Thank you, Marcie. Before we turn to Q&A, I'm going to end with just a few company updates. With regard to the APEX study, the study is now just over 50% enrolled. And to date, there have been no safety signals of concern. We've completed the recruitment of patients with PVR of less than 3, and we're now limiting recruitment to patients with a PVR of greater than or equal to 3 Wood units to enrich the trial for this patient population. By the end of first quarter of 2026, we plan to update and narrow guidance for the top-line readout of the APEX Phase II trial, which is currently guided for 2026. As we look to 2026 for the TX45 program, we will also be initiating a study to evaluate TX45 in pulmonary hypertension associated with interstitial lung disease, PH-ILD, with the potential to further broaden the patient population for TX45.

Our second program, which is targeting the treatment of patients with hereditary hemorrhagic telangiectasia remains on track to enter the clinic in first quarter of 2026. We're really excited to be exploring the potential of TX2100 in this patient population with a high unmet need and no approved therapies. Financially, the company is sound with a runway into fourth quarter of 2028. I'd like to conclude just by thank you for your time today. Operator, we're now prepared to open the line for questions. Please go ahead.

Our first question comes from Tyler Van Buren with TD Securities.

This is Frances on for Tyler. Congratulations on the data. It's great to see the consistency of the effects across the 2 populations. Just curious what in the Phase II APEX trial would make you feel confident moving forward in later-stage trials for PH-HFrEF?

I think if we see evidence of good efficacy and safety, that would certainly give us confidence to move forward in HFrEF as well. And I think we'll be looking for evidence of reductions on pulmonary vascular resistance, increased cardiac output. And while we're not powered fully for 6-minute walk test, we're going to be looking for strong numeric trends there.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on the great data. Would love to understand sort of when we think about the hemodynamic and responses in the HFrEF population, how that could translate sort of prediction on a 6-minute walk test or a functional improvement in the population. You guys have done a really nice job educating us on hemodynamic correlations to the HFpEF population, but I appreciate color on how do we take this really strong data from Part B to think about APEX.

Yes. We think that it's similar and that what you want to see is a reduction in the pulmonary capillary wedge pressure, a reduction in the PVR that also leads to an increase in cardiac output. And if you look at the studies that have been done, there was a surgical technique, PAN, that was associated with about a 20% decrease in wedge and a 30% decrease in PVR, and that led to almost a 70-meter increase in 6-minute walk. That's a high bar. I don't think that's the bar we're aiming for. That was in a very, very high PVR population, but it gives you a sense of -- and that study was done both in HFpEF and in HFrEF. And then there was a PH-HFpEF CpcPH population for -- and then there was a study by Lewis in 2007 done with Sildenafil in PH-HFrEF. And in that study, they saw a 20% improvement in PVR, an increase in cardiac output. Wedge actually didn't go down that much. And in that study, they saw a 30-meter increase in 6-minute walk. So I think the data that we've seen both in HFpEF and HFrEF suggests that if maintained over the 6-month period, we should see clinically important improvements in 6-minute walk.

Our next question comes from David Risinger with Leerink Partners.

Yes. So congrats, Alise and team on today's results and on the strong progress in enrollment in APEX. Could you comment on the lack of fatigue in Part B relative to Part A that was seen? And then also just discuss that patient outlier in a little bit more detail that drove the difference between the mean and median hemodynamic results.

Yes. We didn't see any fatigue-related AEs. As Marcie said, the only AE we saw was procedural back pain and the patients felt better when they got up off the table. In Part A, we saw fatigue only at the high dose, which we think was by chance and only at the end of day 1. And when they came in on day 2, they no longer had fatigue. Nobody thought that, that was related to drug. But I think we heard there were some people talking about wondering whether the fatigue was a result of a lowering in blood pressure. We never saw a correlation there. And I think the fact that we didn't see it here just speaks to the fact that it was related to the time in the cath lab more than anything else.

You asked about the one outlier. The issue when you do small numbers of patients is you can have one outlier that really impacts the mean. And what we saw was a difference in the mean and the median as Marcie outlined, with the median more aligned with what you would have expected to see. And that patient had a very, very large drop in pulmonary capillary wedge pressure that was larger than their drop in pulmonary artery pressure, which meant that their PVR went up, and they started with a not very high PVR. And so the percent change ended up being quite large. And when you do a percent change from baseline, you don't take the absolute value of the mean and figure out the percent change. Instead, for every single patient, you figure out their percent change and then you take an average of those. And so in the percent change in PVR, that one patient had sort of an outsized effect.

Our next question comes from Uy Ear with Mizuho.

Congrats on the great data. Alise, I think you indicated that you've met with the Data Safety Monitoring Board and they've given you pretty much a clean bill of health. Just wondering if you could elaborate that a little more as to when was the Data Safety Monitoring Board, when did they meet? And was it -- were they sort of aware from the Lilly Phase II publications? And if there's anything else that can be shared, that would be great.

Yes, I'm going to let Marcie take that.

Sure. So we met with the DSMB after the volenrelaxin data was released, and we told them about it, and we specifically asked them to look at the unblinded data to see if they saw anything of concern. There was nothing in our blinded data to suggest any issues. And their examination of the unblinded data in mid-September suggested that there was no issues, and they told us to continue the study without any alterations.

And was there any hospitalization or anything to that effect?

We've had one -- we've now had 2 patients hospitalized for heart failure. But again, remember, these are patients with heart failure. And so there's an expected rate of heart failure hospitalizations actually even in the placebo group in this trial. So the rate we have now is completely expected.

