All right. We can get started. Good afternoon. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan, and our next presenting company is Enanta Pharmaceuticals. Presenting on behalf of the company is CEO, Jay Luly. I just want to one program you note, there's gonna be a Q&A after the presentation. Just raise your hand, we'll get a mic to you if you have a question. Also feel free to submit any questions via the digital conference book for those who are joining us online. With that, Jay. Thank you. Thanks, Eric, thank you very much for the opportunity to present again this year. Before I begin, I wanna remind you I'll be making some forward-looking statements. For a summary of the risk 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-focused company, working on a number of different important viruses. A lot of them are in the respiratory category, respiratory viruses like RSV and COVID. We are also working on human metapneumovirus, and we still have sort of a keen interest in liver viruses like HBV based on our success in the past on Hepatitis C. You can see a proven track record, quote-unquote, in Hepatitis C, where we were the inventors of glecaprevir, which is one of the drugs in the two-drug combination therapy known as MAVYRET, commercialized by AbbVie. Together with AbbVie, we have cured over 1 million patients with chronic Hepatitis C. The program now has advanced from, you know, discovery of a couple of different protease inhibitors that made their way into 2 different Hepatitis C cures. MAVYRET is the current one, sold by AbbVie, and it continues to provide royalty revenue for us, which funds a substantial portion of our operations. Enanta has a strong balance sheet, based on this royalty revenue, strong cash position, and you can see the number of almost $280 million at our quarter ended September 30. I'll dive in and start talking about respiratory viruses. You can see the number of targets that we're going after. Respiratory syncytial virus. It's very common in the news to hear about RSV infections flaring now that pandemic mitigation steps are relaxing, mask-wearing is dropping, et cetera, et cetera. Kids are back in school, there's a lot of RSV in the news. One should also be very focused on human metapneumovirus, which is something I'll get into. HMPV, a close cousin to RSV and a really important respiratory virus as well. We were working on these two programs when the pandemic broke out. We couldn't not work on COVID. We have a very strong presence in COVID-19 treatments, so we'll get into that in great detail. Just thematically, we work on a lot of different viruses. Our goal is to focus on these important unmet needs and have multiple approaches in each of these that will hopefully lead to multiple products over time. Up at the top are the liver virus programs. MAVYRET, which again is commercialized globally by AbbVie. It's really AbbVie and Gilead that sell the Hepatitis C cures out there today. We have a program in HBV led by our core inhibitor, EDP-514. You can see the rest of the portfolio, which by the way, was all discovered at Enanta and apart from the Hepatitis C program is wholly owned by Enanta. Respiratory Syncytial Virus was the first respiratory virus we got into, and we have a novel approach with an N-protein inhibitor called EDP-938. It's currently in three phase II trials in different high-risk patient populations. We'll talk about those trials. We have a more recently discovered L-protein inhibitor. That's the polymerase in RSV, a molecule called EDP-323, which is in phase I right now, and we'll have phase I data reading out in the first half of this year. At the conference, we're announcing a new approach with a dual-acting human metapneumo RSV combo drug. It's a single drug that hits both of these viruses simultaneously. It's a really exciting profile. As some of you know, we were working on human metapneumovirus previously focused on a single agent that would go after human metapneumo, but we figured out a way to incorporate activity against RSV as well. It's a really exciting dual-acting chemical class that we've uncovered and we'll be prosecuting it toward a candidate later this year. Shifting to COVID, 3CL protease. This is the same mechanism that Paxlovid targets. Very exciting program there with our phase II SPRINT trial reading out. We're still on track to read out data in the first half of this year and to be poised for phase III in the second half of this year. Also just at this conference, we're announcing our efforts that have been actually ongoing for a few years now in a papain-like protease inhibitor program, PLpro, which has some interesting potential mechanistic twists to it that I'll highlight when we get to that section of the presentation. Let's move straight on to RSV. I think I probably don't need to say too much about RSV. Vaccines are in development. They've been in development for probably 60 years or so. We're getting closer to a vaccine era. We focus on treatments because we know despite efforts in vaccines, vaccine efficacy is never 100%. Vaccine adoption is certainly anything but 100%, and people will still get infected, and we wanna have treatments for those infected. RSV typically hits. Mercifully, COVID didn't hit children so hard. RSV is quite the