Okay, good afternoon, everyone. Thanks for joining us. I'm Brian Skorney. I'm one of Baird's senior biotech analysts. Next company I'm hosting a fireside chat is with Enanta Pharmaceuticals. It's a company that I've covered for quite a long time now. Have the management team, Jay Luly and Tara Kieffer, with us here. Jay, Tara, thanks so much for joining us today. Maybe to just kind of kick things off, can you give the audience a little bit of an introduction into what Enanta has been historically focused on, where your core competencies lie, and you know, what programs you have at what stage of development today?
Sure. Before I begin, I want to remind you that 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. Yeah, so for those of you who are less familiar, Enanta is a company that has been broadly focused in infectious disease pretty much for its lifetime, but zeroed in on virology several years ago, zeroed further in on hepatitis C. We were very good in drug discovery and development, but our hep C assets, the protease inhibitors, we partnered up with AbbVie, and those sequentially became part of two cures for hepatitis C. So the eight-week cure called Mavyret is out there.
It's really AbbVie now commercializing Mavyret and Gilead are the two main players in hepatitis C. We had a lot of other programs in hep C, but ultimately thought, you know, we'll look at other viruses, develop other wholly owned drug candidates that are targeting other unmet needs, having come up with some really good stuff in hep C. So we got into hepatitis B, and at some point, we didn't want to be restricted to liver viruses. And so, before the pandemic, we got into respiratory syncytial virus or RSV, looking at it as a big opportunity. Pretty much every child in the world gets multiple RSV infections in their first few years of life.
Adults, as they become more senior, also become more vulnerable to RSV infections, immunocompromised. Big, big, huge, unmet need and no approved therapies on the market, people at that time had been trying for over sixty years to come up with vaccines, and so there really wasn't much of anything. Now, the vaccines, fast-forward, have started to come across the line. There had been a monoclonal antibody used for prophylaxis in PEDs, and there's a new version of that now, in terms of therapeutics, none, right? We started multiple or multiple different mechanisms in RSV. Pandemic broke out, shut down RSV recruitment globally, for a long time, actually. Flu, nobody got flu anymore, nobody got RSV anymore. Everybody was getting COVID, and/or being masked up and kids out of school.
Kids are the vectors, for the most part, of bringing RSV to sibs and around the house, so when nobody was in school, there was just no RSV around, so we, you know, got into COVID, did COVID protease, but really, finally now, after the pandemic has slowed a bit, RSV, sure enough, emerged, and finally, last year, it came back sort of on schedule.
Mm-hmm.
It had had a hard time sort of finding seasonality again, but last year, it kind of came back in sort of the October time frame and, went through the winter, and so that allowed us to, to start to recruit, heavily, a couple of our phase II studies, so anyway, I'm sure we'll get into all that. We've got multiple RSV, molecules in the clinic, a few data sets, coming out here in the remainder of the year, and then we didn't want to be. You know, you can continue to look for other viruses. So we'd worked on a couple of respiratory viruses, a couple of liver viruses, and then you start getting into, you know, what I would view as, as maybe smaller and smaller opportunities, important ones, but, but smaller.
And we thought, you know, in order to sort of build the next era for the company, we needed to think beyond virology. And so we looked at some of the skill sets we had internally. Turns out a lot of the virology skill sets that we had internally translated well over into immunology. We've got a really strong drug discovery infrastructure in medicinal chemistry and DMPK and toxicology and whatnot, and so those skills are highly translatable to many, many different targets and diseases. And so, we're excited to now be going into that area-
Mm-hmm
Which is more of an expanding universe as opposed to a contracting universe.
Got it.
So we can get into that as well.
All right, great. So, I mean, maybe starting on RSV, you have an N protein inhibitor, EDP-938, where you have a pretty robust amount of clinical data already. You also have an L protein inhibitor. I guess, can you compare and contrast the two mechanisms? Why pursue parallel mechanisms in RSV? You know, what's the ultimate goal with sort of doing each and, you know, is one better than the other? What's the ultimate goal for each of them?
