Morning and welcome to the Enanta Pharmaceuticals, Inc. conference call. At this time, all participants are in a listen-only mode. There will be a question and answer session at the end of the prepared remarks. Please be advised that this call is being recorded. I would now like to turn the call over to Jennifer Viera, Head of Investigations. 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 Investor 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 Pharmaceuticals, Inc. 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 2b study to evaluate the efficacy and safety of Zelekapavir in adults with acute respiratory syncytial virus (RSV) infection who are at high risk of complications. We are very encouraged by these results and believe that the data provide strong rationale for further clinical development of Zelekapavir. Importantly, we identified multiple potential registrational endpoints for a Phase 3 trial in high-risk adult patients. These results demonstrate the ability of Zelekapavir 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 Zelekapavir, 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 two 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 two approved flu treatments: Tamiflu and Zofluza. On the right-hand side is Zocova, which is Shionogi's SARS-CoV-2 protease inhibitor.
Across two different drugs for influenza and one 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 one 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 two goals. The first, to inform the design of a Phase 3 trial, specifically looking to identify the target population and optimal endpoints for registration. The second, to give an indication of treatment effect that could be confirmed in a larger registrational study. As is typical for such a Phase 2 signal-finding study, we look at the totality of data to further inform the design of a Phase 3 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 Respiratory Infection Intensity and Impact Questionnaire (RIIQ) score, additional patient-reported outcomes like patient global impression of severity (PGIS) 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 2, double-blinded, placebo-controlled proof-of-concept study of Zelekapavir 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 predispose to poor outcomes from RSV infection. Enrollment was capped so that healthy adults aged 65 to 74 or young asthmatics comprised no more than 20% of the total patient population. The remaining 80% were higher-risk patients with CHF, COPD, or age 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 Zelekapavir or placebo once daily for five 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 two 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 five components that consist of 29 questions, each of which is assessed on a four-point scale. We asked patients to answer these questions daily. I want to highlight two important definitions. The first is resolution, which means the first of two time points at which all symptoms are scored as mild or absent. The second is complete resolution, which means the first of two time points at which all symptoms are absent.
As shown in the three colored boxes, we focused on three 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 the subset of four 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 PGIS. This is one of the secondary endpoints of our study. The PGIS consists of a single question assessed on a four-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 two 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 Zelekapavir. This population of patients who received at least one dose of study drug constitutes 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. 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 Zelekapavir. It's worth calling out at the bottom of the slide that about two-thirds 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 Zelekapavir than placebo. Zelekapavir exhibited a favorable safety profile in this study.
You can see that treatment-emergent adverse events occurred at similar rates between Zelekapavir and placebo, with 22% to 24% of patients experiencing adverse events. Serious adverse events occurred in about 2% of Zelekapavir patients compared to about 6% of placebo patients. No adverse events led to treatment discontinuation, study withdrawal, or death among patients who received Zelekapavir, compared to one or two 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 two most common adverse events in the Zelekapavir 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 Zelekapavir compared to placebo. We were very excited to see that Zelekapavir 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 Zelekapavir 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 three weeks with placebo to two weeks with Zelekapavir.
These clinically meaningful results using the RIIQ tool provide multiple potential registrational endpoints that could be used in a Phase 3 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 Zelekapavir, shown in orange, had a statistically significant two-day faster time to resolution compared to placebo, shown in green. Here's a summary of symptom data for Zelekapavir compared to placebo.
This table reiterates the data I showed you a moment ago, where patients receiving Zelekapavir 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 four symptoms, which was the primary endpoint. A result that I haven't shown you yet is the RSV-13 symptom score. Zelekapavir 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 PGIS secondary endpoint, where we saw a statistically significant two-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 Zelekapavir 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 Zelekapavir. 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 Zelekapavir hospitalizations to RSV, resulting in a 5% rate in placebo versus 0% in Zelekapavir. We believe that one of the two Zelekapavir 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 Zelekapavir. No patients were admitted to the ICU or received mechanical ventilation. We saw similar incidents in the use of antibiotics, bronchodilators, corticosteroids, or oxygen.
