Welcome everyone. If you don't know me, I'm Brian Skorney. I'm one of Baird's senior biotechnology analysts, and, the next company I'm hosting a fireside chat with is a company I have under coverage, Enanta Pharmaceuticals. With us, we have, the President and CEO, Dr. Jay Luly, and the SVP of New Product Development, Dr. Tara Kieffer. Jay, Tara, kick things off. It'd be great if you could just give us a broad overview of, the areas that, Enanta is focused on.
Sure. So thanks, Brian, for the invitation. So before I begin, I want to remind you, I'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. So yeah, so Enanta is a virology company. For those of you who are less familiar, we cut our virologic teeth in hepatitis C in the early days. We teamed up with various pharma, AbbVie being the long-standing partner that we've had in that space, and together, we've helped bring forward two cures for chronic hepatitis C and have helped cure over 1 million patients with chronic hepatitis C with an AbbVie-containing drug.
So we're very proud to have been a part of that, but we skinnied down our hep C programs at one point because we saw that our path forward was really with our protease inhibitor collaboration with AbbVie. And so, we redeployed efforts into other areas of virologic disease. Hepatitis B became one, and we also got into human respiratory viruses before it was such a topic of interest globally, starting first with RSV. So we felt like RSV was supremely underserved. At the time, there were no vaccines. There were really no drugs available for that, despite the fact that everybody knows pretty much every child in the world develops multiple RSV infections before the age of two. So we set about doing that.
We added on another respiratory virus, human metapneumovirus. The pandemic broke out. Brian, I remember you called me early, early in the pandemic and said that Enanta is one of the few companies that could probably come up with a good molecule to help treat that virus. And sure enough, we jumped, we jumped right into that. So we have a protease inhibitor for COVID-19 as well. So, it's been a lot of work over periods of years, and we've developed a deep expertise in finding drugs for various viral infections, and so yeah, that's our main footprint. And yeah, we're thinking a little bit beyond virology as we you know, think to the future as well, so.
Great. So maybe to start on RSV, and we'll go into the clinical data that you've shown so far, but, you know, you have two assets in development, an N protein inhibitor, EDP-938, L protein inhibitor, EDP-323. Maybe you could compare and contrast the value of each of those targets, the potential for sort of orthogonal treatment for RSV, and how you kind of see development of those two assets to sort of-
Yeah.
Sort of be a treatment.
So it's interesting. So we take just like in the early hep C days, we decided that targeting the virus with a direct-acting antiviral would be the best approach, and it's a tried-and-true approach against many different viral infections, whether you're looking at, you know, HIV, HBV, hep C, many other viruses. Direct-acting antivirals are an interesting and tried-and-true way to go. So we, you know, we looked at the various different targets, and the two that jumped out at us were the N protein and the L protein. So the N protein is a nucleoprotein, the L protein is polymerase.
And why we chose those, again, direct-acting antivirals, in contrast to prior efforts in RSV that had been, you know, substantially unsuccessful, had been focused on viral entry with the so-called F protein inhibitors. So F protein for RSV is sort of like the spike protein on COVID. It's an easy-to-target protein. It blocks viral entry, but it, you know, in our mind, it might be best used prophylactically before the virus had a chance to come into cells. Once the virus gets inside the cells and has entered, it sets up shop and starts replicating and spewing out, you know, millions of different viral particles, and it becomes a very hard thing to extinguish unless you can actually shut down replication. So we decided, well, let's look at multiple different approaches. We took the N, we took the L.
N was the most advanced and took off first. L was coming up behind, but at the end of the day, you know, no one knows which will ultimately be the best. I think either of them has a very strong chance of being successful, again, being direct-acting antivirals. But we wanted to have multiple different weapons at our disposal. You know, our lead horse is moving ahead very nicely in multiple different studies. We've got the second one coming forward, and again, two very strong mechanisms, replication inhibitors, high barriers to resistance, unlike fusion inhibitors... and we think they're very solid choices.
Got it. So maybe starting with 938 specifically, we kind of walk through the clinical development history here. I know you've run an RSV POC study. Maybe you just kind of walk through what we've learned from that study to start.
