Thank you very much for joining us for this afternoon session. My name is Mohit Bansal. I am one of the biotech and pharma analysts here at Wells Fargo, and I'm very happy to have Enanta Pharmaceuticals management team here. We have Jay Luly with us. He's the CEO, CEO of the company, and Dr. Tara Kieffer, she's the SVP of New Product Strategy and Development. Thank you, Jay and Tara, for being here.
Great! Thanks for having us.
So maybe we can start with a brief overview of the company and what is on top of mind for you and all the investors you have met with.
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, Enanta, for those of you who are less familiar with the story, we're a virology company. We've been doing virology for a couple of decades now. Known in the early days of our history for helping to develop two cures for hepatitis C. They were both partnered with AbbVie, and AbbVie commercializes Mavyret, which is the eight-week cure for hepatitis C. We're very proud to have been part of that. We also do some work in hepatitis B.
But I would say that, where we branched out beyond the liver diseases was in the respiratory virus area, so we did this long before the pandemic. We charted out respiratory viruses as being a major unmet need. RSV is a word that, or an acronym that everybody, is aware of, especially more recently. And, you know, RSV has been out there for, you know, over 60 years as a well-characterized virus, but there hadn't been any vaccines, and there hadn't been any therapies. Now, we have some vaccines starting to show up, but there still aren't any really, effective antiviral therapies on the market today. So, that became a big focus for us in respiratory syncytial virus.
We also have a program, so we can-- we'll talk, I'm sure, a lot about RSV, so we have multiple, clinical stage, assets there. We're working on human metapneumovirus also, which is a very closely related virus to RSV. Not only structurally is it similar to RSV, but it's also has a very similar clinical presentation, it affects the same patient populations and so forth. So it's sort of the second leading cause of the things that RSV causes. And even though it was only first characterized a little over 20 years ago, it's already a global endemic, virus. So we were highly focused on those two areas when the pandemic broke out.
So given the trajectory of us getting into human respiratory viruses with direct-acting antivirals, it became clear to us almost immediately that we should be working on this pandemic virus, and so we did. We, again, the two, the two drugs that we brought forward in hepatitis C were both protease inhibitors, and we saw that there was a very nice protease target inside SARS-CoV-2 that became the basis for our lead program. And we developed a very potent molecule that we've now demonstrated efficacy in RSV-infected people, called EDP-235. So, that's a molecule that has finished phase 2, and we're looking to ultimately partner that for phase 3 and commercialization.
Great. I mean, that's so... So I have a lot of questions. So we now prepared a lot of questions for RSV. So, so maybe let's just start with RSV. I mean, it has been a big unmet need, and, you know, there were some, there were a lot of failures. I mean, I followed Regeneron for a long time, and they tried something. All of a sudden, now we have a new wave of vaccines and an antibody coming to the market. So, with this new... Like, obviously, they have new products, but, when you see the landscape now-
Mm-hmm.
So how do you see these drugs catering to that market, and how you could differentiate or provide an edge with an antiviral? Because you have an antiviral, these are all treatment slash, I mean, preventive treatment.
Yeah, they're mostly in the realm of prophylaxis-
Right, yeah
- one way or the other.
Yeah.
Either through, vaccination or maternal vaccination-
Right
... or for, you know, a monoclonal antibody or, again, sort of prophylaxis. But we're going after the treatment market, which is, you know, blue sky-
Right
- effectively right now. It's, it's very wide open, and we have the most advanced, broadest portfolio of programs going after that. Tara, maybe you, you can come in. I don't know how you want to talk about the vaccine thing, 'cause the, the vaccines are a relatively new entry to the field, even though people have been trying... People have been working on vaccines, since the 1950s.
Right.
And so it's been a very, very long and, you know, somewhat tortured path to get to where we are today. But now you're seeing GSK and Pfizer with some vaccine entrants. Largely going after the adult-
Right.
high-risk patient population. Pfizer also has the ability, they're going after maternal vaccination. But, Tara, I don't know if you want to make some comments about vaccines in general.
Yeah, I think, you know, we're excited to see the vaccine come on the market as a prophylaxis for RSV. You know, it's raising a lot of awareness and education around RSV, but there's still an unmet need for treatments. There are no treatments, as Jay mentioned, direct-acting antiviral treatments, and so there's still a significant unmet medical need there. You know, in terms of population, Jay mentioned of patients that are at high, that are at high risk for severe RSV, you'd think about high-risk adults, like the elderly or people that have other comorbidities. The vaccines there have been approved, and will be used with shared decision-making.
