Enanta Pharmaceuticals, Inc. Stock

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Rati Pinge, Priyanka Grover and Joyce Zhou.

Our next presenting company is Enanta, and presenting on behalf of the company, we have CEO, Jay Luly.

Thank you, Anupam. Before I begin, I want to remind you, I'll be making some forward-looking statements. For a summary of the risks associated with these statements, please see our filings on sec.gov and on our website.

For those of you who are less familiar with Enanta, we are a virology and immunology company. Our roots originally were in virology and even deeper in hepatitis C, in the early days of hepatitis C, where we helped bring forward two products with AbbVie to market. Our key program there was hep C protease. And we invented glecaprevir, which is a part of the hep C drug called MAVYRET, which has cured well over 1 million patients chronic hepatitis C.

We moved beyond the liver virology several years ago and got into respiratory virology with RSV being our first target there. Viewing the high unmet need, the virus has been characterized for more than 6 decades. But to this date, nobody has brought forward a safe and effective treatment for the virus. More recently, there have been vaccines but even those have limitations and there's an incredible vulnerable population in the world that we aim to treat. So we'll spend a lot of time talking about that.

The pandemic broke out, we've also worked in COVID in protease inhibitors again. And then we began to branch out beyond virology in immunology. And in fact, just 2 years ago at this conference, we announced our first program in KIT inhibition. Last year, we announced STAT6 inhibitors. And this year, we are announcing a new program, MRGPRX2 otherwise known as X2. So we'll go through these in sequence.

Starting with respiratory syncytial virus. A lot of people only became more familiar with RSV after the pandemic, even though RSV has been around for a long, long time. But I think the acute awareness of respiratory infections became at the highest point during the pandemic. And then after the pandemic, when RSV and flu returned, there were big outbreaks. And ultimately, fits and starts in getting seasonality of RSV back, but it's been an endemic virus for, as I mentioned, decades.

Looking at the statistics from last year's -- the '24-'25 season in the U.S., there were up to 6.5 million outpatient visits, hundreds of thousands of hospitalizations and tens of thousands of deaths associated with RSV in the United States alone.

We're keenly focused on high-risk populations, people who will do more poorly if infected, they're the most vulnerable populations. And you can see those starting at both ends of the age spectrum, you have pediatrics that are vulnerable, you have elderly. And then you have other patient populations, people who have preexisting comorbidities such as COPD, asthma, congestive heart failure and, of course, the immunocompromised.

I mentioned vaccines have come forward in just the last couple of years. But the adoption really hasn't been very penetrating. It's probably estimated around 20% of the eligible population has been vaccinated, and that certainly lags things like shingles and flu.

Further, pediatrics have prophylactic monoclonal antibodies. They don't provide any long-term protection. They help during the first year of life. But then you're basically pushing the age for first, second and third infections to older children. And so we're seeing a shift now in the age of the first RSV infection to children who are not necessarily in their first year. But again, a number of people -- a number of children are still infected, you have breakthrough infections. And again, these prophylaxis don't offer durable protection. So there is a huge vulnerable population.

So I mentioned we're focused on high risk. We've reported out now two Phase II studies that were successful. The bottom one is in peds. We announced that one first in children down to as young as 28 days of age. I'll highlight some of the information from that study. And then more recently, late last year, we announced data of zelicapavir, our lead asset, in high-risk adults. And again, these were people who were over the age of 65, COPD, CHF or asthma.

So what were the results there. Again, we've published or we've presented the full study and those data are available on our website. But suffice it to say, we looked at this high-risk patient population very carefully. And it's in the patient population that I just mentioned, but we further had a prespecified population that was 80% of the study that had three high-risk factors -- one of three high risk factors in the study. So that was the so-called HR3 population. These were people who were 75 or older, people who had COPD, people who had congestive heart failure. And the idea was there to cap at 20% of the study, people who were young, otherwise well controlled asthmatics, people who were otherwise healthy, 65 to 74 years old, we really didn't want otherwise healthy people diluting out too much of the high-risk patient population.

So -- but what you can see is in the HR3 population, placebo had a time to complete resolution of all symptoms of -- on the order of 3 weeks. And zelicapavir shortened that time to complete resolution by about a week. So it was a remarkable result. We saw that across all 13 symptoms in the symptom tool we used and an additional 16 measures that were beyond symptoms, more lifestyle impacts.

So it was a very exciting study. And from that, not only did we see complete time shortening of the complete time to symptom resolution by the RiiQ symptom tool, there was another tool that we use called the Patient Global Impression of Severity. And that score was also a statistically significant improvement there, a 2-day shortening. And perhaps most intriguing was the lowering of hospitalization rate. In the placebo group, we had about a 5% hospitalization rate and that was reduced to about 1% on the drug-treated group. So overall, many signals lining up, many potential registrational endpoints and a very exciting outcome.

We also, of course, looked at virology, saw that in a very consistent, well-tolerated and safe profile that we've seen now in over 700 patients who have taken zelicapavir. So this data in the aggregate support advancement into Phase III in high-risk adults, and we'll talk more about that.

So here's the pediatric study. Again, we're treating children down as young as 28 days of age. So very young children. And for that, you want to be very careful, do a careful dose ranging, which we did. We looked at a lower dose and a higher dose. The key part was establishing that we had an antiviral effect. And we also began to bring on some symptom analysis in this study even though this study wasn't predominantly focused, it was more of an exploratory endpoint. And what we did see was some improvements on symptoms as well. So now we have looked at the pediatric population. We've looked at high-risk adult populations as well.