Sure. And even before RSVP, we had a very solid Phase I healthy volunteer study. We did a challenge study in healthy volunteers that were infected with the virus, where we showed antiviral effects and also improvement in symptoms. And then the next step we did was the RSVP study, which is sort of a standard risk community-acquired RSV study. And I'll contrast that with the high risk community-acquired patient population, which we'll talk about in a minute. Maybe, Tara, I don't know if you want to talk about RSVP?
Yeah. So it was, as Jay mentioned, basically in a population of young, healthy adults that have a good immune response to RSV. And, you know, what we found in those patients is that even getting to them within 48 hours of treatment, which was one of the inclusion criteria of our study, they were already clearing the virus on their own and starting to feel better. So we had seen viral loads and symptoms had peaked and were already on the decline. You know, it seems as though in this patient population, it's a bad cold, self-resolving, few days, limited, you know, window to be able to see an effect with the drug. The one analysis where we did see a statistically significant effect was on the number of patients that had undetectable viral loads at day 5.
So, I think, you know, that speaks to the mechanism of 938 in stopping viral replication. But of course, you know, we believe the opportunity here is in high-risk patients that have much more chances of severe outcomes. Also, the populations that regulatory agencies require you to study it for ultimate approval. And I think, you know, the reason the window is bigger in these patients is, first off, their symptoms are worse, so there's a bigger window there, but they also have much higher viral loads and much longer durations of ongoing viral replication. So that's true in children. That's been studied well in terms of natural history in those patients, and then also in elderly or other high-risk patients, and of course, the immunocompromised.
Great. And then, so I think you have three Phase II programs going on right now: high risk, peds, and stem cell transplant patients. Can you just kind of walk through those three different opportunities, how the trials are designed to show efficacy here, and, you know, what you think the potential outcomes could be?
Yeah. So you outlined the three... those are the three high-risk patient populations. It tends to be the young, the elderly, and the immunocompromised. Peds clearly are very big. They are the biggest portion of this market opportunity. Second would be the high-risk adults that are either elderly or who have COPD, congestive heart failure. These types of sort of comorbidities have shown to have poorer outcomes with regards to RSV infection. The third bucket, the stem cell transplant, we actually have undergone sort of a recent prioritization, where we're focusing our efforts on what we think are going to be the quickest to enroll and the fastest path to market, and we're not going to be pursuing the transplant going forward, at least not now.
We'll probably pick up that population later after we've gotten, you know, our initial approval, we'll broaden the label. And the reason, what we're finding is, you know, number one, there are only a finite number of stem cell transplants in the world at any given time, number one. And number two, in this COVID era, these patients are incredibly cautious, and so they're living inside a very, very contained bubble, if you will, trying to avoid COVID, any other respiratory pathogen, and we're just finding that recruiting that patient population is going to be very, very slow.
So, we're doubling down on peds, high-risk adults in the HR study, and focusing, you know, our resources there to get to the trials that we actually think are going to be the fastest to enroll and ultimately the fastest to market. So, that's where we are. The peds study and the... I mean, they're similar populations on the one hand, because peds get infected because they don't have any natural immunity, right? They haven't been exposed to the virus. Prophylaxis in peds is only going to push the age further down that kids might get infected, but they have to get infected a few times in order to build up that immunity.
Older adults have had that immunity sort of variously throughout their lives, but, immune senescence starts to kick in at some point, and they start to lose it on the, the other end of the age spectrum. And so these are the, people who have, you know, less robust immunologic states as regards to fighting the virus, unlike RSV, where people were, you know, highly immunocompetent in, in that setting. So, there are different patient populations. The trials, you know, the first-in-peds is a study that we're, doing dose escalations in, in children as young as 28 days up to, 36 months. And so that, dose escalation, you know, necessarily proceeds cautiously, but is advancing.
And then, the other patient population, again, very, very different, but the, the common denominator is, you know, viral loads build up, and, and viral loads and symptoms are more persistent in those high-risk patient populations than in, otherwise healthy adults.
Got it. I think you've guided to data in 2024, but I guess pending sort of the RSV season. I know during COVID, we went through some delays over the absence of all RSV.
Yeah.
