Perfect. I guess we'll get started. Hey, everyone. Thanks so much, and welcome to the 2024 Jefferies Healthcare Conference. I have the pleasure of welcoming Enanta, you know, Pharmaceuticals. My name is Amy. I'm a biotech analyst at Jefferies. With us today is Jay Luly, CEO of Enanta, and Tara Kieffer, Tara Kieffer, as Chief Product Strategy Officer. I will turn it over to them for introductory remarks. Thank you. Thank you very much for inviting us. Before I begin, I want to remind you that we'll be making some forward-looking statements, and for a summary of the risks associated with these statements, please see our filings on sec.gov and on our website. I guess we can just dive into- Okay, perfect. Questions. Yeah. So just, I guess, as a general introduction, can you go over the catalyst path for Enanta over the next two years and what programs you're particularly excited about? Sure. So, for those of you who are less familiar with Enanta, we have a sort of a legacy in virology. We've been focused on virology for, geez, 20 years now or so. Starting out with hepatitis C, where we, you know, helped bring two drugs forward to commercialization and to the world with AbbVie, and have cured well over 1 million patients worldwide. We've worked in hepatitis B, other nearby liver virus, but ultimately, we shifted more into respiratory viruses, starting with RSV. We've done work in human metapneumovirus. The pandemic broke out during the course of all this, so we couldn't not work on COVID, and so we've had a lot of different efforts. I'm sure we'll get into RSV in some detail today. And so we have clinical data sets now reading out in RSV. We're in. We have two different molecules moving forward. Our most advanced is a molecule called zelicapavir. It's a N protein inhibitor, and we're currently in two high-risk patient populations, namely, peds and high-risk adults. These are adults who are elderly or who may have other comorbidities, you know, things like COPD, asthma, congestive heart failure, and the like. So these patients tend to have poorer outcomes with our RSV. So we're full up on high-risk patient studies going on around the world. We have another molecule. It's a polymerase inhibitor, the so-called L protein inhibitor, and that is in the process of finishing up a human challenge study, where you infect healthy volunteers with the virus, you wait for the virus to build up, and then you come in and you treat them with the test article, in this case, EDP-323. So, you know, just sort of pausing with RSV, so we have data readouts coming. We expect data from our human challenge study next quarter, and for the first of the high-risk patient populations to read out will be the Peds study, and we're expecting, we're expecting data from that study in the second half. So while all that's been going on, we, you know, we've been scouring the world, you know, during the pandemic and then, I don't want to say post-pandemic, I'm not sure exactly where we are now, but we like to think it's post-pandemic, looking for other viruses, and ultimately, we felt, you know, in order to build value, for shareholders at the next level, we, we needed to move beyond simply just virology. So there's a lot going on in virology, and will continue to be, but we started scouting out, new areas, and that's, ultimately how we got involved in, in immunology. So, we've started up a program, we announced that at the beginning of this year, focused in, CSU, chronic spontaneous urticaria, and, we have a KIT inhibitor program progressing very nicely. Our catalyst for that program for this year is to have the candidate clinical candidate selection process completed. We're doing oral small molecules, and again, we're moving that program along with pace. We're also scouting out other new program opportunities in immunology as well. So, and our plan is to announce the second program in that new area later this year, and then to ultimately use that as a platform on which to build again, further value. Excellent. So I guess just starting off with your oral KIT. On our end, we cover Third Harmonic Bio. We do like the oral KIT approach. So in terms of kind of safety and some of the preclinical analyses that you guys have done, how have you de-risked kind of the liver tox that we've seen with Third Harmonic Bio's asset? What type of preclinical trials have you run, and how high were you able to dose, and what gives you confident that you've ruled out that risk? Yeah, so we're, you know, whether it's KIT or it's, you know, one virus or another virus or any program we've ever worked on, you know, we have sort of candidate selection criteria that we focus on. And, you know, again, we do oral small molecules, so we're almost always looking for once-daily dosing. We're looking for, obviously, safety, and we're looking for, you know, robust efficacy, any which way we can measure it pre-clinically, so as to, you know, increase the probability of success as you enter into the clinic. So one of the sort of deselection criteria we have is anything that has reactive metabolites. I think, that's, I believe, what Third Harmonic says was the issue with their molecule. They've done a fair amount of work trying to untangle that and have landed on the notion that their first molecule had reactive metabolites that then led on to liver tox. So, you know, again, whether it's hep C or hep B or RSV or anything, we're