So this is the data on zelicapavir. We actually have another molecule that's sort of one stage behind zelicapavir. It's a different mechanism, an L-protein inhibitor. And we've talked about this in the past, so I will just summarize it on one slide here. But we had a very, very nice human challenge study with this, which is sort of a rite of passage for RSV agents. You want to be able to go into healthy volunteers who are infected with the RSV virus, and then who are then -- after the viral loads start to build up, they are then treated with drug.

And what we showed was a very high level of viral load reduction, 85% to 87% viral load reduction as measured by PCR. But if you go in and actually look at viral cultures in terms of the impact of knocking down the viral replication, in culture, we actually saw a 97% to 98% reduction in that. And not only that, but it was happening within 12 hours of the first dose. So an incredibly rapid acting agent. We also saw improvements in symptoms as well. So I think we have a good dataset here to support advancement of EDP-323 as a second mechanism into high-risk patient populations of one sort or another.

So let's shift gears to immunology. As I mentioned, on the left, 2 years ago, we announced we were beginning in this field. We announced that we would have a KIT program, again, this is a mast cell target focused on reducing mast cell numbers. It's a target that's been studied with monoclonal antibodies in chronic spontaneous urticaria and CIndU and some other mast cell-driven diseases. What we wanted to do was have an oral small molecule alternative to monoclonal antibodies and potentially something that could be dosed in a very straightforward way versus a monoclonal antibody, potentially with some advantages. And we set out the goal 2 years ago to have a development candidate in KIT rapidly, we now have one called EDP-978 that we're filing an IND on this quarter.

And then on the right-hand side, I mentioned a year ago, we announced our STAT6 program with the goal of having a candidate by the end of last year. We now have one of those. I'll talk about, called 3903. And then this year at the conference, we are announcing our third immunology program, again, with a target of having a development candidate in the second half of this year.

So each one of them is going after type-2 immune diseases, taking different angles, having multiple shots on goal. And in the case of STAT6 going after an oral DUPIXENT profile.

So let's start with KIT. Again, candidate 978 was selected. It's an incredibly potent molecule, both in vitro and in vivo. It's a kinase inhibitor. So you want to have selectivity. We've demonstrated very high levels of selectivity. And importantly, what we think are optimal in vitro and in vivo ADME properties. So once daily dosing, but yet controllable dosing and half life, et cetera, et cetera, to give you something that could be conveniently and maybe very targetedly dosed in this indication. So we're on track to file the IND in this quarter and report Phase I data with biomarkers out in Q4 of this year.

Shifting to STAT6. Again, the goal, in concept, is an easy one. We're trying to come up with an oral DUPIXENT. So DUPIXENT blocks the IL-4, IL-13 signaling at the beginning of the cascade. What we're doing is intervening a little bit downstream by blocking a transcription factor called STAT6. and blocking the activation of that will lead to the transrepression of a whole number of pro-inflammatory gene products.

So what we've done is selected the candidate. We announced it late last year, 3903, very strong potency in terms of nanomolar potency; highly selective, I'll show some data on that. And the key here is that we don't see pulsatile inhibition of this target. We see continuous and complete inhibition of this target. And I'll show some data as it relates to that, some animal models. Again, our -- we're on track to file an IND in the second half of this year.

And how do I know that we have sort of continuous inhibition? Here's the model. So you dose mouse in this case, with drug. You wait 24 hours so that the drug concentrations are at their lowest. You pull a blood sample and then you stimulate it with IL-4, and you ask the question, do you see phospho STAT6. And it turns out in the graph on the right shows the 24 hours post an oral dose, so at trough drug concentrations, you see complete inhibition, over 90% inhibition of phospho STAT6 induction. So that shows throughout the 24-hour period that we have coverage on that target.

We then moved into two different models of looking at efficacy versus dupilumab. And the first one is in atopic dermatitis model that is triggered basically by a vitamin D3 analog. It's a so-called MC 903 model, where you topically dose the animals with this vitamin D3 analog, it creates an atopic dermatitis-like state and then you can look at drug efficacy in that model.

And what you can see is that the drug -- the animal is dosed and then challenged in the air challenge model, and then there are lots of different readouts and different tissues you can look at. So we're looking at phospho STAT6 activation in the skin. What you can see in the panel on the lower left, is on the left-hand side of that graph is our compound, 3903, completely inhibiting the response. And on the right-hand side of that lower left panel is what dupilumab does, which is it inhibits the response as well.

So we're on par with dupilumab in that. You can look at spleen phospho STAT6 levels. Similarly, you can look at serum IgE levels. And in each instance, we're very completely inhibiting that response along the lines of dupilumab.

This is an asthma challenge model where, once again, you have transgenic animals with human IL-4 receptors. They are dosed with EPS-3903 and then they're challenged with house dust mites, which can induce an asthma-like condition. And so in this model, it allows you to interrogate multiple different compartments. We're looking at lung phospho STAT6 inhibition, and it's the same paradigm as the slide before. Our drug is on the left, we knocked the levels down below the quantitation level and similar to dupilumab. You can look at bronchoalveolar lavage fluid eosinophils influx and similarly, we knock it down similar to dupilumab. You can look at lavage fluid TARC, serum IgE, again, it's all very consistent, and we have histologic scoring beyond these data that we'll present at another opportunity, but the drug seems to work incredibly well in these preclinical disease models.