opposite. It hits children very hard. It's typically the young, the elderly, and the immune-compromised. Those are the high-risk patient populations, and we have a phase II trial going on in each of them. Let's skip on to a little bit about EDP-938. As I mentioned earlier, it's an N-protein inhibitor. Many of the approaches to RSV in the past targeted the fusion protein, the so-called F protein. This is a little bit different. It's a nucleoprotein, and in contrast to fusion inhibitors, has a very high barrier to resistance. We have a really impressive virology package that we've presented at conferences and so forth. Suffice it to say, really potent against the two main types, RSV A and B. It works very well against clinical isolates, has a high barrier to resistance, we've looked at it in combination with other mechanisms in RSV, and it's additive to synergistic in those cases. We think it's a very interesting molecule. We took it forward in to clinical trials. Just to summarize a lot of data very quickly, in phase I, we found it was safe and well-tolerated. Gave great PK exposure after single daily oral administration. We saw, you know, quite good multiples over the EC90 at trough drug level concentration. That coupled with the fact that we've been in 500 patients now, has shown a very consistently good, safe profile. We then moved into a challenge study. We presented that data previously. It was just published last year in the New England Journal. It's a very robust human challenge study where you infect human volunteers, you wait till the viral loads come up, you treat them with the drug, and then you monitor virology and symptoms. I'll have a slide that summarizes that data. Suffice it to say, the data were very good, and it was among the best and most robust challenge study ever conducted in RSV. We did another study after that and before we got into high-risk patients and low-risk patients, so-called standard risk, I guess, and found that that is a patient population that really doesn't need treatment. When we went into those otherwise healthy adults, even though we got them into trial within 48 hours of symptoms. Remember, COVID, you can come in within five days of symptoms. We got into these RSV patients very quickly. What we found is even before we were giving the first dose in that time period, viral loads and symptoms had already peaked and were on the decline, and we couldn't show a benefit in that low risk patient population in RSV. What I'll show you in one minute. I'll contrast that with high-risk patient populations, where those are the approvable populations, whether it's pediatrics, transplant, or high risk elderly adults. Those are the approvable populations. In those patient populations, viral loads tend to be higher and more protracted because they're more serious infections typically than in otherwise healthy adults. It should be much easier to demonstrate a drug effect while those symptoms and viral loads are persistent as opposed to rapidly falling. Before I get to those studies, this just shows EDP-938. There are a couple of other fusion inhibitors that are out there, I wanna highlight the challenge study data. You can see we saw over 70% reduction in viral loads and symptoms in that study. I wanna especially point out the high barrier to resistance of this N-protein inhibitor approach. QD dosing is what we're doing, and it's currently in these three phase II studies. The pediatric study, which is in looking at children as young as 28 days, up to three years of age. The transplant study, which is in hematopoietic stem cell transplant recipients who are highly immunocompromised. RSV HR, which is high risk. It's elderly adults over 65 years of age or those who have some other complications like COPD, chronic, or congestive heart failure or asthma. These are the trial designs. I won't go into these in any great detail. They're in our presentation. It's uploaded on our website. Suffice it to say, all three of those studies are up and running. They're recruiting. We expect to be recruiting throughout this year. We're also hoping that RSV, which has been gone during the period of the pandemic, it has recently sort of reemerged with force, and we're hoping that it'll be not just an early and hard-hitting season, but that it'll be a normal duration season, and we'll expect to continue to enroll each of these three studies. I wanna shift gears a little bit to RSV, the L-protein inhibitor. L is the polymerase, as I mentioned before, so it's a different mechanism than the N-protein. We have an incredibly potent molecule. It's a picomolar inhibitor of the L-protein. We took it into the clinic later last year, and we're expecting phase I data in the first half of this year to read out. This just shows you how potent it is against the two major types of RSV A and B. At a recent RSV meeting, we presented mouse data that was showed very impressive protection of mice against RSV infection. That coupled with the preclinical profile that we saw, it was, you know, again, had all the smackings of a good once-a-day orally administered drug. We hope to demonstrate that with our phase I data set that should be forthcoming in this first half. I'll shift gears now to talk a little bit about Human metapneumovirus. Human metapneumovirus