always on the lookout for that at very, very early stages, and it would be a sort of a kill criteria for a molecule coming out of our pipeline. So suffice it to say, we're ruling out molecules like that. We're looking at a lot of in vitro safety measures. We look at, obviously, in vivo tox, and just it's sort of a—it's a standard operating procedure for us as we're building a candidate selection. So, I'm very confident that the team will ultimately select the finalist that has the right characteristics. Okay, perfect. And then one of the potential benefits of an oral KIT is, you know, theoretically, the ability to modulate neutropenia. We haven't really seen... I, I think base case is maybe it's difficult to modulate the rates, but given the reversibility and a shorter half-life than a mAb, maybe there is, you know, a little bit of wiggle room where you could play with PK. On your end, what do you think is causing the neutropenia with some of these KIT approaches? What-- How confident are you on, you know, using a small molecule approach to... And then what are your expectations around neutropenia with an oral KIT? Yeah, well, you know, I do believe a certain amount of neutrophil reduction is mechanism-based. You know, just given how you're going about the process of targeting KIT, you could certainly expect a certain amount of that. But there's been not so much frank neutropenia. There may have been some lowered neutrophil counts, you know, with some of the whether it's antibodies or small molecules out there. Tends to be reversible, tends to plateau on treatment, and so, it's not clear, you know, how much of an issue that will ultimately be. Again, this patient population, you know, definitely needs a therapy. So, the good news is, I think KIT goes right in very directly in terms of impacting mast cell levels. But I think, as you point out, I think one of the advantages of small molecules over antibodies that might have very long half-lives, or some antibodies might have shorter half-lives, but still long half-lives relative to small molecules, is that, is that tunability feature that you can come in, dose, knock KIT down, knock mast cell levels down, and in fact, have potentially a pharmacodynamic effect that long outlives the pharmacokinetic effect. So, mast cell populations may well stay down while other cell populations come back, and other kinds of KIT-mediated processes can stabilize. So, it's, it's still a, a fairly early field, but I think there's a way to navigate it, and importantly, deliver something that would bring relief to this patient population that struggles with this quite a lot. Perfect. And then as you think about moving into clinic, what type of population will you be targeting? Are you going for a Xolair-refractory population, Xolair-naive? Any early, you know, discussions on position would be super helpful. Yeah. I think it would be fairly wide open, but I'll let Tara make some comments there. Sure. Yeah, I do think we would wanna study both of those patient populations. One of the data points from the KIT antibody from Celldex that I think we found interesting is that they showed essentially similar efficacy data in all patient populations, whether those patients were Xolair-naive or, you know, refractory to Xolair. So certainly, we'd be looking for the ability to treat all of those patient populations. And I'll mention as well, you know, I think we are also looking at this target in other indications. We know that mast cells are implicated in a number of different diseases, and so we would look to expand potentially beyond CSU as well with this target. Okay, excellent. Can you give us kind of an example of what type of other indications that you're thinking about? Sure. So I think a clear one is CIndU, so chronic inducible urticaria. There's been data out there, proof of concept in that indication. EoE, and PN, asthma, atopic dermatitis are all things that have been discussed and where there's some rationale for believing the mechanism is important in that disease. So these are all things that we're thinking about, and, you know, ultimately we'll look to explore in the clinic. Perfect. And then with some of the mAb approaches, I think we've seen cases of anaphylaxis come up. Do you think that is inherent to, you know, the baseline population, it's potentially inherent to the mAb mechanism? And how—what are our expectations for an oral KIT approach, on that? Well, KIT, KIT's going after, you know, a very specific kinase, right? And, in some cases, I think with antibodies you have, for example, Xolair, that goes after IgE. And so, you know, some of the drug IgE conjugates in the case of Xolair. You can form immune complexes, and some think that that may be mediating some of the anaphylaxis. But, I think we'll, you know, wait and see. The KIT mechanism's, you know, obviously very, very different in terms of how it's selectively targeting that kinase, so. Okay. Yeah, and you know, I don't know that it's been observed as an issue with the current antibodies. You know, I think the data remains to be seen as they get into later stage and post-marketing evaluations. But, you know, I think to Jay's point, by targeting KIT and sort of depleting some of the mast cells, one might suspect that that would be less than an issue. Okay, that makes sense. So moving on to RSV. In terms of the RSVPEDs, so you've previously said