Yeah, so, you know, we've always had sort of a multipronged approach when we went after disease indication. I mean, when we focused on hep C, we started with protease, but I think by the time we finished research on hep C, we had five different mechanisms going. I mean, we had protease, nukes, non-nukes, host factors, lots of things going on. In hep B, we had multiple different targets. I think, you know, we, when we came into RSV, again, not knowing what would be the best target perhaps at the end, we decided to go after multiple targets. The one thing we didn't do was go after entry inhibitors. That's a target that we could have gone after, the fusion inhibitors or the so-called F protein.
That approach tries to block viral entry, and it's a great way to think about prophylaxis. That's what the antibodies do, that's what the vaccines do. They target that F protein. Sort of think of it a little bit like spike protein on SARS-CoV-2. But we instead thought, well, you know, by the time a patient presents and they're symptomatic, there's a lot of viral replication going on. In fact, it's rapidly expanding, and viral particles are spewing all over the place. So we, rather than to try to catch all the arrows and block further entry, we just wanted to put the replication to rest. And so the two targets that we chose, in contrast to entry inhibitors, were replication inhibitors that would be very focused on replication.
The other thing with fusion inhibitors is they have a low barrier to resistance, and you can get resistance mutations starting to mount after only a couple of days of dosing, and we didn't like that in our profile. So we aimed instead for replication inhibitors with very, very high barriers to resistance. N and L were chosen. Actually, the virus has a fairly small genome, so one is the nucleoprotein. The other, the L protein, is the polymerase, so it's a viral polymerase, which is a very well-known target, you know, going after viral polymerases. The N protein was born first, and so it's moved ahead and is more advanced. But they're both. They're, you know, we've generated really strong virology for both of them preclinically.
Zelicapavir, and we'll talk about some of the clinical studies, but we've generated good virology results in humans with Zelicapavir, and we're in the process right now of wrapping up a human challenge study on our L protein inhibitor EDP-323, and should be able to report results out later this month. So, excited to get that data, hopefully confirming you know what we've been able to generate preclinically. How to handicap the two mechanisms, N versus L, they're both really potent. I look at it at some of the other characteristics of the molecule. They both so far, if you look at phase I versus phase I, they're both safe, well-tolerated.
If you look at PK and phase I studies in healthy volunteers, they both generated very nice drug levels at the twenty-four-hour time point after once-daily dosing, so that's good for a viral. And now it's on to the next steps of potential differentiation. But you know, we'll see.
Okay, great. So I mean, maybe to start on EDP-938, walk us through a little bit of the history of clinical data that you have from the human challenge study, the adult RSV study. Maybe just to start to get a picture of the safety and sort of antiviral activity that you've seen so far.
Sure. So, again, it was in phase I. We knew we could generate very good drug levels, safely, and so that always bodes well for an antiviral. Next step is to take it into a challenge study, where you infect healthy volunteers. You wait around for a few days, and the viral loads start to creep up, and symptoms start to appear, and then you dose them. We dosed once daily for five days, and generated great data, and that data set was published in the New England Journal. The next step, which was, I don't want to call it a misstep, but, the next step that we took was going into standard risk patient population.
Otherwise, healthy adults, as it turns out, simply can't benefit from a therapeutic because they resolve too quickly on their own. In that study, even though we got to patients within 48 hours of symptom onset, which is about as fast as you could recruit somebody into a study. You know, they wake up one morning, and they've got some symptoms. They lounge around that day, not feeling well, call the doctor the next day, and then, you know, maybe by the end of the next day, if you're lucky, you can get them into a drug study. By that point, even at the time of the first drug administration, symptoms had already started to resolve. They had already peaked.
Viral loads had already peaked, were coming down in the placebo group, and it was very difficult to show a benefit on that. And so that's in contrast to some of the high-risk study populations that we have going on that we'll be reading out.