And so what that means is that, instead of sort of a default vaccine, a physician and the patient would sit down and discuss whether the vaccine was, you know, right for the patient. And so we're not optimistic that the uptake of these vaccines is going to be optimal.
Mm-hmm.
If you look at other adult vaccines that aren't shared decision-making, those, you know, in an elderly population, for the flu vaccine, as an example, maybe around 50%. Shingrix is another comparator that's around 35%. And both Pfizer and GSK, who have these vaccines for RSV, have guided towards lower expectations around the initial uptake of the vaccine. GSK guided towards something similar to what Shingrix was in its first year, which is about 7%. So, unfortunately, I'm not sure the uptake is going to be as one would hope.
Right.
And so there's still a lot of room for treatment in the patients. And even with the adoption, there, there'll be breakthrough infection that occurs, as there is with any vaccine. And then if you look at those targeting the children, there's the maternal vaccine that Jay mentioned from Pfizer, and so that is providing passive immunity to, to the infant by vaccinating the mother in the very last weeks of pregnancy. And so there's, you know, some complications there with timing it correctly, but you do need it late as possible because the protection's only about three months or so, and generally doesn't get you a full RSV season-
Right
... which is more on the order of five or six months. You know, I think there's some data around the vaccine, around preterm premature.
Delivery.
Delivery, where they showed there was an imbalance there, and so I think there's some safety concerns around the vaccine as well. So unclear what the uptake will be for that population. Again, even so, this is passive immunity, so it basically just allows for older children to have their first RSV infection, and so will need to be treatment there. And then, as you mentioned, there's also a monoclonal antibody for infants that was just recently approved. Again, we'll see what the uptake is for that. The other thing I'd mention about monoclonal antibodies, because you mentioned Regeneron, is they tend to have a very low barrier to resistance.
What happened with Regeneron, you know, in their phase three trial, there was a variant of RSV that became the predominant circulating strain that season, and rendered their antibody essentially ineffective for that RSV strain. So, you know, we'll see what happens as these antibodies get used, but that's one potential challenge for the antibody.
Whether in every one of these cases of prophylaxis, it doesn't confer any immunity to the child.
Okay
... ultimately, and they have to build that by getting repeated RSV infections-
Right
throughout childhood until they can sort of stabilize. And so those, the ones kind of kicking the can down the road, pushing them into, in some cases, a little older-
Right
-age. But we saw a lot of kids that when the pandemic was in full force, RSV was not that common, nor was flu. It sort of-
Because no one was meeting each other, right?
Yeah, that was meaning-
Yeah
... that kids were not in school, and people were wearing masks and things. But, so these kids became older and yet had not been exposed to the virus and gotten infected. And once that started to happen, you saw older children getting some very severe RSV infections. So-
No, last year, well, last year-
Yeah.
December was probably the worst period of that.
Yeah, yeah.
People got three, all three of them together sometimes-
Right
... right? So yeah.
Yeah. So anyway, prophylaxis variously will be a tool out there, but we still expect a lot of people to be infected in spite of that.
Okay. That's, that's great. And then that's a nice segue into antiviral. So you have an antiviral here. So you'd do, like, I mean, fair to say you don't see any enrollment challenges, because in the, like, even near term, you're probably not going to see a lot of uptake of these vaccines.
Right.
So you don't see any challenges to the enrollment at this point?
No, it shouldn't have an impact.
That's fair. So let's just talk about... I mean, you have an N protein antiviral, and then you have an L protein as well. So for those, like for people who are new to the story, can you help us understand this, these concepts a little bit? And I think Pfizer acquired this company called ReViral.
Mm-hmm.
So they have, what is it? F protein. So can you just help us understand these concepts?
Sure. So, you know, RSV doesn't have a super large genome, so there's only so many proteins that make sense to target. But, you know, we at Enanta go straight after the replication machinery and the virus because, you know, time and time and time again in virology, you know, coming up with a good direct- acting antiviral, something that shuts down replication, is a proven pathway to go forward. So there's a lot of tried and true mechanisms in that area. So I'll contrast replication inhibitors like we work on with entry inhibitors, which some others have worked on. So, in the case of RSV, entry inhibitors focus on the F protein, the fusion protein, and they block, they basically block viral entry.
They try to block the virus from entering cells, and in a very, very loose correlate, it's sort of like the spike protein on COVID. You can target that with vaccines. It's an easy thing to try to target, but it's a site that can mutate. Certainly, we saw that a lot in COVID because it rendered many of the antibodies inactive and also, you know, changed the efficacy of vaccines over time. So rather than blocking entry like the F protein inhibitors try to target, we go after the replication machinery, as I mentioned. So there are a couple different targets there. One is the so-called nucleoprotein.