that it's not powered to hit on viral load or symptoms. What will you be looking at in the data to inform your phase III design? And how should we think about the read-across of what you're gonna present on efficacy to a potential phase III outcome study? Sure. So I think, you know, it's important to keep in mind that this study is our first in pediatrics. So the first goal is really to select a dose, based on the different age ranges that we're studying. So I think the primary outcome, obviously safety is important to show in this young population, and then looking at PK to select a dose. In terms of efficacy, we'll certainly be looking at virology. We will look at other clinical outcomes, like symptoms, and really kind of put the totality of the data together to see, you know, whether the trends in the data are pointing towards efficacy that would lead us into a larger, more well-powered study. And so I think, you know, we'll take a look at that once we have both parts one and parts two of that data set. In terms of read-through to HR, you know, these are very different patient populations. We're studying pediatrics who are at high risk because they have yet to develop an immunity. In the adult population, these are patients that either, due to age, have waning immunity or they have other comorbidities that put them at high risk, you know, lung, chronic lung diseases or, or heart, diseases. And so, you know, certainly a positive outcome in, in the pediatric trial bodes well for, for the HR, population. But, you know, they are different populations, slightly different study designs, bigger study. And so, you know, I think we're optimistic about, about both of those studies. Excellent. And as we, you know, step back, for your EDP-938, as we think about learnings from your outpatient, you know, broad risk population, can you go over how you're incorporating that into your clinical design? And how much of it do you think is, one, drug and dose-related, and how much of the failure do you think was kind of a trial design and patient population-related? I think it was definitely the latter. The trial that you're referring to was one called RSVP, not to be confused with RSVPEDs, but RSVP was our first community-acquired RSV infection. And so in COVID parlance, you know, it'd be viewed as sort of a standard risk patient population as opposed to a high-risk patient population. And one of the things that we found in that study was, even though we had gotten patients in as early as possible and got them on drugs, so within 48 hours of symptom onset. Because, again, there's not a ton of natural history work in that patient population to draw on, but we looked at flu, for example. With flu, you want to try to get, you know, a drug on board within the first 48 hours, maybe 72 hours. COVID's a different story, right? But generally speaking, we, we went into that patient population, got them on drug as soon as we possibly could, within 48 hours of symptom onset, which is about as fast as you can do it. And what we had observed was viral loads had peaked, symptoms had peaked, and were already coming down before we could get even the first dose into patients. And so, the lesson learned there is standard-risk RSV patients don't need a drug, and it would be very, very difficult to demonstrate a benefit in that patient population simply because they resolve so quickly on their own. It's just like a common cold, more or less. High-risk patient population, very different, right? These are the patients, whether it's peds or high-risk adults, viral loads tend to pop up a little higher, especially in peds, and be more persistent. In fact, you can have, you know, detectable virus in a child, you know, for almost a month. And so symptom resolution tends to be very protracted, and viral loads tend to come down, you know, more slowly, be pushed out. That's the backdrop on which it would be more straightforward, I think, to demonstrate a drug effect. Excellent. And it looks like you're recruiting both inpatient and outpatients, you know, RSV ped study. Can you go over, kind of the rationale for that and your expectations on kind of teasing out a response? And is there ability to, you know, as you move to phase III, kind of narrow down on a population within RSVPEDs? Well, that's among the reasons why this study will be so interesting, is because we are looking at both. The advantage of outpatients is they tend to present a little earlier. So that's, you know, that's good. The sooner obviously, the sooner you can, you know, take treatment, the better. Hospitalized patients tend to present a little bit later but more severe, so it gives you a chance to look at more, a more severe case, if you will, because, if the outpatients had been that severe, they would've been inpatients, right? So we're looking at both different patient populations, and we'll tease out, you know, the learnings from that. It will certainly inform how we move forward in later-stage studies. Excellent, and that, and that's a really interesting point. So looking at your inclusion criteria, I know in the past we've talked about you know, days from symptoms cut off and finding the right, you know, time point to get before patients peak on their viral load. In your RSVPEDs study, it looks like you're setting a less stringent seven-day cut. Can you go over the rationale of that seven-day cut and your