The overall rates were low, with about 14% in Zelekapavir 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 Zelekapavir with a 0.6 to 0.7 log viral load drop at the end of treatment. Furthermore, Zelekapavir 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 four days in the efficacy population and five days in the HR3 population. This figure shows the viral load for Zelekapavir, shown in orange, compared to placebo, shown in green, in the HR3 population. You can see a 0.7 log drop at day five, which is the end of treatment.
This Kaplan-Meier plot shows that patients on Zelekapavir had a median time to undetectable viral load that was five days faster than placebo in the HR3 population. In conclusion, we are very pleased that Zelekapavir 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 PGIS, and perhaps most importantly, lower hospitalization rates with Zelekapavir. In addition, we saw a robust antiviral effect, and Zelekapavir was well tolerated with a favorable safety profile. Taken together, these results support further clinical advancement of Zelekapavir. 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 four 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 PGIS, and hospitalization rate. Taken together, these data support advancement of Zelekapavir into a Phase 3 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 Pharmaceuticals, Inc. The Phase 3 enabling results today further validate the potential of our Zelekapavir 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 Zelekapavir 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 Zelekapavir's potential as a first-in-disease RSV treatment. With these data in hand, our conviction in the transformational potential of our RSV portfolio is strengthened, and we look forward to Zelekapavir advancing into a Phase 3 trial. I'd now like to turn the call back to the operator and open the lines for questions. Operator?
Thank you. Ladies and gentlemen, to ask a question at this time, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 11 again. Please stand by. We'll be compelled to queue your roster. Our first question coming from the line of Brandon Fox with HC Wainwright. Your line is now open.
Hi, thanks for taking my questions, and congratulations on the data. Can you just talk mechanistically? Did you expect to see the HR3 subgroup outperform the rest of the population? Similarly, you talked about sort of data advancements moving into a Phase 3 study in high-risk adults. Can you also just talk about, 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. To answer your first question in regard to the HR3 population, yeah, we did expect that to perform better. 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. This was kind of our expectation going forward. We also wanted to see how it performed in the broader population. 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. One could certainly run a trial in that broad population.
Alternatively, it would be an option to go 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.
Great, thank you very much.
Thank you.
Thank you. One moment for our next question. Our next question coming from the line of NRC with West Park Capital. Your line is now open.
Hi, good morning. Thanks for taking my questions. Let me add my congrats on the study results. I just wanted to focus 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 four-symptom LRDT as the primary endpoint. Do you have a sense yet? I know it's early, but do you have a sense for which of those four perhaps was weakest in terms of the overall population versus the HR3 population?
Thanks, Ed. Very good question. We chose the four-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. These were just pull-outs.
The problem was we didn't have any pre-existing 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. As a Phase 2 signal-finding study, our goal was to find the endpoint that we could use for Phase 3. 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. You really do have to look at all symptoms together to see a really robust difference. It seems like the more symptoms you look at, the bigger difference you see, as you could see in our results slide. I hope that answers your question, Ed.
That's great. Thank you. 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. Aside from that, I'm just wondering if you would consider in discussions for a Phase 3 design having the optionality of endpoints of perhaps like a co-primary endpoint where you could win on either the four 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. We are going to need to go to regulators and discuss optimal endpoints, optimal trial design, optimal patient population.
It seems pretty clear from the results that we have at least four potential registrational endpoints: complete resolution of all symptoms, complete resolution of the whole Respiratory Infection Intensity and Impact Questionnaire (RIIQ), patient global impression of severity (PGIS), and then potentially hospitalization. Let us get back to you after regulatory discussions, and we'll figure out the design of the Phase 3.
Ed, this is Jay. 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 IMPEDES study, which we did. The next part of really rounding out clinical data in the two major high-risk patient populations, in other words, the high-risk adult study we're reporting today, 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. We are going to now set apart and embark on those further discussions.
