Cantor Global Healthcare Conference. For our next session, we are very excited to have Enanta Pharmaceuticals, and representing Enanta, we have Dr. Tara Kieffer, Chief Product Strategy Officer. Pleasure to have you with us. Thank you. Thanks for having us. Maybe to start off, for investors who are newer to the story, can you provide an overview of the company, the different antiviral programs, and what the focus is right now? Sure. And before we begin, I'd just like to remind you that I'll be making some forward-looking statements, and for a summary of risks associated with those statements, please see our filings on sec.gov or on our website. So Enanta has a long history in infectious disease, and specifically in virology. Probably best known for our work in hepatitis C, where we worked on protease inhibitors ultimately leading to the discovery of glecaprevir, which is the component, the protease inhibitor component of one of the leading cures for HCV called Mavyret. From there, we expanded into other liver viruses by looking at hepatitis B, chronic hepatitis B patients, and developing core inhibitors for that disease. And then we broadened out into respiratory viruses, starting with a program, multiple programs in respiratory syncytial virus, or RSV. And then when the pandemic broke out, another respiratory virus there, where we could use our expertise in protease inhibitors to also develop molecules there, which resulted in EDP-235, as a protease inhibitor for COVID. But the program in RSV has multiple phase II studies going on, and I'm sure we'll talk about that in a few moments. And then, in the past couple of years, we've been thinking about how to build out the company and what the next pillar might be for Enanta. And immunology really came up as something that we saw some overlap with infectious disease. We had a lot of capabilities and experience internally, and so we came out earlier this year with our first program in immunology, which is targeting inhibitors against KIT, and that is for mast cell-associated diseases such as chronic spontaneous urticaria or CSU. And we'll look to continue to build out that immunology portfolio going forward. Got it. Lots going on, but looking into the rest of the year and next year, what, what as a company are you most excited about? I think the RSV program is very exciting for us. We've got two compounds in phase II studies. The first is called zelicapavir, and that is in two studies in high-risk patient populations. One is in the pediatric population, and the other is high-risk adults, and then our second program, EDP-323, is in a challenge study currently, and we'll have readouts for both of those programs this year, so we're excited to see those data sets and hopefully, obviously, if the data's supportive, moving those forward. We're also excited about our immunology programs and continuing to develop that part of our portfolio. Okay. Maybe let's touch on RSV first. Given the recent launch of RSV prophylaxis treatments, how does this change your view of the market opportunity for an RSV? So the prophylaxis is certainly one part of the solution for RSV, but we still believe ultimately that antiviral treatments will be needed. This is something that we see in other respiratory viruses. If you look at COVID and flu, there are vaccines available there, and antiviral treatments are still very much a part of the picture with Paxlovid, Tamiflu, Xofluza. So I think the difference with RSV is that in pediatrics specifically, those prophylaxis strategies are providing passive immunity to the babies, either through vaccination of the pregnant mother or through just providing that antibody to the baby when it's born. But that protection is as long-lived as the antibody is in the system, and after that, the babies and children will go on to get RSV infection. We know that babies need multiple infections of RSV to develop that robust immunity that you would see in a young, otherwise healthy adult. So we think certainly antiviral treatment will be very useful there. We're also monitoring the potential, you know, issue of resistance developing against these antibodies that has been seen before in RSV, and so it's something where, you know, a treatment also could be useful in that situation. For the adult prophylaxis, those are active vaccines, and I think the challenge there has been just uptake in general. In the last Northern Hemisphere season when they were first launched, I think only about 10-15% of the eligible population was vaccinated. And we'll see, you know, what ultimately that will look like going forward. But generally, in these populations, even if you look at the flu vaccine, you know, at best, you reach probably half of the population, so there'll still be room for treatments there. Got it. Super helpful. Maybe for folks who are not familiar, just talk about the development landscape for RSV treatment. What mechanisms have been studied? Sure. So historically, many companies have gone about the antiviral treatment with targeting the fusion inhibitor, which is on the surface of the