is probably very highly underdiagnosed. It was first characterized about 20 years ago or so, it's basically a cousin of RSV. It's very similar as a virus structurally to RSV. It has a very similar patient population that it hits, namely the young, the elderly, and the immunocompromised. The patient presentation is very similar in terms of symptoms, et cetera. What we're finding is that even though it was first sort of identified within the last couple of decades, it's already a global endemic pathogen that shows up every year just like RSV does. Right now it's the second leading cause. Some years, Human metapneumovirus will actually rival RSV in terms of numbers of cases. It's an important one for us to go after. It's certainly a clear commercial adjacency to RSV. If you're focused on one, you should probably be focused on the other, and certainly vaccine companies are thinking similarly. We have one of the most advanced programs in hMPV, and as I said, we were working on that before. One of the twists that we uncovered, you know, during our development of hMPV molecules was a chemical series that actually had dual activity against not just hMPV but RSV. You can see these two numbers on the right-hand side of the table, hMPV and RSV, very potent at nanomolar or subnanomolar activity against the virus. This is a prototype dual inhibitor aptly named DUL001. It isn't our finalist candidate yet, but we're in very active lead optimization and expect to have a candidate, you know, as soon as we can optimize all these different parameters. But we're getting tantalizingly close. Stay tuned on that front. I just wanna share some in vivo data with this molecule DUL001. I just showed you the in vitro virology. This is in vivo animal data looking at not only animal data against infected mice with either human metapneumo or RSV, but you can see very nice reduction in viral loads in these animals with against either virus. Again, a very exciting development. Two molecules targeted at RSV, one for human metapneumo and RSV. Now I'll shift gears to our favorite virus, COVID-19, not Enanta's favorite, but the world's topic of the day in the last few years. We discovered a protease, a 3CL protease inhibitor. I'll contrast that with another protease that we're working on, EDP-235. EDP-235 is a very potent 3CL protease inhibitor. We've looked at it extensively virologically, preclinically. You know, ultimately, not only did we find that it was a good against SARS-CoV-2 but against other common coronaviruses, the common cold coronas that had been, you know, around for a long, long time pre-pandemic, the original SARS virus as well as MERS. It's, it has pan-coronavirus activity, and even when you get inside the different subtypes of SARS-CoV-2, we've demonstrated consistently very high activity. We took it into the clinic. We took it into phase I. We announced that data late last July. Our predictions of having good oral bioavailability were borne out. Good trough drug levels after once-daily dosing were borne out. We also hit the target range that we had predicted of 1-500 mg QD without the need for ritonavir boosting. That was also borne out in our phase I study. We moved it into our so-called SPRINT study late last year, and that is the phase II study that we'll be reading out in the first half of this year. Before we get to that, I wanna just show this slide shows just how uniformly potent it is against the proteases of all the common variants of concern, all the different variants of Omicron, and you can read the slide. Up and down and very consistently, you know, low single-digit nanomolar potency against against this protease. I wanted to share some in vivo data today. This is ferret data in ferrets. Ferrets can be infected with the conventional coronavirus that is running around right now. Very interesting animal model, because what you do here is ferrets are infected, you can see the scheme of dosing on the, in the upper right-hand corner of the slide. There's an infection, then there's a pause while the viral loads start to build, and then EDP-235 or placebo is dosed. If you look at the graph in the lower right-hand corner, the black dots show the placebo group, how the viral loads start to come up, and when dosing begins, you can see there's a few logs of virus there. If you don't treat with EDP-235, the viral loads continue to go up and then ultimately to plateau and start to slowly come down. What you do see in the bottom part of that graph, in the orange and green figure, is that the minute EDP-235 is dosed, you can see the viral loads start coming down right away. I think one of the most interesting bits of this whole experiment is what happens two days, after two days of dosing with either placebo or 235. The placebo-treated group, which is off in a different room, if you will, was then co-housed with uninfected animals to see what would happen to the uninfected animals. You can see by the black circles and dotted lines that these animals were infected and the viral loads were high. What you can't see because it's buried down in the flat part of the bottom part of that curve is that the animals that were co-housed with EDP-235-treated animals after only two days of treatment did not get infected. 