And this is just a cartoon, the last slide on STAT6, showing that EPS-903 has very good drug exposure. And that's why at the Cmax and the Ctrough, Cmax, Ctrough, as you dose continuously, the key thing is having those trough-level concentrations above the EC90 required for the response. And in that way, we can see the same sorts of effects as any degrader would. So we like small molecule inhibition. It's what we do. It's what we do well. We like the predictability of dosing PK drug-like properties that we know well from many other experiences.

So let's talk a little bit about X2. X2 is another mast cell target. It's expressed predominantly on mast cells, although we can see it on peripheral neurons as well. And agonism of that receptor leads to degranulation and a whole bunch of inflammatory release. And so it's yet another path to target the mast cell, gives us optionality in terms of multiple shots on goal in some of these mast cell-driven diseases. But importantly, it also gives us, to our growing armamentarium, an opportunity to begin to explore combinations of these agents such that we might see potentially even stronger efficacy than either alone, given the orthogonality of their mechanisms.

So just a little bit of evidence for X2, we'll call it, playing a key role in CSU. It turns out that patients with CSU have more X2-expressing mast cells. You can see that on the left panel. And they also have a greater response to X2 agonist of one sort or another in terms of being responsive. So it is -- it's a phenotype that is consistent in CSU patients and probably driving a component of that disease is X2.

So where -- our goal is to develop a really strong inhibitor here. We have prototypes that are very potent that block mast cell activation in a mouse model. They're highly selective for X2 versus other GPCRs. And as always, we're always trying to optimize ADME properties to support once daily dosing. So we're feeling good about our prototypes, on track to have a development candidate second half.

Just a little bit of data just shows the potency in the mast-cell cell line called LAD2, also primary skin mast cells, very consistent. And then the in vivo model is you take a mouse, they're injected with a blue dye and then you can come in cutaneously and stimulate with an X2 agonist and look for changes in vascular permeability that would be driven by mast cells. And that's what the panel on the right -- lower right shows that vehicle versus prototype just knocks that response straight down.

There are a lot of ligands that trigger X2. And what we like is whether it's neuropeptides some of the antimicrobial peptides, peptide hormones, we have a very consistent high level of potency against all these different ligands. So excited about the new program. We'll have a lot more to say, and we're on track to announce a candidate in the second half of this year.

So just to summarize, in virology, we're focused on really aiming for that Phase III. We're in -- beginning discussions with FDA around what the Phase III design would look like and the registration path. We expect to have that alignment done in Q2. We are preparing for a Phase III study in zeli. It's a seasonal thing, right? So you want to be ready to pull the ripcord when the virus comes. Usually starts to really come in earnest in Q4, but it could start in Q3. So we want to have the program enabled. We built up drug supply and trying to grease the tracks so that everything could be done.

And simultaneously, we're exploring BD opportunities in this RSV field, knowing that ultimately somewhere between now and commercialization. We want to have a commercialization partner who could really make an impactful launch with the -- what we believe could be the first-ever treatment for RSV and to do that on a global basis to get these vulnerable populations treated.

Immunology, just to summarize again, we're on track to file the IND for 978 in Q1, report Phase I data in Q4, STAT6 IND in the second half and then development candidate for X2 also in the second half.

So with that, thank you very much.

All right. I will ask the first couple of questions, but there will be opportunities for the audience to also get some questions in, if you have them, just raise your hand, and the mic will come or -- and/or I can repeat your question.

I wanted to start out with zelicapavir here. I know this slide says, hey, you're going to explore business development opportunities. But you also just now said you're going to need a partner at some point. So would you be willing to start a Phase III study after alignment with the FDA on your own?

Well, that's certainly in the constellation of possibilities. Again, I think anytime you have a dataset, you owe it to yourself to explore opportunities and see if you can find the right value and if you can find the right committed partner.

That said, this study is probably on the order of 500 to 700 patients. So it's not a huge study. And whether a partnership or not, we probably have one of the world's best teams in terms of knowing how to conduct these studies on a global basis. So we'll see how the path proceeds.

But it's a -- we also don't want to squander our leadership position here, right? The competitive landscape has fallen a bit to the side with some of the pharmas that we were working against stumbling last year, but we're not alone, but we are ahead. So I want to make sure one way or the other, this thing gets the development it deserves.

And with the Phase IIb zeli data in hand, how are you thinking about next steps for EDP-323 in RSV?

Tara, do you want to take that one?

Sure. Yes, as Jay said, I think with zelicapavir, we have the potential for a first-in-disease treatment for RSV. We're developing that in high-risk adults, also pediatrics are another high-risk group. I think EDP-323, we have challenge study data that probably is some of the best data, at least from a virology perspective that we've seen in a challenge study. So there is a potential for that to be a best-in-disease asset.

It seems like for the majority of patients, probably monotherapy, one agent would be sufficient. But there are situations where a combination might benefit, if you have a severely immune compromised or other sicker patients. So I think there's a lot of opportunities here and something where, again, as Jay mentioned, we want to maintain leadership in this space.

