Good morning, everyone. My name is Liisa Bayko. I'm a biotech analyst at Evercore ISI, and this is HealthCONx , and we're very pleased to be hosting Enanta for a fireside chat. Known Enanta for a long time, and you've kind of had some success in hep C, and now you're going on to other viruses, so we're gonna dig into all of that. I want to introduce Jay Luly and Tara Kieffer. You're head of new product strategy and development. Yes, and Jay is CEO. So, I'm gonna turn it over to Jay. Maybe you can give us a sort of a brief overview of Enanta, just to get everyone on the same page.
Sure. 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. For those of you less familiar with Enanta, we are a small molecule drug discovery and development company. We've been focused heavily in infectious disease for the last, few decades, couple decades now. Going way back, an early legacy in antibacterials, actually, and then, moved into antivirals, starting with hepatitis C, and, had multiple approaches in hepatitis C over the years, and then skinnied it down to one that we teamed up with AbbVie on, and, ultimately brought two drugs to market with them. Spread out into other liver viruses and ultimately into respiratory viruses, began in RSV, added on human metapneumovirus.
Pandemic broke out. It was a very obvious thing for us to do, so we got into that. So we've mined respiratory viruses really well, I think. We've looked a lot at other viruses and, you know, we're actually looking forward to branching out into other new areas that go beyond virology.
So, Jay, your history has spanned hepatitis C, hepatitis B, MASH, COVID. I think there's flu, there might be some others in there. RSV, of course, which we'll get into. But what, what would you say? Like, what are Enanta's core capabilities in terms of, like, your platform, what you bring to the table?
It's always been a sort of tradition of just great and small molecule drug discovery. I think, you know, the core strength in the company is, has been chemistry.
That's, that's...
Very, very strong in chemistry, whether it be medicinal chemistry, process chemistry, you know, scale up. It's also. But, you know, we've got very good biology as well, and when you put those together, you start generating really interesting molecules. And I would say we've got very highly integrated metabolism, toxicology, biodistribution. We really interrogate these molecules extraordinarily carefully before we pick a candidate and then ultimately, you know, move it into the development. So I think it's just a very tightly integrated, very capable, strong, small molecule drug discovery organization.
So you had made a kind of big splash from MAVYRET and hepatitis C, and then, you've had some development along other areas, but nothing's really kind of like reached that level of success. Like, what have been your learnings, and how has it shifted your strategy at all as you kind of move forward into these other areas? And I know you've got some new breaking things you're gonna talk about soon, but as you think about where you go next, how has your thinking evolved through these experiences?
Yeah. No, it's been interesting journeys on each of these things. I mean, Hep C, going back to the early days, I mean, we—one of the things we learned was, you know, just keep focusing on best-in-class, if you can. First to market, which, and you were very active in the Hep C space-
Mm-hmm
... you know, back in the beginnings of that. First to market is not always the one that's gonna end up, you know, sort of taking the most market penetration. And so Enanta, you know, wasn't first in that, but we ended up creating the best-in-class, you know, protease inhibitor for that. I think the other thing as we look at hep B, or NASH, or hep C, is some of those learnings are combination therapy is tough. You know, you have to figure out what are the right mechanisms and to figure out how to put them together in the right manner, and that's not always easy. It's hard enough with one, you know, trying to figure out what's the best mechanism for any given disease.
And so that, I think, is, you know, a learning there, that combination drug development can be very humbling. But you often need it to get the best treatment for, you know, for the patient. So we think about that as you know, going forward or in anything we do. Is it gonna be combinations? How is the development gonna be? Is that gonna be-
Well, in Hep B, you were sort of relying on external partners to maybe come in. I think it seems like-
Right
... your approach to RSV is a little different. Like, you're gonna develop your own combinations.
Well-
It kind of puts you more in the driver's seat, right?
Yep.
Is that fair to say?