It's a critical protein that the virus uses to help replicate, and there's a polymerase in there as well, called the L protein, and it's basically a polymerase enzyme. And so we've targeted both of those. Our most advanced program is going after the N protein. And the more recent molecule that entered the clinic, EDP-323, targets the polymerase. And we like direct- acting antiviral mechanisms because at the time a patient presents with an infection, if you think about it, they're always... By definition, they're going to be symptomatic, and they're probably several days into their infection. Viral replication is expanding like crazy, so you're having, you know, a very, very rapid viral expansion.
At that point, it's probably a little bit late for an entry inhibitor to be maximally effective. Ideally, an entry inhibitor would be best used very, very, very early in the infection, or maybe even prophylactically early, before the virus has even come in.
Right.
You can block the entry. If you can block the entry, you can stop things from getting set into motion and the brush fire starting. But once that fire is burning hot, we feel that it's best to just go in there and shut down the replication rather than to try to catch all the viral particles from getting into other cells, because it stoichiometrically becomes a very challenging problem at that point. So, and there have been a number of F protein inhibitors that have been out there that people have looked at. You know, Biota had one a long time ago that didn't work so well. Gilead had probably one of the best pre-F protein inhibitors, and it didn't... It wasn't successful in their phase two studies, and so they stopped that.
J&J had one. They stopped that. But Pfizer does have one that they're progressing, so that is the advanced one.
The other distinction I'll just add is, you know, resistance-
Yeah
is always something we have to think about with direct- acting antivirals, something that can develop with treatment. And we do know that the barrier to resistance with replication inhibitors is quite high, and in contrast, for entry inhibitors, for fusion inhibitors, it's low. The fusion inhibitor that Jay mentioned from Gilead, actually, in their clinical trials, saw resistance developing, you know, within a few days of treatment. So that can be a challenge, too.
Got it. So can you talk a little bit about where your... I think N protein is probably the most advanced one, so where is it in the clinics, and what could we learn about it in the next?
Yeah. The N protein inhibitor is called EDP-938. It's currently in phase 2 in multiple high-risk patient populations. That is sort of the charted path to, you know, to gain approval. It's the one that's in the sort of the FDA guidances, the, you know, high unmet needs are in basically in three buckets. There's the pediatric population, which is probably the largest high-risk patient population, you know, getting RSV infections, so peds. There's the immuno compromised, people who are on, you know, for one reason or another, are immuno compromised. They're quite vulnerable and can have very poor outcomes in RSV infections. And then there's an adult population that's just a high-risk adult patient population. In that category, often the elderly.
So it's typically the very young, you know, patients or the very elderly patients, or immunocompromised, or people who might have some other comorbidities, whether it's congestive heart failure, COPD, asthma, these can be triggers to put somebody into a high-risk bucket. So, in these patients, the infections are typically a little bit more severe. They can be longer in duration, and so, it's a good backdrop to be, you know, to be testing a drug. So right now, we have trials going in all three of those patient populations, the phase 2s. I would say, again, sort of rank ordering them, peds is probably the largest footprint from a perspective of patients out there.
Next would be, I would say, high-risk adults, and then, you know, a smaller patient population, but one, you know, still ultimately needing care is the immunosuppressed patient population. So those are the ones that are going there with our lead molecule. We're gearing up for the RSV season.
Right.
It's coming. It's already starting to come. You know, there's some reports in the, in the Southeast, United States that it's starting to show signs of coming back, just like you're starting to hear headlines about COVID. You know, wastewater levels of the virus are going up, and so, you know, 'tis the season. Kids are back in school. Everything's gonna be heading toward winter and, you know, I think we're well poised to capitalize on that. We've been setting up sites in all the major world territories. You know, we're not only in the Northern Hemisphere, but we are in the Southern Hemisphere, in countries like Brazil and Argentina, New Zealand, Australia, South Africa. In the Northern Hemisphere, where we have dozens and dozens of sites.
I think, we've got over, you know, 75 ped sites and over 100 sites working on, you know, adults, so. And they're geographically dispersed over 15, 15 different countries. So, big catcher's mitt on waiting for the virus to come, and, and hopefully we'll be able to, you know, to wrap up enrollment on, on one or more of those studies in this next Northern Hemisphere season.
Got it, and this is helpful. Can you help us understand how the trial designs look like in terms of, you know, what do you have to prove, the endpoints and what would be good data when you see the data?
Sure. So they're all slightly different. The HR, the high-risk population study, that's about 200 patients, and we're looking there at symptoms as the primary endpoint.
Right.