Questions from the audience? Maybe switching gears a little bit here. How are you thinking about STAT6 as a target post some recent competitor data? What gives you confidence in your oral small molecule approach, such as the one you have with 3903. And I think there's this view out there that, I mean, this has to be a target that's degraded, right?

Yes. Well, I think what I hope I have shown at least in the data, if you look at that -- I don't know if I want to go back to slide, maybe I'll click back just while I'm talking here. But it really comes down to -- well, this is a good cartoon. As long as you can -- it's with any drug target, right? So we come from a virology background where at trough concentrations of drug, you don't want the drug to not be there and have an effect because a virus can start to do mischief, right? It can start to mutate. You need to keep the pressure on 24/7. So we're used to putting high degrees of pressure on targets even at the 24-hour time point.

So as long as you do that, it's not mysterious. Even on the cartoon, the orange bit on the left here, as long as that trough concentration can be maintained above the EC90, you are going to -- you're going to see efficacy. And that's what this mouse study really showed that 24 hours after dosing, you take the blood out, you stimulate and you just -- you can't demonstrate activation because the drug is still inhibiting. So we don't believe you need to degrade the target, sort of take that nuclear option on the target. You don't have to do that. You can just have a straightforward inhibitor.

And then for the KIT program for EDP-978, just the final gating factors to getting that IND filed, but then what's going to be kind of the size and scope of the Phase I data that you're going to have in the fourth quarter? And what should we be looking for?

Sure. Yes, we're wrapping up the -- all the activities. It'll be filed in Q1, so very shortly. And then the Phase I will be a typical healthy volunteer SAD, MAD study. We'll be able to read that out in Q4 of this year. We will get a lot of information on sort of safety and tolerability profile, some PK to inform dosing.

And then the nice thing about this target and this indication is you can look at biomarkers like serum tryptase, which give you a really good idea of activity of your compound. So early on in development, we're able to get some target engagement and derisk the asset.

Questions from the audience? And then maybe a final one for me here, just on X2 program. I didn't want to say the whole thing, I just called it X2 because you did. So just on maybe expanding on why this target is so exciting to you? And then what are the kind of steps here that you're going through in your library to kind of get that development candidate nominated?

Yes. So I can come back to there's -- if we look at the slide where we have all three, it's one of the things where -- among the things I like about the setup is it's the sum of the parts, I think, is bigger than one could potentially think about from any of these alone because X2, you have -- the obvious ones are indications you could go after and sort of follow other mast cell-driven diseases, CSU, atopic dermatitis, asthma, CIndU and so forth.

But the other thing is these are -- the target is somewhat interestingly expressed on peripheral neurons, and there's a feedback loop between mast cells and neurons that can cause inflammation, and that has the potential in other things such as migraine, for example. So there's ways to think a little bit out of the box with some of these targets.

And like I said before, STAT6, we're going after a straightforward product profile of having an oral DUPIXENT. But could we begin to merge some of our other targets into some of these indications and do try to aim for even better than DUPIXENT efficacy with an all-oral approach. So we'll be -- we'll begin to explore that now that we have multiple tools. So just -- it's about optionality in some of these important disease areas where oral options don't exist.

Any final questions from the audience? Thank you, guys.

Thank you.

Thank you.

Good morning, and welcome to Enanta Pharmaceuticals Conference Call. [Operator Instructions] Please be advised that this call is being recorded. I would now like to turn the call over to Jennifer Viera, Head of Investor Relations. Please go ahead.

Thank you, operator, and thanks to everyone for joining us this morning. The news release announcing the top line results of our RSVHR study became available earlier this morning and can be found on the Investors section of our website. Today's conference call is being webcast with slides. A copy of the slides is posted on the Events and Presentations section of our website.

On the call today are Dr. Jay Luly, President and Chief Executive Officer; Dr. Scott Rottinghaus, Chief Medical Officer; and Dr. Tara Kieffer, Chief Product Strategy Officer.

Before we begin with our formal remarks, we want to remind you that we will be making forward-looking statements, which may include our plans and expectations with respect to our research and development pipeline and financial projections, all of which involve certain assumptions and risks beyond our control that could cause our actual developments and results to differ materially from those statements. A description of these risks is in our most recent Form 10-K and other periodic reports filed with the SEC. Enanta does not undertake any obligation to update any forward-looking statements made during this call.

I'd now like to turn the call over to Dr. Jay Luly, President and CEO. Jay?

I'm pleased to be with you this morning to detail the positive top line results announced today in RSVHR, a Phase IIb study to evaluate the efficacy and safety of zelicapavir in adults with acute RSV infection who are at high risk of complications. We are very encouraged by these results and believe that the data provides strong rationale for further clinical development of zelicapavir. Importantly, we identified multiple potential registrational endpoints for a Phase III trial in high-risk adult patients. These results demonstrate the ability of zelicapavir to meaningfully shorten the duration of RSV symptoms and reduce hospitalization rates in a high-risk adult patient population.

As you can see on the pipeline, we have a robust portfolio of antivirals in development for the treatment of RSV. In addition to zelicapavir, we also have EDP-323, an inhibitor of the L protein, which demonstrated best-in-disease activity in a challenge study setting. Across our RSV portfolio, our goal is to develop safe and effective treatments for high-risk patient populations who currently have no treatment options. To that end, today marks a meaningful milestone for our company. The data we're about to present are the first to show that an antiviral can have a clinically meaningful benefit in this high-risk adult outpatient population. I want to thank all the participants in the RSVHR study, their families and caregivers, trial investigators and importantly, our Enanta team who contributed to the success of this study.