proteins of the virus, and really what they're doing here is preventing viral entry into a cell. I think what Enanta's doing that's different is that both of our programs, zelicapavir and EDP-323, are replication inhibitors, and the difference is when somebody gets RSV and you have viral replication going on enough to make the person feel sick enough to seek treatment, at that point, many of the cells are already infected, and productively in producing numerous viruses every day, and so going in with a fusion inhibitor or an entry inhibitor at that point you're just blocking infection of new cells, but nothing, you're not doing anything to the cells that are already infected. What we're doing with the replication inhibitors is going in and shutting down replication at its source, so even productively infected cells are no longer producing the amounts of virus that they would be without treatment, and so, you know, I think, moving both of these programs forward, we're very excited about some upcoming data that will come out soon. Okay. Maybe let's focus on the mechanism. How is zelicapavir, your N protein inhibitor, different from 323- Mm-hmm. Your L protein inhibitor? Sure. So zelicapavir targets the N protein or the nucleocapsid protein, and EDP-323 targets the L protein or the polymerase, and so again, both are replication inhibitors. You know, EDP-323 is quite a potent molecule. We see picomolar potency there, and we'll see what the challenge study data looks like, but you know, both of these are viable options to move forward, either as a monotherapy or one could contemplate using them as a combination for different situations, whether that might be a very hard-to-treat patient population, somebody that's severely immunocompromised, as an example. Or might you be able to expand the treatment window, and meaning that a patient's coming in a longer duration from when the symptom onset was, and, you know, could it be more beneficial in those situations to have a combination treatment? Or might they be used separately in different populations, I think are all things that we're thinking about moving forward. Okay, and you have a next milestone coming, the challenge study readout for EDP-323. What do you hope to see in that trial, and maybe confirm the trial design, et cetera? Yeah. So the challenge study is essentially the same design as what we ran with zelicapavir. It's being run at the same location, so with all the caveats of being able to do cross-study comparisons, we'll be able to look at the same endpoints and compare the data we get with 323, with zelicapavir, and we view that as the bar. zelicapavir showed some of the best challenge data in a challenge study setting, and so we're looking to at least meet that as a goal. Got it. Any changes that investors should be aware of compared to the prior study, or is it mostly similar? No, it's very similar. I mean, you know, these studies are done widely in this space to kind of show some antiviral activity and some effects on symptoms in these patients. So they're generally run the same way, where you're giving virus to the patient and then monitoring those viral loads before treating, and then checking the effect on viral load and symptoms compared to placebo. Got it. And, pending positive data, what would be the next steps for EDP-323? Yeah, so I think the nice thing about our datasets coming out, EDP-323 will be in Q3, so coming up soon, and then RSV Peds for our zelicapavir program will come out in Q4. So having these datasets in a similar timeframe will really allow us to take a look at the portfolio and make the best decisions about how we might move forward these compounds. Okay, and so you mentioned the Peds data coming in Q4 for zelicapavir, so walk us through what investors should expect from the efficacy and safety data. Sure. So zelicapavir is currently in two phase II studies. One is in pediatrics, the other is in older adults and other high-risk adults, and we can talk about that study. But for the pediatric study, it's a phase II, but we have to think about it a little bit differently because it's the first time that we've dosed children. So we have a dose for the adults based on the challenge study data, but in this study, we first needed to select a dose for pediatrics. So the study was done in two parts. Part one, we're primarily looking at, first and foremost, safety, 'cause we need to confirm that the consistent safety profile we've seen in adults is replicated in children. And then we're also looking at PK in that study to select a dose. It's been done in two age cohorts, so 28 days, 28-day babies to six months, and then six months to three years. That selected dose then moved into part two of the study, where we primarily looked at virology endpoints. We'll also look at symptoms and other clinical endpoints that we can, but, you know, the study's about 90 patients, so we don't have, you know, powering to look necessarily at all of the symptomatic endpoints. Got it. And so how would this readout guide the future registrational trial, and what should we