Great. So the first one you have reading out is RSV PEDs. It's a phase II study in pediatric patients. I guess, compare and contrast your adult study with the RSV PEDs. What's different about the population, the time course of symptoms? Why is this study more likely to succeed in terms of a reduction in symptoms?
Yeah
-versus, the adult study?
The adult study that we did, again, was in otherwise healthy adults, and you know, sort of a, quote, "standard risk population." The PEDs and the high-risk adult study, both of those are high-risk populations. And in, for example, in PEDs, PEDs haven't developed any sort of immunity yet. You know, many of these children are probably getting their very first RSV infection. I mean, we're dosing children down to as young as 28 days old in this study. And so they have no pre-existing immunity. In fact, children usually need, you know, a handful of RSV infections in childhood before they start to develop any sort of a durable or semi-durable immunity. So they're fragile from that perspective.
They can spike much higher viral loads than adults, and the viral loads can be more persistent as well, and when you get into the high-risk adult population, again, very different than the standard risk, we're looking at patients who are over 65, again, many are over 75. We're looking at adults that have COPD or asthma or congestive heart failure, and these put them at higher risk for a more severe disease. You also, with age, you know, have sort of an immune senescence going on, and so they suddenly become more vulnerable to the virus. So there are some vaccines out there now. GSK has one. Pfizer has one, to vaccinate, you know, the elderly population at higher risk.
But again, vaccination effectiveness is never 100%. Certainly, adoption of the vaccine isn't 100%, and a lot of people get infected. We saw that with COVID. In each of those high-risk patient populations, we expect the, you know, the viral kinetics of the disease, as well as the symptom kinetics of the disease, to be much more significant than otherwise healthy adults that start to resolve in less than 48 hours on their own.
Great. And in terms of when you kind of think about the sample size and powering there, what are your expectations in terms of what that can translate into in the final results? Are you looking at, like, a statistically significant difference in viral load reduction, symptoms? Do you need both? Do you need just some combination that's close?
Yeah.
What-
Yeah, so maybe I'll hand it over to Tara. I mean, these aren't powered studies per se on symptoms or viral loads, but we can talk about it. It's a 90-patient first in PEDs study, but let Tara talk about it-
Yeah
- endpoints.
So, as Jay mentioned, it is the first time that we're dosing pediatric patients all the way down to 28 days. And so the study was designed in two parts, where the first part primarily is making sure that the drug is safe in these young children. We have seen a consistent safe profile in dosing adults, but we needed to confirm that in children. And then the first part also did a little bit of dose ranging. We knew what the adult dose was based on the challenge study, but we needed to understand what the dose would be for different age ranges of children. So it's 28 days to six months in one cohort, and then six months up to about three years. So once a dose.
So we're looking at PK there, and then once the dose was selected in each of those age cohorts, we moved to part two of the study, which is looking primarily at virology. But we'll, as Jay say, we'll look at a number of endpoints there for efficacy in terms of virology and clinical symptoms. It is a 90-patient study, as Jay mentioned, so it's not necessarily powered on any of those endpoints, but we're really just looking at the totality of that data to see, you know, trends that would give us confidence that there's an antiviral effect there, and that, you know, the data directionally would give us confidence to move into a larger, more well-powered study, you know, in the future.
And then, RSVHR, which is our study in adults, the adult population that Jay mentioned, that's a little bit bigger of a study, so it's about 180 patients. And there, the primary endpoint is symptoms. We're looking at reduction of the time it takes to feel better, essentially, on drug as compared to placebo.
Got it.
We'll look at virology as well and a number of other endpoints, but,
Okay.
Um...
I guess when we see the RSVPEDs study, is there anything to take away from that in terms of a potential protocol change to RSVPEDs high risk? I don't know if, like, you're close on PEDs. Does that mean you expand in high risk in terms of sample size? Or are the patient populations and sort of time frames too different to have too much of a read?