As you all know, the goal of our RSV program is to treat patients at high risk for developing severe infection leading to hospitalization or death. This includes 2 primary populations, infants and young children and adults aged 65 or older or those who suffer from chronic heart or lung disease. We previously reported positive data in pediatric patients with a favorable safety profile and robust antiviral activity. Today, we present results from our adult study, demonstrating the ability to improve symptoms and reduce viral load across broad patient populations.

As a reminder, since there haven't been any registration studies for RSV in this age population, we looked at how clinically meaningful is defined in symptomatic endpoints and registration studies for other respiratory drugs to create a benchmark for our desired outcome. On the left of this slide are 2 approved flu treatments, Tamiflu and Xofluza. And on the right-hand side is Xocova, which is Shionogi's SARS-CoV-2 protease inhibitor. Across 2 different drugs for influenza and 1 for COVID, we consistently see an improvement in symptom duration of about a day. We too hope to see a reduction of symptom improvement of at least 1 day, and we are pleased to see improvements of even greater magnitude on complete resolution of symptoms.

Finally, before we dive into the data, I want to reiterate that RSVHR was designed as a proof-of-concept signal finding study with 2 goals. The first, to inform the design of a Phase III trial, specifically looking to identify the target population and optimal endpoints for registration; and second, to give an indication of treatment effect that could be confirmed in a larger registrational study. As is typical for such a Phase II signal finding study, we look at the totality of data to further inform the design of a Phase III development plan. In this study, we evaluated multiple endpoints to assess which ones would best elucidate a treatment benefit. For example, we looked at all 13 RSV symptoms, a subset of lower respiratory tract disease symptoms, total RiiQ score, additional patient-reported outcomes like Patient Global Impression of Severity score, virology and hospitalization rate, among others. We believe the results today mark an important step in closing the treatment gap and bringing forward the first treatment for RSV.

With that, I'll turn the call over to Dr. Scott Rottinghaus, Chief Medical Officer, to go through the data in detail. Scott?

Thank you, Jay. This is an exciting time at Enanta, and I'm eager to share results from the RSVHR study with you today. I'll begin with a review of the study design.

As Jay mentioned, RSVHR was a Phase II double-blinded, placebo-controlled proof-of-concept study of zelicapavir in 186 high-risk adults. Patients had to have chronic obstructive pulmonary disease, congestive heart failure, asthma or be 65 or older, all factors that predisposed to poor outcomes from RSV infection. Enrollment was capped so that healthy adults aged 65 to 74 or young asthmatics comprise no more than 20% of the total patient population. The remaining 80% were higher-risk patients with CHF, COPD or aged 75 or older, a predefined analysis population that we will refer to as the HR3 population.

Patients were enrolled within 72 hours of symptom onset and randomized to receive 800 milligrams of zelicapavir or placebo once daily for 5 days with follow-up through day 33. The primary endpoint was time to resolution of RSV lower respiratory tract disease symptoms as assessed by the Respiratory Infection Intensity and Impact Questionnaire, or RiiQ symptom scale, a patient-reported outcome tool, which I'll talk about in more detail in a moment. We also looked at time to resolution of all symptoms by RiiQ as well as the total RiiQ instrument. Other secondary endpoints, as you can see in the red box, included additional patient-reported outcomes, medically attended visits, virology and hospitalization.

Before we get into the results of the study, I want to give you more detail on 2 PROs that we use to measure symptoms, so you can understand the results I'm going to share with you in a moment. First, I'll go through the RiiQ, which is the measure of our primary and many of our secondary endpoints. You can see here that the RiiQ is composed of 5 components that consist of 29 questions, each of which is assessed on a 4-point scale. We asked patients to answer these questions daily. I want to highlight 2 important definitions. The first is resolution, which means the first of 2 time points at which all symptoms are scored as mild or absent. And the second is complete resolution, which means the first of 2 time points at which all symptoms are absent. As shown in the 3 colored boxes, we focused on 3 different RiiQ endpoints. In the blue box, you can see the total RiiQ score that includes all 29 parameters. In the orange box are all 13 RSV symptoms, including respiratory and systemic symptoms. Finally, in the green box is a subset of 4 lower respiratory tract symptoms.

At the bottom of the slide is the second PRO I'd like to go through, which is the Patient Global Impression of Severity, or PGI-S. This is one of the secondary endpoints of our study. The PGI-S consists of a single question assessed on a 4-point scale and collected daily. The question is, in the past 24 hours, what was the severity of your overall RSV-related symptoms at their worst? We consider this question resolved at the first of 2 time points when the patient answers that they have no symptoms.

This slide shows the patient disposition in the study. We randomized and dosed 186 patients, 65 on placebo and 121 on zelicapavir. This population of patients who received at least 1 dose of study drug constitute the safety population and is used for all the safety analyses I will show you. We also have an efficacy population that consists of all patients who had a positive PCR at the central lab. You can see that this is the great majority of patients in the study. And finally, there's the HR3 population that I mentioned to you earlier, who are the patients at highest risk for RSV complications, those who have CHF, COPD or age greater than or equal to 75. This HR3 population included 142 patients or about 80% of the efficacy population. At the bottom of the slide, you can see that over 93% of patients in the safety population completed the study.