I guess your thoughts on your level of confidence going into the season that you'll be able to successfully enroll and-
Yeah, so COVID did, you know, as though the world... Maybe one of the only good things that came out of COVID was that it suppressed RSV infections for a little while. Flu was suppressed, too. Nobody got the flu. Very few people got RSV during some of the height of the pandemic years. As that has backed off, and we saw it first raise its head last year, as you remember, kids were not in school, you know, kids were not going to daycare, everybody's locked at home. And young children are the vectors of this virus, so you rely on them to go to school and to go to daycare and come home. In fact, siblings and grandparents, this is how the virus naturally gets spread.
Last fall, sort of a year ago, kids went back, they started going back, and the mask restrictions started to lift. And what we saw was, okay, all of a sudden, the virus suddenly popped back. It spiked very early, hit with a vengeance, probably a lot of people saw it on the news, and then it kind of disappeared pretty quickly. But it was at least a sign we're coming back to a somewhat normal seasonality. We followed it through the Southern Hemisphere, and were able to do at least some recruiting. We don't have as big a footprint in the Southern Hemisphere as we do in the North-
Mm-hmm
...but in Brazil and Argentina, New Zealand, Australia, South Africa. But now we're coming back to the fall, and there's already signs that the virus is picking up in the South Florida. And that they're usually the early sentinel of-
Mm-hmm
... some things that come, and then it radiates out across, at least North America from there. So we have a big footprint in those, two studies. We're in 15 different countries. We're throughout North America. We're in multiple countries in Europe, in the Middle East, also in Asia, with, you know, sort of in one study, 75 sites, and then the other, over 100 sites. So we're if we have a, a fairly normal season, this year in the Northern Hemisphere, we're hopeful that we should be able to, to wrap up at least one of those studies.
Great. And then maybe shifting a little bit to 323, I think you have a human challenge study ongoing right now. I guess, what do we, what do we expect to see from that? Is there anything unique in terms of the study relative to the human challenge study that you've done with 938? Do you expect some level of differentiation as sort of success or is success here just to show that you're successfully-
Yeah
... suppressing the virus?
Well, it hasn't quite started. I think we guided to early Q4. We're still on track for that, so it should initiate in the coming weeks. I mean, we're getting everything ready, at the same site that we used for the 938 study. And it'll be... Again, this is, 323 is an incredibly potent molecule. It's a picomolar inhibitor of the polymerase. It's very well behaved. We've got a great phase I data set in healthy volunteers. And the human challenge study is sort of a gateway study that you do in order to demonstrate that you have an antiviral in humans. And you can... It's a nice way to do that. It's not dependent on the season-
Mm-hmm
... because we take healthy volunteers, and we infect them. We wait for the virus to build up, and then you come in with the drug several days later, and then you can measure the course versus in terms of antiviral effect or symptoms versus placebo. I think one of the things that will be interesting, so we've got a very nice data set on 938, as I think you know, and we'll be doing 323. It's always a little tough to do cross-trial comparisons-
Right
... in this business, but I think this will be-
Do it all the time. Yeah.
People do it all the time, right?
It's done now.
You can't not do it, to some degree. But, so it'll be really interesting to see, you know, any differences. Obviously, if it's not as good as 938, that's illuminating-
Mm-hmm
... but we expect it to be, you know, very ... 938's a tough bar to beat. You know, there's been very little data that has ever been generated as good as 938 did in that human challenge study. So but what you might be able to see, and one of the things we'll keep our eye on is, you know, might it knock viral load down even a little faster than 938-
Mm-hmm
... in the, you know, sort of come on and hit it harder, and in part because we have such high multiples over the targeted protein-adjusted EC90 with-
Mm-hmm
... with 323. It's very high. It's even higher than with 938. So we'll keep our eyes out. Again, we want to have multiple approaches going in after this with direct-acting antivirals. There are no approved drugs, and if we can be the first, you know, first to market with one of these things, I think it could be, you know, really a change for the medical profession-
Mm-hmm.
and pediatrics especially.
So there may not be that much of a timeline between, sort of 323 human challenge data and some of the 938 studies. I guess, assuming success, how do you think about developing the two assets in parallel? Are they parallel developmental pathways? Is there a combination approach that you start taking?