So with RSV, mercifully, I think we might not need combinations necessarily to get-
Right
... It's an acute virus, or it's acute viral infection, so short treatment with a single agent may be enough, especially if it's a drug like some of ours that have high barriers to resistance. You can get in there, treat for several days, and, and do that. So I'm, you know, we're hopeful that we may not, sorry, may not need combinations, but if we do, we, we've got multiple different approaches. Again, when you're there early and kind of at the forefront, having multiple tools that you could potentially combine or at least choose among over a longer time period as you figure out, different patient populations, is a real, is a real strength, I think.
... So you're making this foray into RSV. I've always thought this was the crown jewel of your pipeline, so I feel like now this has finally bubbled to the surface, and it's kinda getting the most attention.
Yep.
Why have you been able to make inroads in RSV? I'm just surprised. It's such a big market opportunity, there's really very few players involved. I mean, Pfizer bought ReViral.
Yeah.
Mm-hmm. And then there's you guys, and I'm not really sure there's no one else prominent at least, that's worked on really the antiviral category-
Yeah, so-
-for this disease. And now with, you know, vaccines, there seems to be, like, a lot of attention on RSV, and we know there's vaccine hesitancy. There's just obvious need for antivirals, and I'm just curious why. Is it just a hard virus to crack? Like, what's been-
Yeah
-the hang up?
So I can opine on that a little bit. I mean, you know, number one, one of the teachings, I think, in this, you know, modern-day world is that, vaccines aren't enough. You know, you need to have therapeutics because vaccines are never 100%, effective. Their adoption rates can be challenging sometimes. And people, even if you've been vaccinated, are, you know, sometimes still likely to get infected. You know, I didn't get COVID until I had had 5 vaccines, and then I needed Paxlovid, right? So, I think. When we sat down and looked at RSV, we asked ourselves kind of the same question, just, you know, a few years ago, and where have the challenges been?
We distilled it down to everybody in the world had been focused on entry inhibitors. You know, going after sort of the equivalent of the spike protein on COVID is the fusion protein.
Right
... on RSV, and everybody had come up with these F protein inhibitors. I think in part because Synagis, which is a monoclonal antibody that got launched years ago, had shown some efficacy when given prophylactically, not therapeutically, but prophylactically, it worked. And so people zeroed in on that target, tried to develop small molecules against it, and then one by one, various of the programs, you know, didn't ultimately deliver what was acceptable. So Gilead had an early program, probably created the strongest F protein inhibitor, and it struggled in some of the Phase II studies. It also had, as do all fusion inhibitors, a low barrier to resistance. And so dosing fusion inhibitors for two, three days, you'll start to see resistance mutations building up.
That is not the case with EDP-938, where we wanted it to have a high barrier. So, you know, Gilead fusion inhibitor, and then that program shut down. J&J had one, shut down. Biota had one, shut down. Pfizer bought a company called ReViral to get,
Mm-hmm
... you know, another fusion inhibitor, and so they're in development. But we decided, let's go after-
Yeah, they also have an N protein.
But I don't think they're developing that anymore.
Oh, really?
Yeah.
Oh, interesting.
Yeah.
It disappeared off their pipeline chart.
Oh, okay.
So, we, we focused on direct-acting antivirals. Let's get inside, shut down the replication machinery, not focus on viral entry, because when a patient presents, they're going through this massive viral replication, and the virus has already gotten into a lot of cells, and viral entry, you're trying to catch every other viral particle and preventing it from... And stoichiometrically, after a while, you just sort of, you know, are up against, a, a big, big challenge. So instead, we go in, try to shut down replication at its source, and we do that with a couple different mechanisms. You know, we have the N protein inhibitor, we've got the L protein.
But you said you probably don't need more than one.
We probably don't, but-
Is that just like a backup? Is that how you're thinking about it, or?
Well, or it's a backup or-
For some resistant cases.