expect? Mm-hmm. So really, what we're looking for here is that we'll be looking at the totality of the data, both on virology endpoints, symptom endpoints, and we'll look at a number of these. So for virology, we'll look at the viral load curve over time. We'll look at AUC, we'll look at time to undetectable, how long it takes patients to become undetectable, and then symptoms. And so I think the goal of this study is really to generate directional data that is showing trends in the right direction on these endpoints, to give us that confidence to move into a larger, more well-powered phase III study. And that's something we're already planning for success and engaging in some early start-up activities for a phase III study. Okay. And assuming a positive study with the pediatric portion of the pediatric trial, how soon can you start the phase III, or will you wait for the data from the high-risk patient first? No, I think if the data's supportive, we would not wait for the adult study, and we would just move quickly as we can into a phase III study, and obviously interrogating the phase II data to really understand how to design that phase III study. The nice thing about the RSV Peds study is we have both inpatients and outpatients. We have, we'll look at how long it has been from time of onset to enrollment. Patients were allowed up to five days, but we can look at, you know, whether they were enrolled within four days or three days, and just look at all of the different patient populations to best design our phase III, and then obviously having regulatory discussions to finalize a phase III plan and move forward. Got it. And if the Peds study is negative, what read-through does it have for the high-risk study? So I think it depends a little bit on what happened with the Peds study. I think the adult study is different in that it's a different population, so different reasons for having high risk to RSV. You know, these are older patients that tend to have waning immunity, as opposed to peds, which are starting out with no immunity. And then we're also including adults that have comorbidities like COPD, asthma, congestive heart failure, and these things put them at high risk for RSV. And then the other important thing is that the study design is different. So it's a larger study. It's about twice the size. We're looking at symptoms as an endpoint in that study and enrolling patients that are within three days of symptom onset. So, you know, there's probably some amount of read-through. Obviously, if the Peds study is positive, that bodes well for the adult study. But I think, you know, there's enough differences, between the studies that, you know, we'd want to understand what it looked like in adults. Okay. And so maybe just walk us through what success looks like for the high-risk trial, the patient population that you're studying, and the trial design? Sure. So, that high-risk study is in about 100 high-risk adults. As I mentioned, that would be people that are over 65 years of age, or have the comorbidities that I spoke about, generally chronic lung and heart disease. They're dosed for 5 days with EDP-235, and then we're looking at symptoms in that study, to see whether or not patients have a shorter time course of symptoms than against placebo, so if the time to symptom amelioration is quicker. It's powered to show a reduction in symptoms of about 50%, which is a high bar, and I think, you know, it's something that we're looking to hopefully achieve. But I think the ideal profile would really be something that's clinically meaningful. If you look at Tamiflu, for example, they shorten the duration of symptoms by about a day, as an example of something that's clinically meaningful. So we'll be looking at all of the data in that study, also to make a decision moving forward. Got it. So I guess, as you said, the 50% time to symptom resolution is a high bar to meet. If that endpoint is not met, how does it impact your future trial design? Would you continue taking this drug forward in the high-risk population? Yeah, so it is a high bar, and I don't know that we necessarily need to hit statistical significance. I think we need to see an improvement and something that, you know, is going in the right direction. You know, whether we hit 50% exactly, I think, would be nice, but we would look at all of the data points, and we're looking at virology in that study as well. We'll look at other clinical endpoints, and again, if all of that data is trending positively, you know, we would think about moving that forward. There really hasn't been a study in adults that has shown statistical significance outside of a challenge study setting, so I think if we show some positive data trending in the right direction, that is good news. Right, and the timeline for RSV-HR? So that study, as I mentioned, it's larger, so we're continuing to enroll that as the Northern Hemisphere season kicks off. The goal is to fully enroll that in this upcoming Northern Hemisphere season. Got it. Okay, in the interest of time, moving on to the immunology side of your