Yeah, so it's not clear yet that we would exactly create two identical parallel paths. I think we'll be watching... The nice thing is they're staggered a little bit, right? So hopefully we'll be getting insights in 938 as we're getting other insights into 323. They're two, both again, strong horses pulling ahead. It's better to have multiple shots here. But you know, so to come back to the combination question, I mean, I spent many years at Enanta hoping to figure out a way to not have combination therapy if I didn't have to, right?
Right.
So we did it multiple times in hep C, which was combination therapy. Hepatitis B was combination therapy. You remember we were in NASH. That was ultimately, I still think the win in NASH is gonna be combination therapy of multiple different agents to most optimally treat a patient. And then we got into acute respiratory viruses like RSV or COVID, and there's significant evidence that you should be able to do this with a single agent. Tamiflu is a single agent. Paxlovid is two drugs, but one because it's a boosting agent stuck in there, but the antiviral against the virus is a single agent. And I think 938 could well be a single agent drug. Might there be really difficult to treat patient populations where two drugs is better than one?
Mm-hmm.
Absolutely. Not clear we need to do it for reasons of resistance, which is often why you do combo therapy, because we have such high barriers to resistance with these drugs-
Right.
And it's an acute therapy. So, so we're thinking about it more from maybe a different patient population perspective, or from maybe an opportunity to open a treatment window to be wider if you were using two drugs rather than just one.
Got it. And then, last question on RSV. I think there's been a lot of activity in sort of the active immunization space for RSV. With sort of the oncoming vaccines coming out there, how do you kind of think this impacts the potential commercial—
Sure.
-for antivirals?
Yeah, the vaccines, I think, have been a big step forward in the RSV field and certainly raised a lot of education and awareness around RSV. You know, unfortunately, as we've learned from other respiratory viruses like flu and COVID, the prophylaxis piece is not gonna be the entire solution, as there will always be a need for treatment of these infections for a couple of reasons. You know, firstly, any vaccine is not gonna be 100% effective, so you're still gonna have breakthrough infection. We certainly saw that in COVID with some of the vaccines that had some of the best data out there in terms of efficacy, and yet, you know, people still had and are continuing to get infected, and so there's a treatment need there.
I think the other reason is unfortunately, the uptake may not be as optimal as one might hope for a couple of reasons. Generally, if you look at universally approved vaccines, things like flu, that people are recommended to get every year, vaccination rates in the elderly population is only, you know, 50% for flu. It's lower for Shingrix, let's say, is thirty-
Mm-hmm.
-in the 30 percentile. COVID boosters, quite low as well. The RSV vaccines were actually approved, or recommended for shared decision-making, so patient and physician would sit down and, you know, in an individual case-by-case basis, decide whether it was appropriate in that situation. And so I think, you know, the uptake there also can be limited just based on that recommendation. That's on the elderly vaccines. There also has been some activity, as you mentioned, on the pediatric side. There's a maternal vaccine that Pfizer has, a number of challenges with that. You know, there's some dosing, timing issues in terms of making sure it's being given at the end of the pregnancy and providing the longest duration of protection-
Mm.
that you can, because it's basically about three months of protection.
Mm.
And we know, you know, in RSV seasons longer than that. Also depends on the, you know, the time... the seasonal timing of the birth.
Yep.
There's also, you know, a challenge, given that they saw a numeric difference in the number of preterm births with that vaccine. And then, the vaccine, as well as the monoclonal antibody that has also been approved, both of those, as Jay mentioned earlier, only provide passive immunity.
Yep.
And so the children still will go on to get infection, you know, maybe push up the age range a little bit older, but there certainly will be need for treatment there as well.
Great. Maybe moving on to EDP-235 for COVID-19 for a few minutes here. Obviously, pandemic drove a lot of people to look into antivirals, and as you said, I knew Enanta to be an expert in sort of the approach here. So maybe can you just review, you know, that protease inhibitor, sort of the advantages it potentially has over PAXLOVID that's out there right now, and the phase II data that you announced earlier this year, and kind of next steps for that program?