Here are the baseline characteristics of the study population. You can see the safety population on the left and the HR3 population on the right. Treatment groups were well balanced with the exception that there was a greater proportion of women on placebo than zelicapavir. It's worth calling out at the bottom of the slide that about 2/3 of the patients were enrolled within 48 hours of symptom onset. This slide shows the breakdown of patients with congestive heart failure, COPD and asthma as well as baseline symptom score and viral load. Characteristics were, again, fairly well balanced across treatment groups with the exception that there were more patients with CHF on zelicapavir than placebo.

Zelicapavir exhibited a favorable safety profile in this study. You can see that treatment-emergent adverse events occurred at similar rates between zelicapavir and placebo with 22% to 24% of patients experiencing adverse events. Serious adverse events occurred in about 2% of zelicapavir patients compared to about 6% of placebo patients. No adverse events led to treatment discontinuation, study withdrawal or death among patients who received zelicapavir compared to 1 or 2 events in each of these categories on placebo.

This slide shows treatment-emergent adverse events occurring at a frequency of greater than 2% in any treatment group. As you can see, the 2 most common adverse events in the zelicapavir group were diarrhea and asthma, both occurring at low frequencies. These asthma events were all exacerbations of underlying asthma and not related to study drug. The most common adverse event on placebo was nausea.

Now let's turn to efficacy results, starting with reduction in symptoms. Here is the time it took for all symptoms to completely resolve for patients on zelicapavir compared to placebo. We were very excited to see that zelicapavir consistently reduced that symptom duration across populations and across multiple RiiQ measures, including lower respiratory tract symptoms, all RSV symptoms and the total RiiQ. This effect is even more pronounced in the HR3 population of patients with CHF, COPD and age greater than 75, shown on the right-hand side of the slide. In the HR3 population, all RSV symptoms completely resolved about a week faster with zelicapavir than with placebo. The duration went from 19 days to 12 days, which represents a 35% improvement. You can see the results were similar for the total RiiQ where the duration went from 3 weeks with placebo to 2 weeks with zelicapavir. These clinically meaningful results using the RiiQ tool provide multiple potential registrational endpoints that could be used in a Phase III study.

In the next few slides, I'll share the rest of the efficacy data, which identify additional potential registrational endpoints. Here's the first one, Patient Global Impression of Severity score. Recall, this is the patient-reported outcome that asked about the severity of symptoms over the past 24 hours. This is a secondary endpoint in our study. These are the Kaplan-Meier curves for the overall efficacy population on the left and the HR3 population on the right. As you can see, patients treated with zelicapavir shown in orange, had a statistically significant 2-day faster time to resolution compared to placebo shown in green. Here's a summary of symptom data for zelicapavir compared to placebo. This table reiterates the data I showed you a moment ago where patients receiving zelicapavir had a faster time to complete resolution of all RSV symptoms to absent.

Now remember, in contrast to complete resolution where all symptoms are absent, we also looked at the time to resolution of symptoms to mild. No effect was observed on this partial resolution, including on the lower respiratory subset of 4 symptoms, which was the primary endpoint. A result that I haven't shown you yet is the RSV 13 symptom score. Zelicapavir showed a statistically significant improvement compared to placebo at days 9 and 13 in the HR3 population.

Finally, I'd like to again reiterate the PGI-S secondary endpoint, where we saw a statistically significant 2-day median time to improvement in both the efficacy and HR3 populations. In addition to symptoms, we evaluated a number of other clinical endpoints. One of the most important clinical endpoints is hospitalization. Treatment with zelicapavir resulted in a lower hospitalization rate, 5% or 3 out of the 60 patients who received placebo required hospitalization compared to 1.7% or 2 out of the 115 patients who received zelicapavir. Investigators were required to make a prospective blinded assessment of whether these hospitalizations were related to RSV. They attributed all of the placebo hospitalizations, but none of the zelicapavir hospitalizations to RSV, resulting in a 5% rate in placebo versus 0% in zelicapavir. We believe that 1 of the 2 zelicapavir hospitalizations could have been related to RSV.

Moving to the mortality endpoint. One of the hospitalized patients on placebo died. There were no deaths on zelicapavir. No patients were admitted to the ICU or received mechanical ventilation. We saw a similar incidence in the use of antibiotics, bronchodilators, corticosteroids or oxygen. The overall rates were low with about 14% in zelicapavir versus 10% in placebo. Finally, there was no difference in medically attended visits with about 7% in both arms.

Now let's look at virology results. We saw a robust antiviral effect for zelicapavir with a 0.6 to 0.7 log viral load drop at the end of treatment. Furthermore, zelicapavir showed a statistically significantly greater proportion of patients with undetectable viral load at the end of treatment in both populations. There was a faster median time to undetectable viral load of 4 days in the efficacy population and 5 days in the HR3 population. This figure shows the viral load for zelicapavir shown in orange compared to placebo, shown in green in the HR3 population. You can see a 0.7 log drop at day 5, which is the end of treatment. This Kaplan-Meier plot shows that patients on zelicapavir had a median time to undetectable viral load that was 5 days faster than placebo in the HR3 population. In conclusion, we are very pleased that zelicapavir demonstrated compelling results on multiple clinically meaningful endpoints measuring different aspects of RSV disease in this high-risk adult population.