I mean, I think the patient populations are, they're the same in that they're both high risk for RSV, but they're just very different in terms of how they're,
Mm-hmm
How they're at high risk. So I don't. You know, obviously, if we have positive results in RSV PEDs, I think that bodes well for RSVHR, but, you know, I don't envision us making any, certainly any changes to the ongoing study.
Okay.
Yeah.
And then on EDP-323, I think you have a challenge study that's expected even sooner, end of this quarter, right?
Mm.
I think the study's pretty similar to the one that you ran with Zelicapavir I guess, what do you expect here? Is it going to look just like what the Zelicapavir results were? Is there an outsized impact potential? Is there anything in this data set that would turn you back towards sort of a healthier adult patient population, or do you ultimately look at segmenting between high, different high-risk patient populations?
Yeah. So I don't think, regardless of what the data show in the challenge study on our polymerase inhibitor, the population, the standard risk population is the standard risk population. You know, they get better so quickly on their own. I just don't see that you could take another mechanism and probably end up with a different result based on, you know, how quickly the placebo curves were moving. In terms of how to compare the two mechanisms, the data sets, you know, as we know, cross-trial comparisons are always, you know, dangerous to do. That said, we're using the same CRO who did the EDP-938 ones. It's effectively the same study design, different mechanism. But. So, you know, there should be some degree of comparability, you know, to them.
I would say that Zelicapavir sets a very high bar. It probably has the best efficacy that's been seen in a challenge study, in a human challenge study. So, you know, that said, 323 is an incredibly potent polymerase inhibitor. It's a picomolar inhibitor of the enzyme, and it's got very good human exposures that we can deliver safely. So, you know, it should be a mechanism that's up to the task, a molecule that's up to that task. So we'll get the data set, as I said, later this month. We'll be able to compare, and then we'll figure out, obviously, next steps as to how we think about that. I mean, you can think about. People have asked us, you know, would you ever use them in combination?
For an acute viral infection like this, we're hopeful that one mechanism used for a reasonable period of time, like five days, should be sufficient, you know, sort of like COVID, sort of like flu. But we could envision too that there could be more difficult-to-treat patient populations, perhaps severely immunocompromised patients, where there could be an advantage of coming in with two mechanisms. You could also imagine that, you know, if you don't get to a patient fast enough, you know, could you still reel them in if you went after it with a combo mechanism to therefore, you know, effectively widen the treatment-
Mm-hmm
... window? That's another thought. Or maybe even segmenting a second mechanism into a different patient category entirely. So these are the kinds of things that we're considering. But first things first, we'll get the data again later this month and move from there.
Great. So you mentioned earlier that you're starting to work towards a pivot to also look at INI. You know-
Mm-hmm
... if you exclude sort of some of the work in FXR that you've done, you could say the KIT inhibitor that you're planning on selecting this year will be your first entry there. I guess, what is it about KIT that sort of attracted Enanta to focusing here, and how do you kind of see your ability to differentiate with your KIT inhibitor versus what's out there in development?
Yeah. So we're looking at a KIT inhibitor for the disease called CSU, which is chronic spontaneous urticaria. So this is a severe inflammatory skin disease which patients have for multiple years. It's, you know, symptomatic in terms of wheals that develop on the skin. They're very itchy, and also associated with angioedema or deep tissue swelling. So it's, you know, affects about 0.5%-1% of the population. And so there's a high unmet need here. The treatment, the current standard of care is antihistamines that can go up to about four times the standard dose. But, you know, unfortunately, only about half patients have a response to this. There's one approved biologic, but most patients don't choose to go on that. The efficacy is not ideal.
So I think, you know, there's a, there's an unmet need there for, something that's safe, efficacious, and potentially oral molecule. So we like, the mechanism of KIT inhibition because CSU, is a mast cell-driven disease, and KIT is essentially a signaling, pathway that allows the cell survival of mast cells. So by blocking KIT, drives the cell towards apoptosis, so you're essentially reducing the quantity of mast cells that are available to induce this pathology. The other nice thing about KIT inhibition is that there is clinical validation of the target, with phase II data from an antibody.