Sure. So, when we got into COVID, it became clear there were multiple different places you could start. I mean, one way we were doing it was screening our large antiviral library against different targets. And then we said, "Well, screening is one thing, but we shouldn't leave everything to chance," right? Let's focus on what we know how to do, which is to make targeted antivirals based on mechanisms. And we, you know, started working on multiple different mechanisms, but the protease, again, we have a legacy in protease inhibitors and that one just really jumped out to us and obviously to others, Pfizer, Shionogi, for example, also pushing ahead in that field.
So, what we decided to do was, let's look and try to make the- just as we do almost in every program, even though in the middle of a pandemic, you might be willing to set your standards a little lower just to get something out more quickly. But we said, "Let's focus on something that's very potent, ideally, that could be given once a day," which is in our product profile for everything we do. That, you know, ultimately, doesn't have boosting-
Mm-hmm.
has good PK on its own. And, and further, we said, "Let's look for something that has good tissue distribution," because it's one thing to have good PK in your blood, which is what everybody measures, but the virus is not hanging around in your blood so much.
Right.
It's in the tissues. And so we started focusing on how to optimize tissue uptake of the drug into compartments where we knew where the virus was hiding. And so we felt if we did all of those things, we could potentially have something that was differentiated, and that was EDP-235. So it's. And sure enough, all the modeling that we did preclinically, you know, was borne out in terms of PK. It's once a day. It requires no ritonavir boosting. It's very potent against SARS-CoV-2, but also the original SARS and the common cold corona, so it has sort of a pan-corona benefit, which is nice if you're looking forward to future pandemics. And it's also a highly conserved activity against all the variants of concern.
Mm-hmm.
The proteases in those variants of concern didn't have any mutations that affected the activity of 235. It's a very well-rounded drug from that perspective. We moved it into a phase II, and we reported that data earlier this year, the so-called SPRINT Study. You know, in that study, we were able to see something we weren't expecting, which was an effect on symptoms.
Mm-hmm.
It was only about a 200-patient study, and, you know, showing effect on symptoms is, you know, probably challenging to do in a statistically significant... It wasn't powered-
Mm-hmm.
- for that, but the effects were such that we were able to see. Viral load, as measured in the nose, was a little trickier to figure out, but we saw that in people who had more recently been infected with COVID, it was hard to get the viral load measurements in the nose, probably because of built-up mucosal immunity from having been exposed. But when we looked at people who hadn't been recently infected-
Mm.
We were able to see, you know, sort of what other people have been able to see. It's roughly about a log drop in viral load. We also think treating earlier is better, so probably three-day window treatment is better for COVID drugs than a five-day. And so that's the Phase II study, and I think we've said for a while that our plan is not to become a commercial COVID company. I think we want to seek a partner with regards to that, and also for the Phase III development.
Mm-hmm.
Because we're highly focused on RSV execution, and there's a lot going on with us right there. So, that'll be more of a partnering story as pursuing that front.
Got it. In addition to my job description, is doing cross-trial comparisons more often than you'd believe. I find myself reading patent litigation. You have an ongoing dispute with Pfizer over just this exact mechanism. I guess, can you give a little bit of background on that dispute and what should we be looking forward to, or are there any updates to consider there?
Yeah. Well, there's not a lot I can say about ongoing patent litigation. What I would say are a couple of things, our 235 program, which is our lead molecule, it's in a completely different patent estate as nirmatrelvir, which is Pfizer's protease inhibitor that's inside PAXLOVID. So we have multiple IP estates in this area, but 235 is separate and distinct, just to make that abundantly clear. And with regards to our other intellectual property, you know, we believe that Pfizer is infringing our intellectual property as it relates to the protease inhibitor in PAXLOVID. And not much more I can say about the ongoing patent litigation, other than that it is very much ongoing, and we expect to go to trial late next year.
Okay, great. Just wrapping up in the last couple of minutes here. Human metapneumovirus, how are we looking in terms of progressing that into the clinic? When will we get, like-
Yep.
- an update there?
Well, it's a novel molecule because it hits two viruses, you know, with one molecule, so it hits human metapneumovirus and RSV. It's very potent against both.
Mm-hmm.
We're doing the final stages of making sure we have the candidates selected properly, and we hope to have an announcement on that in Q4.
Okay, great. Okay, Tara, thanks so much for joining today.
Thank you.
Appreciate it.