We saw a clinically meaningful effect on symptoms with multiple patient-reported outcome tools, including multiple measures of the RiiQ showing symptom reduction of up to a week and a statistically significant improvement in PGI-S and perhaps most importantly, lower hospitalization rates with zelicapavir. In addition, we saw a robust antiviral effect and zelicapavir was well tolerated with a favorable safety profile. Taken together, these results support further clinical advancement of zelicapavir.

So what did we learn from this study? We saw compelling results, most pronounced in the HR3 population that allowed us to identify multiple clinically meaningful endpoints that could potentially be used as a primary endpoint in a registrational trial. Here, you see 4 of them: time to complete resolution of all 13 RSV symptoms by RiiQ, time to complete resolution of the total 29 parameter RiiQ, time to resolution of PGI-S and hospitalization rate. Taken together, these data support advancement of zelicapavir into a Phase III study. Thank you for your attention, and I'll now turn the call back over to Jay.

In closing, this is a pivotal time for Enanta. The Phase III enabling results today further validate the potential of our zelicapavir program and our RSV portfolio. Notably, this represents the first time an RSV antiviral treatment has been shown to demonstrate a clinically meaningful benefit in high-risk adult outpatients. These results underscore the potential for zelicapavir to meaningfully reduce the duration of all RSV symptoms in a high-risk patient population. Building on the antiviral activity and favorable safety profile from our pediatric study, these findings continue to validate zelicapavir's potential as a first-in-disease RSV treatment. With these data in hand, our conviction in the transformational potential of our RSV portfolio has strengthened, and we look forward to zelicapavir advancing into a Phase III trial.

I'd now like to turn the call back to the operator and open the lines for questions. Operator?

[Operator Instructions] And our first question coming from the line of Brandon Folkes with H.C. Wainwright.

Congratulations on the data. Maybe can you just talk mechanistically, did you expect to see the HR3 subgroup outperform the rest of the population? And then similarly -- or maybe then you talked about sort of data advancements moving into a Phase III study in high-risk adults. Can you also just talk about then, so are you contemplating a broad high-risk adult patient population similar to what we saw in this study? Or are you thinking about focusing on that HR3 population?

Thanks, Brandon. This is Scott. Okay. So to answer your first question in regard to the HR3 population, yes, we did expect that to perform better. And we kind of engineered it so that we would have 80% of our patient population in the HR3 because the protocol limits the young asthmatics and the healthy 65- to 74-year-olds to 20% of the population. So this was kind of our expectation going forward. But we also wanted to see how it performed in the broader population. And that kind of leads into your second question.

I think certainly, as you can see by the results in the efficacy population, it did work in the broad population, and one could certainly run a trial in that broad population. Alternatively, it would be an option to go somewhat narrow -- somewhat more narrow as in the HR3 population to try to get a smaller study to show the magnitude of benefit that you need for registration.

Our next question coming from the line of Ed Arce with Westpark Capital.

Let me add my congrats on the study results. Just wanted to focus on a little bit further on the previous question in regards to how you're thinking about a registrational endpoint. If you could remind us of why it was that you chose the 4-symptom LRDT (sic) [LRTD] as the primary endpoint? And do you have a sense yet, I know it's early, but do you have a sense for which of those 4 perhaps was weakest in terms of the overall population versus the HR3 population?

Thanks, Ed. And yes, very good question. We chose the 4-symptom lower respiratory tract disease just because those seemed like an important subset of symptoms. It turns out that the instrument is validated more broadly to look at the whole instrument, all the symptoms, the wider domains of respiratory and systemic. And these were just pullouts. And the problem was we didn't have any preexisting data in a high-risk adult population. As I think Jay mentioned earlier, this is the first study to be completed in RSV in the high-risk adult outpatients. So as a Phase II signal finding study, our goal was to find the endpoint that we could use for Phase III. And it looks like partial resolution of lower respiratory tract disease symptoms isn't it.

To answer your other question, which one of those symptoms was weakest, I'm going to kind of turn it around. It was really a conglomeration of symptoms when you look symptom by symptom. All of these patients presented differently and resolved their symptoms differently. So you really do have to look at all symptoms together to see a really robust difference. And it seems like the more symptoms you look at, the bigger difference you see, as you could see kind of in our results slide. So I hope that answers your question, Ed.

Yes, that's great. And then just as a follow-up, I know you had discussed the potential to move this forward with partnering. I don't know if you can comment on where that might stand today. But aside from that, I'm just wondering if you would consider in discussions for a Phase III design having the optionality of endpoints, perhaps like a co-primary endpoint where you could win on either the 4-population or perhaps, say, the HR3 population.

Right. Let me take the second half of your question first, and then maybe I'll turn the first half back over to Jay. Times are early. We obviously have just seen these results initially. So we're going to need to go to regulators and discuss optimal endpoints, optimal trial design, optimal patient population. But it seems pretty clear from the results that we have at least 4 potential registrational endpoints, complete resolution of all symptoms, complete resolution of the whole RiiQ, PGI-S and then potentially hospitalization. And so let us get back to you after regulatory discussions, and we'll figure out the design of the Phase III.