235 not only brought viral loads down, but it prevented the transmission of the virus, which is a very nice thing to see pre-clinically, and hopefully a manifestation that will be a characteristic of our drug clinically. This is, I won't go through all this data, but suffice it to say, we think that 235 stands out strong. Amongst the protease inhibitors that are highlighted here, it's very potent. The preclinical oral bioavailability was very good. The projected human clinical dose is 200 or 400 milligrams, once daily dosing, no ritonavir boosting. Not only that, our phase I data demonstrated that we showed good safety and tolerability at those 200 and 400 milligram doses, which we chose to take forward into phase II. Also at those doses, you can see what really good multiples against Omicron we have. These are trough multiples at the 24-hour time point after a single dose of administration without ritonavir boosting. We have very high multiples, either seven or 13 times the plasma-adjusted EC90. That's a lot of pressure on the virus. The other characteristic of 235 that's quite interesting is that it, we know it has great tissue uptake into target organs of infection, namely the lung and other tissues where the virus could be hiding. We think that may have consequences in terms of a further elimination of the virus. Having really good uptake, and in fact, we've looked at this versus other protease inhibitors like Paxlovid. We know that we have better uptake into tissues than Paxlovid in these preclinical models. Maybe that will have an improvement opportunity in either viral rebound or perhaps even in long COVID. The SPRINT study, which is the phase II that's up and running, is outlined here. Again, we should have data. We're looking at safety and tolerability. We'll get virologic trends. It's not really powered for all these secondary endpoints. We certainly won't see powering for symptoms, for example, in such a small study. We should get virologic trends that will help us select between 200 or 400 milligrams for the go-forward dose in phase III. This is just a summary to wrap up. I won't go through all the information that's conveniently summarized on this page. I just want to draw your attention to the bottom highlighted area, and that is, you know, we think that these 200 or 400 milligram doses without ritonavir boosting and once daily, you know, offer the potential opportunity for one pill once a day as a cure for COVID. Stay tuned. We look very much forward to our phase II readout in the first half. I wanna just quickly go to our PLpro program. This is the papain-like protease. Again, Enanta has a long legacy for literally decades, I guess, working on protease inhibitors of one sort or another, and a couple that made it as Hepatitis C cures. We've got the 3CLpro in the, in the molecule I just described. Here's another protease. Again, we got going on this program very early in the pandemic, but we didn't really talk too much about it until we had the chemical matter that was starting to get exciting for us to be close to a candidate. I will highlight some data here on this PLpro 001. It's a prototype. It's going under going final lead optimization, but you can see we've got, once again, very potent, nanomolar activity against this. The reason why PLpro is a little bit interesting is 3CLpro, the prior target, the target of Paxlovid, will clearly stop viral replication. We've seen that with our own molecule, EDP-235. papain-like protease will not only do that. It turns out that protease is also involved in some of the tricks it plays on the immune system in terms of compromising the immune response to the viral infection. If we can shut down that enzyme, we should simultaneously be able to shut down viral replication as well as the virus's damage to the immune system that's, you know, trying to fight the virus. It's a very interesting mechanism. We'll have EDP-235 going forward. Hopefully, you know, soon enough, we'll be able to have a candidate for PLpro. It's just good to have more weapons and optionality going against COVID rather than less. The potential for combinations in the future, if it's ever needed, is certainly available to us. Stay tuned on that front. Very exciting program. HBV, it's the largest liver virus population that still has no treatment. Hepatitis C, at least we have multiple cures. It's really a question of time and money to cure the Hepatitis C that's in the world. With HBV, you know, there's a vaccine, but there's still millions of people, almost 300 million people worldwide with chronic HBV for which the vaccine does nothing. We do need treatments, we do need cures. To that end, we still wanna try to make an impact there if we can. I won't spend a lot of time on our Core inhibitor EDP-514. We've spoken about it in the past, but it's among the best Core inhibitor datasets that's ever been generated, not only in vitro and in vivo, but also in the clinic where we've shown good clinical data in multiple different HBV-infected populations. Namely, those who were naive to any therapy, as a single agent, we saw multiple log drops in that, of the virus in that patient population after a month-long treatment. Also in patients who were on stable NUC therapy as an add-on to that. We believe that two drugs, a NUC and a Core inhibitor