Jay, I thought I'd just. Sorry, Ed.
This is Scott again. I thought I'd just break in a minute since you mentioned the pediatric study, which is a very exciting study to us because it met its primary and secondary endpoints. 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 had some promising results.
Fantastic. Thanks for mentioning that, Scott. Jay, thanks.
Thank you, Ed. Your comments. Appreciate it.
Thank you. Our next question in queue coming from the line of Ryan Scorney with Bayer. Your line is now open.
Hey, good morning. Thanks for taking my questions. A couple from me. To start, there's a little bit higher incidence of antibiotic, bronchodilator, corticosteroid, or oxygen use on Zelekapavir. I'm just wondering, is this inclusive of baseline use, or is this use as rescue medications? 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.
Thanks, Brian. They are new or increased doses of those medicines or treatments, all kind of piled together. We didn't see a meaningful difference between the whole population and the HR3. Nothing really fell out amongst those things.
Could you call out a difference in hospitalization attribution for RSV between yourselves and the investigator in the study? In one case, it seems like you're making the more conservative call to attribute this hospitalization to RSV. 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?
Yeah, it was certainly a somewhat ambiguous case. There's a footnote on that slide to give you a little more detail on it. 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. We felt that you couldn't definitively say that it wasn't related to RSV. In contrast, the other Zelekapavir hospitalization was a patient who completely resolved all symptoms by day 11 and then was hospitalized three weeks into the study with influenza A, a totally different disease. 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.
Great. Thank you.
Thank you. Next person in queue coming from the line of John Miller with AVA-CORE-SI. Your line is now open.
Hi, guys. Thanks for taking my question and congrats on the result. I would love to zoom in a little bit on the non-HR3 population. It seems to me, looking back at 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, you know, based even on all RSV symptoms. Is there a reason those younger elderly adults or otherwise healthy asthmatics, for instance, would do worse on Zelekapavir than placebo? Does that increase risk in Phase 3, even if you attempt to zoom in on an HR3 population?
Yeah, it's an excellent question, John. 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 Zelekapavir than placebo. We've always showed a very clean safety profile with Zelekapavir in more than 700 patients who have received it, including pediatric patients down to 28 days old. 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. 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. That's the young asthmatics and the healthy 65 to 74-year-olds combined.
I do think there would be a possibility to go with a broad population in Phase 3, just that it would 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 elderlies?
It was really hard to separate those things out. Small, small patient populations, and we couldn't really tell.
OK, fair enough.
Thank you. Now, next question coming from the line of Roy Battan with Citizens Bank. Your line is now open.
Thanks for taking the question. Maybe, sorry if I missed it, but the partnering discussions, can you just characterize the degree of interest you've seen in RSV assets out there? Thank you.
Hi, 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. I think it was a good opportunity for a party to be first in disease and really hit this area hard.
OK, thank you.
Welcome.
Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. Our next question is coming from the line of Mazi Al-Mohamed from Luring. Your line is now open.
Great, thanks for taking our question. Just kind of one from us, but could you provide more color on the timing of symptom benefit in the HR3 population? Specifically looking at your complete resolution data showing the 6.7-day median improvement, when did you start to observe meaningful separation between treatment arms? Was it during the active dosing period, or did the benefit emerge more gradually over the subsequent weeks? Thank you.
Right, yeah. Thanks, Ali. Thanks, Mazi. We saw benefit around the end of treatment that, you know, continued on and separated. You can see on the total symptom score endpoint that I kind of glossed over. We actually had statistically significant difference at days 9 and 14. If you look at the earlier time points, there were differences, but not statistically significant. It looks like it takes a little bit of time for the real differences to be seen. That's consistent, say, if you're treating a community-acquired pneumonia with an antibiotic, it takes a little bit of time to see that effect.
Got it. Thank you.
Thank you.
Thank you. 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 email 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.