Mm-hmm.
That's from a company called Celldex, where they've shown what we would consider best-in-disease efficacy in CSU in a phase II study. They've also had proof of concept in CIndU, or chronic inducible urticaria. They're also now looking at other skin diseases like EoE or PN. I think the other thing about this mechanism, because you are targeting mast cells directly, is that there are many other diseases one might think about. You know, asthma, atopic dermatitis are all ones that are being thought about. So, you know, we're looking at this mechanism from an oral perspective, so trying to develop an oral inhibitor. As you mentioned, there's a couple of other ones that are also in development, early stage. So both.
There are two of them that have just recently entered the clinic, so a little bit early in terms of understanding what the clinical data will look like and what differentiation there would be, but, you know, we're looking to. Our goal is really to develop a, you know, best-in-class, potentially best-in-class molecule, targeting good safety if we can replicate what the antibodies do.
Great. And then, I guess as we start moving into clinical development and look at initial first-in-human studies, what are sort of the major points to look at beyond safety, which obviously-
Mm-hmm
... is the goal of an initial phase I study? What are sort of the biomarker endpoints that are potentially translatable to disease control?
Yeah, and I think that's one of the nice things about this inhibition mechanism against KIT, is that you can look even in phase I healthy volunteer studies at serum tryptase, which has been a biomarker that has a lot of data generated now that it correlates to downstream clinical endpoints. So this is something that we certainly can look at in our phase I study, and really helps to de-risk the program early on.
Great. And then, just maybe to wrap up, touching on HCV, which was how we started, talk a little bit about.
Mm
The current royalty runway that you get from AbbVie, how that kind of offsets R&D, and what your expectations, given your cash position, are. How far can that get you in terms of development?
Yeah, so, our current guidance is that we've cashed through to the third quarter of 2027. The royalty revenue that we received, we monetized just over half of that last year.
Mm-hmm
T o a Canadian pension fund called OMERS, but we still receive royalty revenue on the other not quite half. So, Mavyret sales have, you know, post- I don't want to say post-pandemic, wherever we are right now-
Mm-hmm
H ep C sales for both Gilead and AbbVie took a big hit in the pandemic, and they haven't really fully recovered, but they have stabilized.
Mm-hmm.
I think you know it should be just a nice little steady stream of revenue to help offset spend. Once we reach the cap with OMERS, then 100% of the royalties revert back to us. Anyway, it's a good balance overall, good balance sheet overall.
Great. And then maybe just to refresh in the last couple of minutes here, the cadence of catalysts that we're going to see both for RSV as well as the KIT inhibitor.
Yep. So RSV, again, later this month, we'll get the challenge study on our second mechanism, the polymerase inhibitor EDP-323. Next quarter, we'll have the PEDs data set coming in, which is great. We announced on our last earnings that we had completed recruitment of that in the Southern Hemisphere. We had a really good season in the Northern Hemisphere last year, topped it off in the Southern Hemisphere, and again, data in Q4. As Tara mentioned, the high-risk adult study is about twice the size of the PED study, so it has about 180 patients in it. We made good progress in that one as well last season, continued to recruit it in the Southern Hemisphere, but we expect to, in a few weeks, to be bringing that study effect.
We're not bringing the study up. The virus should be coming up to our sites in the Northern Hemisphere, which are scattered throughout Europe, and North America, and parts of Asia. So we're hoping that we can wrap that one up in this upcoming Northern Hemisphere season. We have lots of activity going on in immunology internally, not only for KIT. We have you know several molecules that we're pitting against each other to you know pick our finalists from. But also in other programs, we're working on a few other things internally, and we expect to be announcing a second immunology program later this year.
Great. I guess in the last minute, anything I didn't ask that is a huge omission.
Um-
You can bring up now?
I don't think so.
No? Okay. Well, thank you very much. Jay, always a pleasure.
Yeah.
Tara, thanks for coming.
Thank you.
Thank you.
It's great.