... you know, you could think about different patient populations, different potentially positioning in the marketplace. If you do need a, you know, to go after it with two different mechanisms for really difficult-to-treat patients, highly immunosuppressed, for example, maybe that's an arena where you know, you could really benefit from that. And so, since we're kind of at the front edge of all this, nobody knows all the answers. When we were working in hep C, at one point, we had five different mechanisms going, right? We had proteases, polymerase inhibitors, host targets, and then there's five.
That was different, though, because I think in that case, we knew that one wasn't gonna be enough. In this case, it seems like one might be.
Yeah, but even sorting out which one, even if it could be one, which one, right? And so I think. But so far, so good on EDP-938.
Yeah.
I think we've got the profile that we're looking for.
So we're looking forward to Phase II data next year. I know you haven't said kind of maybe which program, maybe two of them, maybe one, we're not sure. How important is this data? I mean, I feel like it's actually pretty critical, right? Because-
It is
... you had this great, challenge study.
Yep.
Then it was followed by which, you know, I was a little bit concerned about the sort of normal adult, like, otherwise healthy adults, right, study, which I think they clear virus quickly on their own. So, like, that was a very difficult poor background in which to show a benefit.
Yep.
So the data there didn't work out, but now we're in this kind of population where you really could see the benefit. Can you tell us a little bit more about how you've designed the study, how you're powered? Like, how confident are you that you can really show a benefit there? Because it seems like this is really a critical point for the program.
It is, and getting the patient population right is always, you know, key. So after we figured out, we didn't. That otherwise healthy adults really don't need a treatment, in fact, can't benefit from a treatment because they resolve so quickly on their own, even when we got to patients within 48 hours. The so-called standard risk patients in RSV just simply don't need treatment, and otherwise, healthy adults. High risk, very different. I'll let maybe Tara speak a little bit.
Great.
Yeah, so we have two studies ongoing in high-risk patient populations. One is in the pediatric population, and the other is in high-risk adults, so that would be people over 65, folks with COPD, asthma, or congestive heart failure. And what's different about these populations is the viral kinetics and kind of symptomatology, where they've got much higher viral loads to begin with, and then, longer durations of ongoing replication. So as an example, in the pediatric population, they can have two to three logs higher viral load, and there have been studies showing that even out to 30 days, from symptom onset, you can still detect the virus in these children. So this just provides a much bigger window with which to have an impact, with treatment. Symptoms as well, you know, more severe and more prolonged in these patients.
Our studies are designed to look at these high-risk patient populations. The adult study is looking at symptoms as a primary endpoint, so we are looking to see time to resolution of symptoms with EDP-938 as compared to placebo.
Can you talk about how you've powered that?
Yeah, so it's powered on symptoms, and we're looking to see whether we can reduce it by 50%.
Okay
... from placebo.
50% faster resolution?
Faster resolution.
Okay.
Yeah, and I think really what we're looking for here is something that would be clinically meaningful. You know, these are Phase II kind of proof of concept studies, and so we are looking for data that would enable us to move into Phase III.
What would the background rate be? So then what are you hoping to see? You know, how long is it?
For-
Yeah, what are you assuming for placebo-
For placebo
... or standard of care?
Yeah. I think, you know, some of those studies, there's been limited data in high-risk adults where we can model off of that, and so, you know, I think you take into account the best assumptions that we have.
That must make it difficult then. Is that, like, a key risk for the study, do you think, just not knowing exactly the-
Well, I think really what we want to see is something, again, that's clinically meaningful, that we can show patients are feeling better and resolving their symptoms quicker than patients on placebo. Again, you know, Phase II study, proof of concept, so seeing something there that would give us the confidence to move into Phase III, where you really can, you know, have a larger, a little bit larger of a study.
It'll be a lot of learning, too, about what the background rate is...
Yeah
... for placebo.
Yeah.
Okay.
Yeah.