or a NUC plus almost anything else, is not enough to get to a reliable, durable cure for Hepatitis B. We continue our hunt for what could be the third mechanism to add to this. At some point, we hope to have identified that, and when we do, we'll get back on the horse and start riding again with clinical trials. Until then, we won't. That's a simple way to think about that program. Hepatitis C, it's really a royalty story for us. Whereas, Hepatitis C sales haven't returned to pre-pandemic levels, they do still represent a very significant cash flow for the company. Over time, between milestones and royalties, we've received over $1 billion in non-dilutive capital from AbbVie. It's been a very successful program. As I mentioned, we've cured lots and lots of patients around the world, and we aim to do that with many of our other programs as well. Just a summary of the sort of the balance sheet. Again, strong cash position and we've already given guidance for the year in terms of R&D spend, et cetera. Okay, just to wrap up on key catalysts. Virology, SARS-CoV-2, just putting them in an order of things that are coming, quote, "coming soon." We have SPRINT data from that phase II of our protease inhibitor coming in the first half of 2023. The plan is, assuming a good data set to be enabling for a phase III study in the second half of 2023. PLpro, this really exciting new target that we just talked about in our new, newly revealed program, we'll be optimizing lead candidates this year and hopefully be able to harvest a very strong molecule for clinical development later. In RSV, you know, we'll see how the RSV seasons play out. You know, we're certainly gonna need the Northern Hemisphere. Undoubtedly, we'll move to the Southern Hemisphere, and we'll just have to see how we're able to recruit into those different studies in these different geographies during this year. EDP-323, which is a phase I study, feel very confident about data readout there in the first half. Human metapneumovirus, this fascinating new dual acting agent, we're very close to a candidate. You're never done till you're done. We plan to hopefully have selected that finalist candidate in Q4 this year. With Hepatitis B, as I just mentioned, we'll be looking for agent 3, as it were. With that, I'll stop and shift things to Q&A, I'll also bring up Dr. Tara Kieffer, who's our senior vice president of New Product Strategy and Development at Enanta. Thank you. Great. Well, thanks for that, Jay. Just as a reminder, if anybody wants to ask a question, just raise your hand, and we'll bring the mic around. Just, maybe just picking up on the RSV programs with EDP-938. Obviously, Jay, you kind of highlighted the, you know, the high circulating rate of RSV this season. I guess how, well, it's an opportunity perhaps to sort of leverage that to facilitate enrollment. Any challenges or how well have you been able to leverage the higher circulating rates of RSV this season and any challenges, I guess, to kind of, to do that across both RSV peds or RSV transplant. As I mentioned before, maybe only in passing reference, you know, RSV had disappeared as far as anyone could tell from Earth for a few years while the pandemic was going on, the mask wearing, the social distancing, the lockdowns, travel bans, and importantly, school closures. Because the vector for this virus is typically ambulatory peds who are either shedding virus to their siblings, to their parents or grandparents. I mean, that's usually the axis that you need to follow. We haven't had a normal RSV season for quite some time. Frustrating as that has been, you know, that's allowed us to, you know, get multiple sites up around the globe for each of these studies. When the virus returns to somewhat of a normal behavior, you know, we'll be able to capture as much as we can. You know, I will contrast that with COVID, which is, I've not seen a lot of masks in the audience, but I dare say I can tell you for certain that there are a lot of COVID patients out there flying into clinical trials. It's really a question of having RSV come back, get into its normal pattern to have normal season, maybe a couple normal seasons, Northern Hemisphere moving down to Southern Hemisphere, to get us, you know, really advance this. We saw in RSV peds when, you know, masks came down and RSV came back briefly, that we were able to zip up that study in short order based on, you know, the geography, positioning of that and the timing of it. Masks came right back on people's faces, and things changed around a little bit. What we do know is, RSV certainly came early, and it hit hard. You heard a lot about it because all these children that weren't infected in the early days of the pandemic, 'cause there was no RSV, the kids who were, you know, born in, well, I would guess, you know, the 2020 crop of children, the 2021, they didn't see RSV. You rely on multiple RSV infections when you're a child to build up some sort of an immunity. You had a warehousing of children that started to pop and created a lot of this, you know, crisis in emergency settings and so forth. We need to, we need to have some of that be durable for a period of time. Stay tuned. I think we'll know more as we get further through this season. Okay. Great. That all being said, I