All right, good afternoon, everyone. My name is Akash Tewari . I'm a pharma and biotech analyst here at Jefferies. We have Enanta and Jay. Always great to talk to you, Jay. Enanta will have some brief opening slides that will give a bit of a background on what's going on in the company, and then we'll get started with Q&A. Thank you very much. Go ahead, Jay.
Thank you very much. Here's the clicker. Before I begin, I'll remind you that I'll be making some forward-looking statements. For a summary of the risk associated with these statements, please see our filings on fcc.gov and our website. For those of you less familiar with Enanta, we're historically a virology infectious disease company, and more recently have moved into the space of immunology. I'll touch a little bit on respiratory virology and immunology in my opening comments, and then we'll turn it into a fireside chat. In terms of virology, I want to just focus on catalysts that are coming up in our program. Recall zelicapavir is an N-protein inhibitor. We reported pediatric data last December. This is one high-risk patient population that we're studying. The other is a high-risk adult, which I'll talk about in just a second.
To remind you of the PEDS data that we did, the objectives were to look at safety and PK as a primary objective in part one, and then antiviral activity. We set out and hit those objectives that were defined. As an exploratory endpoint, we began to look and to begin the validation process on a new tool for observer-reported outcome information called RESOLVE-P, and got encouraging early data in that as well. The data set that is coming is on the high-risk adult study. We expect to report that in late Q3. We recently completed enrollment of that study. It is about 180 patients who are at high risk, either because of their age or because of some other comorbidity. We dose for five days for patients who come into the trial within 72 hours of symptom onset.
We're trying to bring people in fairly early for treatment, and we treat them for five days. The primary objective is a symptomatic endpoint, looking at lower respiratory tract disease using a tool that's been used before, a patient-reported outcome tool called the RiiQ symptom scale. We'll be looking at that as well as a number of secondary objectives as well. How do you benchmark a study like this when there is no approved treatment for RSV? We hope zeli and our other program will bring some of the first therapies for RSV infection forward. We really have to kind of look at how is clinically meaningful defined in symptomatic endpoints and registration studies for other respiratory drugs. I have on the left of this slide Tamiflu. Sort of in the middle right slide is Xofluza, otherwise known as Baloxavir.
On the right-hand slide, ensitrelvir, which is a SARS-CoV-2 protease inhibitor of Shionogi's. Each of these drugs was proved on about a day symptom improvement in terms of reduction of symptom duration. You can also see that these were in registration studies. The N is at the bottom, about 500 to 700 patients in the phase IIIs that were run. These are at least some guidelines that we can use to be thinking about expectations for what is clinically meaningful in an RSV study. RSV HR is about 180 patients. We're aiming to show clinically meaningful reduction duration about a day or more. We'll also be looking at a lot of other aspects of the study, including virology and other symptoms, bronchodilator use, and so forth, so that we'll get a really complete picture of all of this.
Once we've determined the effect size in this phase II proof of concept study, of course, we would move into a phase III study that would be a bit larger and would be powered to show statistical significance on that about a day duration. That is the plan. We've also indicated that our preference is to move this forward in the context of a partnership. We have another RSV drug behind this one called 323, which has probably a best-in-disease profile if you look at stage for stage of data, even comparing it to zelicapavir versus any other RSV therapeutic that's ever gone into clinical trials. We're excited about both of these molecules, but this is the next catalyst for us in this program. Shift gears quickly to immunology, set the stage there. We have two announced programs in immunology. One is in wild-type KIT.
The other is in STAT6 inhibition. I'll touch on those briefly here. For KIT, basically this year is focused on IND-enabling work. We announced our candidate, our development candidate, 1421 late last year. It's an animal molecule. It's very potent in terms of in vivo activity, highly selective for KIT versus other family kinases and broader-based on kinases in general. Doing what Enanta does well, we've optimized ADME properties. It's a very nice-looking molecule. Right now, again, we're scaling up and pushing or knocking down the IND-enabling activities this year. Our aim is to get it IND as early next year as possible. STAT6 is a very interesting target. We are focused on oral small molecules here at Enanta. I think everyone's familiar with the drug Dupixent, which works through the IL-4/ IL-13 signaling pathway.