So really looking to see if you can reduce the duration of symptoms that these patients have. So the treatment is 5 days, and then we'll monitor them for both virology and symptoms, as well as other, you know, clinical endpoints from a secondary endpoint perspective. In the immunocompromised patient population, as Jay mentioned, those patients tend to be much sicker and many times will need longer treatment duration. So in that study, we're looking at a 21-day dosing period, and the endpoint there, primary endpoint there, is looking to prevent the progression of upper respiratory tract infections or lower respiratory tract infections. And then the last study is the pediatric study, and this is a little different because it's the first in ped study, and so you first have to figure out what your dose is there.
Yeah.
The first part of it is dose ranging-
Right
... in distinct age cohorts, 'cause you need to be, you know, quite careful as you dose children and go down from a higher age to a lower age. So we're dosing 28-day babies all the way up to 3 years of age. So once a dose is selected in each of those age cohorts, then that moves into a second part of the study, where we'll be looking at virology as the primary outcome there. Certainly, safety and PK in that first part, and then we'll look at other clinical endpoints like symptoms as well. But primarily there, we're looking to select a dose and glean a little bit of virology information.
Got it. And then, also, can you help us understand how the results of human challenge studies translate into efficacy in the... like, how translatable are those results in these bigger trials?
Yeah. So I mean, you know, the design of the challenge study is basically taking a healthy patient, and you infect them with-
Right
... the virus, and then you monitor them as the viral loads come up, and once infected, you begin treating them, and you measure the viral load and the symptoms, you know, over time. So it's slightly different, or it is different than the community-acquired setting, where patients will typically be coming in later, once they're symptomatic, in infection. And so, you know, the challenge study is sort of a setting where you can demonstrate virology and an effect on symptoms and show some antiviral activity with these, with these treatments. But certainly, you know, need to go on then and test the compounds in real world-
Verify it in the real world.
community-acquired setting.
We have obviously with EDP-938, before we went into all those different phase 2s, we had demonstrated extremely good challenge human challenge study data clinically. And our second RSV molecule, EDP-323, that's the L inhibitor. We expect to initiate that challenge study early next quarter. And again, it's as Tara mentioned, it's very good for demonstrating an antiviral effect, an effect on symptoms, and also for helping to pick a dose, right? So you can do a little bit of dose ranging, looking at different dosing possibilities there, and get all that information. It's a really efficient way to go do that because it's not dependent on seasonality, it's not dependent on anything other than bringing in you know healthy human volunteers and infecting them with the virus.
Right.
So you're not, you're not waiting for the season, you're bringing the season to the patients. We expect to conduct that study and have data in Q2 next year.
Got it. I remember back during the Hep C days-
Mm.
There used to be like, after you give a dose, like how within 28 days, how much... how many logs of viral reduction.
Mm.
-you see? Is there a metric like that here, which actually tells you that this is a good, great, drug for-
Well-
-antiviral? Yeah.
The difference with Hep C and these respiratory viruses is, you know, in Hep C, you're talking about a chronic-
Right
-virus, where the viral loads are chronically high.
Right.
They're not, they're not coming down on their own.
Right. Okay, so you cannot compare them.
And so they're up there...
Yeah
... you know, very high, you know, 7 logs or something.
Yeah, right.
And then you dose with some of those Hep C drugs, you could dose a single dose and see a five-log drop-
Right
-after a single dose.
Right.
But because you're measuring it against something that's high and not coming down by itself-
Right
... With the acute respiratory infections, they do resolve themselves, even with COVID. You know, you will get better over time without an antiviral. So the viral loads are starting to come down by themselves, and you're trying to demonstrate a drug effect on top of that, you know, bending the curve-
Mm-hmm
... so that you're seeing a more rapid drop. So that's, that's the type of thing you see there.
Yeah, that completely makes sense. So between N protein and L protein, would you have to pick a horse to go with? Or do you think... I'm sure you like both your kids, but yeah, like in terms of, can you combine them, or is there a reason to combine? Because you said that viral resistance are very high here, so do you really need to combine them? So how-
Yeah. So, you know, how do you pick among your children?
Right, exactly
... sort of thing? Well, it's, you know, you have an N inhibitor and an L inhibitor. You know, neither, you know... Whereas these mechanisms have been studied, you know, variously, you know, in the past, particularly L protein inhibitors, none of them have ever made it to market in RSV. You know, nobody's had a good molecule to take all the way. And, so we don't know the exact answer about, you know, could one have slightly better efficacy than the other? I mean, I suppose the answer, you know, has to be yes-
Right
in some fashion.
Yeah.