portfolio, so maybe just talk about CSU, what's the unmet need there, and what are you trying to solve? Sure. So we're our first program in immunology is looking at CSU, chronic spontaneous urticaria. This is a severely debilitating skin inflammatory disease that results in wheals, itchy wheals, developing all over a patient's skin. It can also result in angioedema, which is deep tissue swelling, and this can last for many years in patients. I would also add that there's other quality of life symptoms as well, such as sleep disturbances, anxiety, depression, so these patients are really desperate for an efficacious treatment. It can affect up to about or anywhere from 0.5%-1% of the population, and the current standard of care is really dosing antihistamines that can go up to four times the standard dose. But unfortunately, that really only works in about half of the patient population, and the other half, there is one approved biologic, which is Xolair, that, you know, isn't as used as frequently as it could be for various reasons, and, you know, this leaves really a need for having an efficacious treatment. We're looking at going after the disease via inhibition of KIT. And so the KIT mechanism is, a KIT is a signaling molecule for mast cells, which we know drive the disease. And so by blocking KIT, you're reducing the number of mast cells that are available to drive that pathology. Right. So maybe, just on that, if you could provide more details on what really motivated you to develop an oral KIT? Mm-hmm. So the thing we like about KIT is the mechanism. So you're really having an impact on the mast cells themselves, and we know that CSU, for example, is driven by mast cells. The other thing about inhibiting KIT is that you can imagine if it's successful on CSU, other diseases that are driven by mast cells may be amenable to this type of inhibition, and there are many of those types of diseases out there, chronic inducible urticaria, prurigo nodularis or PN, eosinophilic esophagitis or EoE. And the other thing that we liked about this mechanism is that there is clinical validation of the target through antibodies. And so there is an antibody by Celldex that had phase II data showing some of the best in-disease efficacy for CSU. And they are now running POC trials in these other indications that I mentioned, and so we'll be able to understand a little bit more where these KIT inhibitors might be useful. The other nice thing about the target is that there is a biomarker in serum tryptase that you can monitor early on in the program, even in phase I healthies, that is, correlates very well with downstream clinical outcomes. And so you're able to really de-risk the program early on, even in phase I, with that type of data. Obviously, the unmet need and commercial opportunity that we spoke about is another reason why, you know, we're interested in this target and mechanism. Right. So how do you compare orals versus antibodies? Is it mostly about convenience, or is there anything that you can differentiate on efficacy and safety? Hmm. I think certainly the route of administration is an advantage to be able to dose oral versus injectables. I think another thing that is possible is with some of the antibodies, there have been observed. I don't know if they're anaphylaxis or hypersensitivity reactions, but, you know, one hypothesis is that might be driven by cross-linking of the antibodies. And so one may not expect to see that as much with oral antibodies. Again, something that we'll have to determine clinically, but that could ultimately be one advantage. The other hypothesis is that you may be able to mitigate some of the on-target liabilities with different dosing strategies. And what I mean by that is, once you deplete mast cells or reduce the number of mast cells, it takes some time for the mast cells to repopulate. And so if you could remove the pressure while that is happening, you might be able to have a regrowth of other cell types and mitigate some of those on-target tolerability and safety issues. So I think that's one thing that is being currently tested by Jasper, who has an antibody with a shorter half-life. And if that pans out to be successful, then I think an oral molecule would even have finer tunability because, you know, you're dosing daily, and one might be able to have a dosing strategy that results ultimately in a better safety profile. Right. And anything specifically you want to see from the Jasper readout or the Celldex longer-term readout on the efficacy and safety front as it relates to your oral KIT? Yeah. So I think Celldex is launched into their phase III program now, and we certainly would be interested in looking at that data from an efficacy and safety perspective to see if they replicate what they looked at or what they found in phase II. And our goal is really to be able to do that with an oral molecule. And I think the long-term data is also gonna be important. They've generated some data from phase II, I think, going out to about a year. But I think, you know, that longer-term data and a larger patient