confidence? I know you've talked about kind of the dynamics within peds being slightly different, that you can get these patients before they peak. It's actually a five-day cut- Five-day, sorry. - in peds. Yeah. It's a five-day cut in peds, three-day cut in, in adults- Right in the high risk. And so, it's basically for the reason, you know, I mentioned, that peds tend to be. This whole thing tends to be a little bit more protracted. And the kids that you know, the inpatients or the outpatients, you know, will be in the earlier side of whatever the spectrum of patient enrollment is. The hospitalized kids will be probably on the a little bit on the later side of whatever, you know, bell-shaped curve, presumably, we get on you know, on treatment windows. So it'll all be part of the data that we analyze, but again, looking at the natural history of peds, where there is a little bit more, it does seem to be a more protracted patient journey than that the children. Okay, excellent [audio distortion] Excellent. And then I know you mentioned that 232, the challenge study data, is going to come out this year. Given that... I guess, what are you looking for in the challenge data? I think we've seen a lot of antivirals have kind of passed the hurdle in challenge data. Given your learnings from, you know, 938, what exactly is your internal bar for that challenge data, and how de-risking do you think it is for your phase II and phase III trials? Yeah, so for EDP-323, it's a high bar. I mean, EDP-938, otherwise known as zelicapavir, performed incredibly well in the challenge study, so you know, we're using that sort of, sort of as our internal benchmark. There's only so much you can do, you know, ahead of the clinical trials, but I think we've done it all. It... The L-protein inhibitor that we have is actually picomolar, so it's super, super potent. We are able to dose once a day. We're able to achieve, you know, sort of whopping multiples of the protein-adjusted EC90. You know, again, in part because of its so, so potent. And so I think... And we can deliver those doses, obviously, with good safety, as we demonstrated in phase I. So it's, it's kind of set up for success. And again, we'll be looking at it in the context of, you know, the challenge study for EDP-938, and others. But I think, I think, you know, preclinically, everything in early clinical, all, everything is shaped up to have it be positioned anyway to take the test in the human challenge study, which is a rite of passage. You know, succeeding there is not a guarantee of, you know, future performance, as some drugs have failed out, particularly, in the fusion protein category. But again, this is a replication inhibitor, just like the N protein is, and we, you know, we've said for a long, long time, we're very bullish on replication inhibitors in this, in virology, whether it's, you know, going after a protease, in hep C or a protease in COVID or what, you know, whatever. We like replication inhibitors. Perfect. Yep. You've alluded to potentially having a combo approach going forward. In terms of your current thinking, what indications do you think would be best fit for a combo approach, and what indications would you kind of take it as more of a monotherapy? Well, you know, we're hopeful that the, you know, standard everyday case of RSV, could be substantially, taken care of with a single agent. It's acute viral infection. I mean, we've seen from COVID that you can have benefit from single agents. You're only dosing for, you know, five or so days. But there may be patient populations, whether they be, you know, highly immune-suppressed patients, that, you know, need everything they can get because they, don't have a fully competent immune system to sort of help them out. That may be one, case, and, the other case that's kind of intriguing, you know, we'll figure out ultimately what is the acceptable, dosing window for an, for an RSV drug? And whatever that window is for a single agent, the question is, you know, could you widen that window coming in with a combo? In other words, catch somebody a little bit later in their infection and still be able to reel them in, if you go very aggressively at it with, with two drugs. So that would obviously increase the, addressable patient population if you could. So, it's better... Again, we've got two different mechanisms here. We, wanna try to establish sort of a leadership in the area of RSV therapeutics, for which there are no approved drugs, and, having two mechanisms has gotta be better than one. Excellent. Excellent. Thank you. It looks like we are five till. I will leave it to, Jay, for any closing remarks. Well, I think, again, we can maybe just sort of summarize some of the key catalysts. We have... We're moving ahead with the RSV data readouts, and the first of those should be the challenge study on EDP-323, the polymerase inhibitor, next quarter. And then the first of the high-risk patient populations, which would be the pediatric population, reading out in the second half. Also, by year-end, we're aiming to have our KIT candidate nailed down and to be moving it into the clinic, you know, rapidly thereafter. We'll be also peeling another card off the deck in terms of immunology program. So- Great. I think that's what Very exciting. How the rest of the year is gonna roll. Great. Well, thank you. Thank you so much, and thank you, everyone. Thank you.