But they could both be very good, right? Preclinically, they're both very good. Clinically, so far, they're both very good. We'll get more information in the challenge study with our L inhibitor, because then we'll have a challenge study on each of them looking at antiviral effects, and it's being run by the same organization. I mean, no two studies... It's not the same study, but at least we'll be able to get information there. But I think the way we're thinking about RSV is, there are no approved drugs. When we got into this space or when we get into any space, we're almost always committed to having multiple mechanisms going after whatever it is we're trying to fix.
And, you asked the question, "Do we, you know, could you do combinations?" You know, after Hep C and after having worked in NASH for a while, and HBV, I was hoping someday I would have something that I didn't have to do combination therapy with. And it turns out I, I'm not convinced that you have to do combination therapy in RSV if you've got a good single agent-
Right
If it's an acute therapy. It's like COVID, you know?
Right.
You can use a drug like Paxlovid or the protease inhibitors that we or others have, and a single agent seems to be fine. That's different than the question you're asking, you know, could two agents be better?
Right.
The field simply doesn't know that. I mean, intuitively, it would make sense. You don't probably need to do it for the reason you might have been suggesting with regards to resistance.
Right.
Because in chronic therapy, it makes a lot of sense because you've got to treat for a long time, and you want to make sure you're coming at the virus multiple different ways so that resistance doesn't emerge. With acute infections, there's... That's less likely to happen, especially if you have a single agent with a high barrier. And so, we'll have more information coming out of the conference on, you know, what 938 looks like with regards to resistance in a, in a challenge, in the challenge study. That'll be at IDWeek. But, the data are very good. We know it's got a high barrier. You asked, could they be combined? We've done the preclinical combinations, and the preclinical combination data look good. It looks additive to synergistic, and it's...
You certainly don't want to see antagonism, and we didn't see that. But why would you do it then, if not for resistance? The possibilities are you might have a really difficult to treat patient population. And there where, you know, no matter what the efficacy is with one drug, going at it with a couple of mechanisms, hitting it harder, faster might push those numbers up. Or said another way, if somebody were further along in their infection, you know, because nobody's completely defined the optimal treatment window. Is it 3 days? Is it 5 days? But the later you are in that infection, we know it's gonna be harder and harder to cure somebody or have a drug effect.
But maybe two drugs could do that, and that would open up the treatment window horizon and therefore the addressable patient population. So these are the kinds of things that are on our minds, but no one knows the answers yet.
Very helpful. Thank you. We spent most of the time on RSV, as I promised, but talking about COVID a little bit.
Mm.
I mean, you have EDP-235.
Right.
You're trying to differentiate from Paxlovid. So talk a little bit about that program, and then where is it now, and what are the plans to move forward then, so?
Yeah. So as I mentioned, I mean, we finished a phase 2 study where we saw something that we weren't sure we would see in such a small study, which was improvement on symptoms.
Mm-hmm.
And, that's, that's been reported, and we've got a deck on our website showing all of that data. We saw an effect on viral load. It's hard to see a robust effect with these 3CL protease inhibitors on viral load. And it's getting increasingly difficult because as people become more and more experienced of having been infected before, it's harder to measure viral load reductions in the nose. It's a long story, but let that be the summary for the moment. But with regards to the opportunity, you know, there's one major drug out there right now, which is Pfizer Paxlovid.
You know, it came at a good time in the pandemic, where there was not a lot out there, and Pfizer brought it forward fairly quickly, at a time when you could do clinical trials very easily-
Right
... in phase 3. I mean, they could... Hospitalization and death, it went from phase 1 to phase 3.
Right.
Hospitalization and death was an easy endpoint to do back then, and it was approved. The problem is, though, it's given twice a day. It would be given three times a day, but for the fact that they boost it with ritonavir-
Right
... which is an HIV drug. So if you boost the COVID drug with ritonavir, you can get the dosing frequency down to twice a day, but then you have the boosting agent-
Right
to worry about with drug-drug interactions across a wide swath of the pharmacopoeia. Has a bad taste and other kinds of issues. So, 235 is once daily dosing. It's very potent. It's more potent. It's got a very good tissue uptake, which we think could tap the drug into different reservoirs where the virus might be hiding. And it doesn't need ritonavir boosting, so we get that once daily dosing. In our case, our dose is 400 milligrams without the need for ritonavir. So, based on the preclinical profile, which is very good, phase 1, which was very good, phase 2 study, very strong. You know, we had always set out to find a commercialization partner who would handle-
Right
late stage and commercialization to get into that marketplace, which is bigger than we are. So, that's still our plan, is to focus on getting that done.
Great. Thank you very much, Jay, and Tara, for this.
Yeah.
Really appreciate it. Thank you very much for providing us the time.
Yeah.
Thank you.
Thank you very much. Have a great day.