guess if we're trying to think about the baseline rate of RSV-related symptoms that could be sort of detected in either the pediatric or the transplant population, which are generally higher risk. I guess how would you relate sort of the baseline the anticipated in-infection or symptomatic symptom risk, I guess, in those populations relative to those that you previously studied in the RSV trial in the general population, general adult population? One of the things... In the general population for otherwise healthy adults. Otherwise healthy adults have made it through childhood. You see, you continue to get RSV infections throughout your life, periodically, but you have some sort of immunity, except at the beginning of life and later in life, as in later years. Those symptoms were relatively mild and short-lived, as were the viral loads in that patient population, in those otherwise healthy adults. As I mentioned briefly, by the time we're dosing the first dose within 48 hours of symptoms, everything had peaked and was coming down. It was hard to demonstrate a drug effect on something that was already coming down. In these high-risk patient populations, it's very different. Again, symptoms go up and are much longer in terms of persistence. Viral loads can go way up. Peds have much higher viral loads than even adults do, and they can be persistent out for weeks. You have this big disease window, if you will, at the commencement of therapy that you can start to alter and push down. You know, that's a, that's just a lesson that we learned that, you know, otherwise healthy adults don't need RSV drugs. That's... By the way, that's not in the FDA guidance, that patient population as an approvable, patient population. That was more of a translational study that we did on our way to the high risk. The FDA guidance specifically calls out, peds, they call out immunosuppressed patients, and they call out, elderly high risk. Those are the three phase II that we've got going. Okay. Okay. Just, I'm just wondering if there's sort of any challenges or logistical hurdles in screening patients in the RSV transplant program. Also sort of the... Is it sort of uniform, the type of, let's say underlying comorbidity that the subjects might have that would necessitate a stem cell transplant. Well, I mean, the main risk with the transplant patients, especially in this case, they're hematopoietic stem cell transplants. You know, post-transplant, there's a very high-risk period of when they're highly immune compromised. If they get an RSV infection, it can be very serious. You know, I think one of the challenges in that patient population during the pandemic is, the first challenge was, no RSV around. The second challenge is, it's among the most cautious patient population as you will find people who are immediately post-transplant in the middle of a pandemic. They're likely to be the most highly masked and cautious people at avoiding respiratory risk. On the other hand, at the slightest risk or slightest sign of a respiratory infection, they do seek treatment right away. That patient population is a little bit different. Because they are in an immune-compromised state, we do increase our dosing from five days of therapy to 21 days of therapy. I guess, do you have a sense from the preclinical data with EDP-323, whether that compound might be, you know, differentially, clinically active compared to EDP-938? I mean, obviously the clinical data will kind of help bear out that answer. I guess, is there anything preclinically that sort of informs the relative potency or activity between the two compounds? I guess, looking longer term, is, do you anticipate or do you expect there to be a rationale for combined treatment and arriving at an ultimately anti-RSV regimen? Yeah. It's a little hard to know, because again, there hasn't been, there hasn't been a lot of data generated along the way yet. This is again, it's a polymerase inhibitor. It's a non-nucleoside polymerase inhibitor. We want to characterize that in full. It's obviously exquisitely potent, picomolar. Exquisite potency can sometimes manifest itself in interesting ways from an efficacy standpoint, but sometimes it just manages the size of the pill to be exquisitely small, because the dose you need is so low. We don't know the answer to that question yet, but it's a really potent antiviral. It could be that having that potency could help you know, get viral loads down faster and quicker, which will always help you. Regarding the combo question, it is a combo possibility for sure. We're not sure that we need combos in RSV because it's an acute infection, a five-day therapy. 938 already has a high barrier to resistance. You might think about it in terms of the hardest to treat patient populations. You know, maybe, immune-suppressed patients having a two-drug combo might help. You know, could you widen the treatment window even further? In other words, somebody further along in their infection, if you attack that virus with two different mechanisms, not just one. Those are among the. If we could open the addressable treatment population, that would also be an enticing possibility. Okay, great. I think we'll have to call it there for time, but thanks very much, Jay. Thanks for joining us. Thank you.