Our next question comes from Cory Jubinville with LifeSci Capital.

Congrats on this really exciting data. I guess just building off the previous question, we saw with the volenrelaxin data presented at ESC last month that they saw a significant increase in plasma volume as early as 3 weeks post treatment, which is what they thought contributed to some of the adverse outcomes. I mean you pretty encouragingly reported no signs or symptoms of congestion. Can you just quantify the magnitude of change in plasma volume, if any, you observed following the treatment period? And similar to the DSMB update in APEX, is there any signs of congestion at all in those patients?

We -- there were no AEs suggestive of congestion. And if you looked at hemoglobin and hematocrit, which is how you get at plasma volume, there was nothing suggestive that we saw an increase in congestion.

Very good. And just as a quick follow-up, can you help us contextualize the clinical significance of some of these echo parameters, Specifically, if my math is right, you're bringing the average ejection fraction above 40% out of that HFrEF range in the HFrEF patients, essentially changing some of these patients' classification from HFrEF to heart failure with mildly reduced ejection fraction. Is that meaningful at all? Or is that predictive of potential cardiac remodeling or outcomes that might occur down the line? How should we think...

Yes. I'll see if Marcie knows the data, I'm not aware of data probably because there aren't too many drugs that do that, that link an increase in ejection fraction to outcome. I'd have to go back to look at the literature. I think it's positive. It reminded me of the monkey study done by AZ in a monkey model of reduced ejection fraction heart failure where over 5 months, over that 5-month period, you saw the ejection fraction continue to go up over 5 months. And in our study, even over the day 2 to day 15 to day 29, we saw it go up. It sort of raises the question of what we -- are we seeing a remodeling effect? Why is it taking time to go up over time? It's interesting.

Our next question comes from Danielle Brill with Truist.

This is Alex on for Danielle. Congrats on the data. I'm just going to zoom out a little bit and ask a more philosophical question about your dosing. Can you just remind us where you are in the dose range as it pertains to relaxin receptor agonism? And additionally, how your strategy compares to the current AZ approach and the prior Lilly trial in heart failure?

So our 300 q2 dose at trough levels, we should be probably about between 90% and 95% of agonizing the receptor. At our 300 q4 dose at trough, we're probably somewhere between 75% and 80% at trough exposure. The volenrelaxin study, their lowest dose was already above, we think, 95% agonism. And then the other doses were on top of that. So we really think they were at the upper edge of the dose range. And that may have had an impact on their study.

The one endpoint, and I don't want to make too much of this because I've heard 2 competing views of this. At the lowest dose, they did see a significant improvement in left atrial strain. And then you lost that at the higher doses. Some people have said that they think that could signify that a little bit of a lower dose was better. I don't know whether to make too much out of that. AZ is probably testing the widest dose range. We think their top dose is similar to our 300 q2 dose. And their middle dose is probably more similar, maybe a little bit lower than our 300 q4. And their lowest dose, we don't even think gets to an [ EC50. ]

Our next question comes from Martin Auster with Raymond James.

Congrats on the favorable consistent hemodynamic effects shown today. Alise, I appreciate the clarity on the Phase II APEX enrollment and the disclosure on targeting 70% CpcPH patients. I was wondering if you could comment on if that's sort of been the consistent plan through. I know previously, you just said it was going to be sort of generously enriched. Curious if that's sort of evolved or that's always been sort of the team's thinking internally. And then also, I just wanted to check in on now that you've probably got most or all of the sites sort of up and running in terms of screening failures and kind of finding eligible CpcPH patients, does that do anything to sort of adjust the rate of enrollment going forward? Are you still pretty confident that you can sort of benefit with all the sites up and running now?

Yes. It's been 70% since we wrote the original protocol. So there were no changes there. I don't know why I was being coy about sharing that data. And I finally said we might as well share it. So that was no changes there. We're seeing about 45% of -- when we were doing all comers, about 45% had PVR greater than 3. I don't know, 70% to 80% had PVR greater than 2. I think those were actually a little higher than we thought. And I think we'll have a better sense -- we want to give it a few months with just enrolling the PVR greater than 3 until I can give you more clarity on timing for ending the study. And that's why I said in -- by the end of first quarter of 2026, we'll be ready to narrow the guidance there.

And our last question comes from Leland Gershell with Oppenheimer.

Congrats on these terrific data and again, reiterate the consistency with the Part A data set. Just wondering with respect to the PVR, we saw it was a wider confidence interval for those measures in the HFrEF versus HFpEF. Just wondering if that is incidental to this part of the study or if it may be a function of the different nature of the heart failure.

And part 2 of my question, which I guess relates to that is as you look to contemplate next steps in development for HFrEF, it sounds like we won't see that until the APEX data are in hand. But thinking -- should we presume that you take TX45 forward for HFrEF, would you look to conduct a Phase II similar design with respect to PVR being primary endpoint and 6-minute walk secondary? Or how might it differ with respect to endpoints?

Yes. So we saw a little bit more variability on PVR than we did in the first cohort, not completely unexpected. I don't know that I can say that's because of HFrEF versus HFpEF. We'll just need to study more patient numbers in order to get an idea of that. And with regard to the later, I think it's premature for us to say how we would move forward. We wouldn't necessarily have to do a stand-alone Phase II. We could potentially go to a Phase II/III. We'd have to get alignment with regulators on that. So I think there's a variety of ways that we could incorporate HFrEF into the program without delaying it too much.

Thank you for your participation. This concludes the question-and-answer session, and you may now disconnect. Good day.