And Ed, this is Jay. So you're correct as it relates to partnering, that is our first choice. I think we've reached a stage now where first, we wanted to demonstrate safety and virology in our first in ped study, which we did. And then the next part of really rounding out clinical data in the 2 major high-risk patient populations. In other words, the high-risk adult study we're reporting today, that, I think, is a second linchpin in terms of further discussions. As you know, we want to focus on a symptom readout in registration, and this was the trial designed to give us that. So we're going to now set apart, embark on those further discussions.

And Jay, I thought -- sorry, Ed, I thought -- this is Scott again. I thought I'd just break in a minute since you mentioned the pediatric study, which are -- which is a very exciting study to us because it met its primary and secondary endpoints. And the data are embargoed at present, but I just wanted to give you a little advertisement for an ID week presentation where we're going to talk some more about complete resolution of symptoms in that study where we have some promising results.

And our next question in queue coming from the line of Brian Skorney with Baird.

A couple for me. I guess to start, there was a little bit higher incidence of antibiotic bronchodilator, corticosteroid or oxygen use on zeli. I'm just wondering, is this inclusive of baseline use? Or is this use as rescue medications? And if you look at the HR3 subgroup, is that breakdown consistent or greater or lesser separation? Just trying to think about the potential for some of these to have an impact on symptom scores.

Thanks, Brian. So they are new or increased doses of those medicines or treatments and all kind of piled together, and we didn't see a meaningful difference between the whole population and the HR3. So nothing really fell out amongst those things.

And then maybe you called out a difference in hospitalization attribution for RSV between yourselves and the investigator in the study on one case. It seems like you're making a more conservative call to attribute this hospitalization to RSV. But can you give any color on this patient, given that it seems ambiguous at least whether or not the asthma exacerbation was due to RSV or not?

Yes, it was certainly a somewhat ambiguous case. But the -- and there's a footnote on that slide to give you a little more detail on it. But it was a person who had underlying asthma and was hospitalized based on an asthma exacerbation prior to the resolution of all the RSV symptoms. So we felt that you couldn't definitively say that it wasn't related to RSV. In contrast, the other zelicapavir hospitalization was a patient who completely resolved all symptoms by day 11 and then was hospitalized 3 weeks into the study with influenza A. So totally different disease. So we just felt like it would be most transparent to report that a little bit more conservative than the investigators did in their blinded judgment.

Our next question in queue coming from the line of Jon Miller with Evercore ISI.

Congrats on the results. I would love to zoom in a little bit on the non-HR3 population. And it seems to me look -- backing out what they must have done given how small a population they were, they must have gone backwards versus placebo on, for instance, LRTD symptom score based even on all RSV symptoms. Is there a reason those younger elderly adults or otherwise healthy asthmatics, for instance, would do worse on zeli than placebo? And does that increase risk in Phase III even if you attempt to zoom in on an HR3 population?

Yes. It's an excellent question, Jon. So I guess the first thing I would call out is that there shouldn't be any reason to think that those younger, healthier patients would do worse on zelicapavir than placebo. We've always showed a very clean safety profile with zelicapavir in more than 700 patients who have received it, including pediatric patients down to 28 days old. So we're not really concerned about safety.

In terms of efficacy in that population, it's really hard to tell what the efficacy is in this study because remember, we limited that to 20% of the enrolled population. So in that group, if I remember correctly, there were only 10 placebo patients, which makes it very hard to draw meaningful comparisons between placebo and active in that small patient population. And again, that's the young asthmatics and the healthy 65- to 74-year-olds combined. So again, I do think there would be a possibility to go with a broad population in Phase III, just that it have to be powered with a little bit bigger sample size to manage the potential treatment effect.

Is the problem coming from young asthmatics or from healthy younger elderly?

Again, it was really hard to separate those things out. Small, small patient populations, and we couldn't really tell.

And our next question coming from the line of Roy Buchanan with Citizens Bank.

Most have been answered. I guess just maybe -- sorry if I missed it, but the partnering discussions, can you just characterize, I guess, the degree of interest you've seen in RSV assets out there?

Well, Roy, this is Jay. I certainly can't get into any details, but suffice it to say there is interest in RSV out there. I mean there are no approved therapeutics to treat these high-risk patient populations and the Enanta pipeline assets are the most advanced in the industry. So there's, I think, a good opportunity for a party to be first in disease and really hit this area hard.

[Operator Instructions] Our next question coming from the line of Mazi Alimohamed from Leerink.

Just kind of one from us, but could you provide more color on the timing of symptom benefit in the HR3 population? So specifically looking at your complete resolution data showing the 6.7-day median improvement, like when did you start to observe meaningful separation between treatment arms? Was it during the active dosing period? Or did the benefit emerge, I guess, like more gradually over the subsequent weeks?

Right. Yes. Thanks, Mazi. We saw benefit around the end of treatment that continued on and separated. You can see on the total symptom score endpoint that I kind of glossed over. We actually had statistical significant difference at days 9 and 14. If you look at the earlier time points, there were differences but not statistically significant. So it looks like it takes a little bit of time for the real differences to be seen. And that's consistent, say, if you're treating a community-acquired pneumonia with an antibiotic, takes a little bit of time to see that effect.

And I'm showing no further questions in the Q&A queue at this time. I will now turn the call back over to Jennifer for any closing comments.

Thank you, operator, and thanks to everyone for joining us this morning. If you have additional questions, feel free to contact us by e-mail or call the office. Thanks, and have a great day.

This concludes today's conference call. Thank you for your participation, and you may now disconnect.