population and dataset will be quite helpful to inform our own program, as well as the other POC studies that they're running in other indications, will be helpful. Right, and there are a number of oral KIT inhibitors in development, a lot in earlier stage. What aspects of the molecule are you trying to improve upon? Mm. -versus competitors? Sure. So we're aware of a couple of KIT oral KIT inhibitors that have just started in the clinic. And I think there's, you know, no clinical data yet, so limited data to understand what a differentiated profile would look like. But I think what we're doing, our goal is to develop a potentially best-in-class molecule by doing optimization around efficacy, making sure we're driving down the potency to the extent we can. Selectivity, something we're very thoughtful about, making sure we can be as selective as possible against the KIT inhibitor versus other kinase inhibitors. The PK profile, so we always aim for something that's QD, daily dosing, low potential for DDIs. I think tissue targeting is something we're also thoughtful about in terms of making sure you're getting it to the location you want and not to other tissues, to the extent that that can be done. And so obviously, driving towards a best-in-class compound is what we're striving for. It's early days for the inhibitors. Third Harmonic had a compound that initially went into the clinic and was stopped due to toxicity. So I think, you know, we'll have to see how these move forward. Generally, I think it's a big space, a big unmet need, probably room for multiple molecules there. But, you know, our goal is to deliver a best-in-class compound. Right. And you mentioned Third Harmonic. They had some tox issues with their first gen c-KIT inhibitor. What could you learn from their approach, and how are you implying the learnings from their molecule? ... So I think they have now said that the reason for that toxicity was due to a reactive metabolite that they found with that first compound. So those are things that we actively screen in our preclinical studies, and so anything with that type of a profile we wouldn't move forward. So I think we're confident that our program you know would not have at least that profile from a reactive metabolite. They did generate some nice data from that study in terms of the activity on serum tryptase. I think they showed about an 80% reduction, which was nice to see some of that data coming from an oral KIT, as that was the first time that we've seen the data from an oral molecule. It gives us some ideas of how to move forward in our program. Okay, and remind us about the next steps for this program. When do we hear? Yeah. So as I mentioned, we're optimizing that candidate, hopefully to select the best one we can. Looking for a development candidate later this year, and then, you know, moving that forward, as quickly as we can. Great. And what immunology indications could you go after, same as the competitors, or anything else that we should be aware of? Yeah. So I think anything that is mast cell-driven, diseases that are known to be driven by mast cells, because we are having an effect on the mast cells themselves, gives us confidence in those indications. You know, many of the things that are either approved or in development, for these diseases are inhibiting downstream, mediators like antihistamines, or they're, you know, impacting a signaling component. But what we're doing here is really having an impact on the mast cell itself. So it gives us confidence in mast cell-driven diseases. There are other mast cell-associated diseases where one could think about also being useful. I think the ones that I mentioned earlier in EoE and PN are where there's active development. People are also looking at asthma and potentially atopic dermatitis, so there's companies that are pursuing that as well. So it's a broad patient population where this might be useful. Right. Maybe, you know, a lot going on with the RSV portfolio and the immunology. What are investors missing on Enanta right now? Well, I think, you know, we're excited about our RSV portfolio and having what we think are two best in disease molecules and having, you know, the broadest portfolio. We'd like to have multiple opportunities to go after these diseases, and then looking forward to building out our immunology portfolio. I think the one thing we didn't touch on is another program in immunology, which we'll be looking to roll out later this year as well. You know, the types of programs we look for there are really things where you have good validation around your target, things that have good unmet needs, and so we're looking forward to broadening our immunology portfolio going forward as well. Okay. And remind us about the cash runway and what does that guidance envision? Sure. So we've guided to runway through the third quarter of 2027, and that includes moving our RSV program and zelicapavir forward into a phase III study, as well as moving that immunology program with the KIT inhibitor forward into the clinic. Okay, so that includes the phase I for-