That's what we did in the standard risk study, right? Nobody knew exactly what-
Right
... you know, the natural history would be in that patient population until we did it, and we looked at the placebo, so-
Is it the same for the pediatric study, Tara? Is it, it like, kind of not very well defined what to expect-
So the-
... the background, or is it more well understood than the adult?
It's a little bit better understood in peds. That study is a little bit different because it's a first-in-pediatric study, and additional issues there where, obviously, safety is very important, and you have to dose range in these children based on age and weight cohorts. So the first part. It's a two-part study. The first part is doing that dose ranging within different age and weight cohorts, and then selecting the optimal dose for each of those patient groups, and then looking in part two at virology, and we'll also look at symptoms and other endpoints. But the idea there is, you know, it's a little bit smaller of a study, again, proof of concept, to give us some data to enable moving into a registrational Phase III.
The challenge in each of these studies is defining the size and the endpoints that you're looking for in a way that gives you sort of actionable information without them being so large that it takes you forever to recruit.
Right.
Right.
I mean, recruitment during the pandemic was a challenge in these things already. But, you know, it's looking like a sort of so-called normal Northern Hemisphere season right now, which is great because we haven't seen a sort of normal one in a while, you know, kicking up in late October and moving right now into the year. But the, on the HR, you know, the powering assumptions there are pretty aggressive, but-
Do you need to hit stat sig in these studies?
I don't. I mean, that's the thing-
Or is it more like a, you know, a Phase II-
We're-
Exactly
... learning exercise, and now we'll figure out for Phase III.
I think that's right.
Would you do Phase III on your own? Like, or do you need a partner for that?
Yeah.
I mean, these seem like they could be-
No, I don't think we need-
Okay
... Phase III partner.
Okay.
I mean, we could end up in, well, you know, with a partner. I mean, we gotta think about how we, you know, ultimately, the path to market here is something that's really, you know, on our minds. But I think in terms of the execution of the Phase IIIs, given the unmet need and these different high-risk patient populations where there's no drugs available-
Yeah
... we think there can be, you know, a very concise, registration program. And so, again, I think we're looking for actionable information that gives us clinically meaningful results that, you say, "Yeah, yeah, you have an effect there.
Absolutely.
And then you can ultimately get the bigger powering in a Phase III.
Jay, I know you're about to roll out some new programs, and I've told my team internally. I'm curious if you're working on GLP-1, but we'll just put it there. Are you focused, do you feel like your core capabilities are on viruses, or might you kind of move beyond that? How are you thinking about that?
Yeah, you know, I think, the drug discovery organization, especially when we think about ways that we're targeting stuff, I think... I mean, we don't get into stuff that we don't think we can do, right? Feasibility is important. And usually, I remember several years ago when we were sort of opening up HBV and RSV, we were at a similar stage, and I told you we're gonna move beyond hep C and start to work on some other things. And you said: "Well, what are those?" And I said, "Well, we're working on them, and once we've got certain things, you know, we've got, assays set up, chemical matter being produced, intellectual property being filed, market analyses done." You know, once we've started to check all of these boxes, and especially the internal feasibility, then we talk about them, right?
But I think we're at that point now, so early next year, I think we're, you know, we'll plan to start rolling these out, you know, multiple new things. It's only after we've gestated them appropriately.
The remaining time we have, which is just,
Sure
... less than a minute. You've always kind of like funded the company on the nice royalty stream you've gotten-
Yep
... from AbbVie, but that, that's starting, you know, kind of like, you know, it's getting smaller and smaller as that market kind of contracts. And I think your spend, if RSV works out, is gonna be going up as you go into Phase III. How do you see, like, funding-
Well, we've mapped-
... going forward?
We've mapped all this out, and we did, we did monetize, you know, a little over half of the royalty for hep C for $200 million earlier this year. I mean, we still have roughly the other half. But we finished the last quarter with $370 million in cash, and we projected it with the pipeline that we have going, that we should have sufficient funds to get us through fiscal 2027. So, good runway, even contemplating all the things that are currently on our plate.
Okay, great.