STAT6 is the key transducer in the downstream effects of blockade. Our goal is to disrupt at that stage and then basically try to recapitulate the broad clinical benefit that Dupixent has served with, but with an oral agent. To that end, we have been working very hard in this program, making some very good progress. We have very good potency and selectivity. Again, we focus on ADME to get these molecules very well-behaved into high-quality drug candidates. Ultimately, highly selective for STAT6, that's important. There are a lot of other STATs that you do not want to disrupt. We have put out some of that data in our other corporate deck. You can find more detailed slides in that. It is highly selective. We have also demonstrated really good target engagement in vivo.
In fact, we see rapid and complete inhibition of phosphorylated STAT6 after a single dose in a mouse model. We've shown that data. Also, a little bit newer now, we've now demonstrated a good anti-inflammatory profile in an ovalbumin asthma challenge model. We are continuing to do a little bit more apple polishing, although we've got some great prototypes. Our goal, we're still very much on track to select a development candidate in the second half of this year. Things that we're demonstrating already, good intrinsic permeability. We're looking at metabolic stability, clearance, target distribution, and again, looking for once-daily dosing, low DDIs, et cetera. This is this ovalbumin asthma model. This is new data that we're showing, which basically shows that you sensitize the animals with ovalbumin, come in with the oral inhibitor, and then challenge.
You can see, in fact, a very good reduction in lung phospho-STAT6 activation. If you look at the slide here, it is showing the concentrations or the percent activation at Cmin concentrations of the drug. That is a very conservative way of looking at it. Obviously, at Cmax and higher levels than Cmin, you are going to see a much more robust inhibition than that. We were looking at Cmin just to characterize that. We have got many other molecules going through this process right now as we zero in for our finalist candidate. This is just a little bit more data from it, showing that you can see lots of other effects in terms of looking at cytokines and chemokines in the bronchoalveolar lavage fluid, as well as inhibition of eosinophil infiltration into the lungs.
All in all, very robust effects shown with some of our early prototypes here. I think I'll just put it there. Here are the key catalysts for the year, which are pretty much what I've already gone through. With that, turn it back to Akash to open things up.
All right. Love it. Thank you. It's interesting. You've got RSV, STAT6, KIT. These are hot targets right now. I think it's going to be a timely conversation. Obviously, it's a tough biotech environment. You guys have royalties from Mavyret, but I think there's an element of being pragmatic in this space as well. I want to be clear. You guys are interested in RSV. I just think with the viral kinetics, running any study is just incredibly difficult because of how hard it is to identify and get them into that kind of sweet spot. You're going to have data, let's say that you show a one-day benefit. That probably doesn't sound like a statistically significant benefit for what the phase two is powered at.
Would you then go into phase III with a one-day benefit, or would you say, you know what, now I'm going to look at my backup L inhibitor and say it's actually the combo that I'm more excited about? How do you balance those two decisions?
Yeah. Ultimately, it is a good question. Ultimately, again, our aim in this, as we've started our migration into immunology, is to gather these key data sets. We have the first NPED study in our hands, incredibly safe NPEDs. We showed a great viral load drop. We're about to come on data here, which, if positive, is phase III enabling. I think we would have that conversation in the context of a partnership because, again, our goal is ultimately to find our commercial partner after these data sets, which will allow them to progress. We do have 323, and it's a great, great molecule. One could imagine taking zelicapavir forward first, getting it approved, moving into the RSV treatment landscape, and then bringing up 323 as a sort of next-gen molecule. They can also be used in combination. We've looked at that at least preclinically.
They're well-behaved. You can think of patient populations that are highly immune compromised, for example, that might benefit from two mechanisms rather than one. You can think about prophylaxis with one. There are lots of different ways that you could play a commercial portfolio here. Again, our objective was to bring forward two replication inhibitors, not entry inhibitors, but bread-and-butter replication inhibitors, different mechanisms, and then have a portfolio that we can team up and get through the finish line with the first-ever treatment for RSV.
Kind of a pointed question here, but I think it's important to understand because, again, this is a large-cap development program for RSV. Do you feel like there's alignment with strategic discussions? Because I'm sure you're talking about you have to partner this out. Is that day of symptom benefit a profile that you think a strategic partner, they've kind of communicated to you, "Hey, we'd be excited if you're able to deliver that as well?
Yeah. I won't talk about business discussions, but again, what I can say is that historically, when you look at respiratory drugs that have been approved based on symptoms, the improvement as clinical benefit has been about a day. Yeah, whether that's two different flu drugs, COVID. I think it's in line with what you would expect.
Helpful. The previous RSV studies, you would assume maybe there were more elderly patients. In reality, you ended up getting a pretty healthy cohort in South America. Talk to me about how.
I'm sorry. I'm not tracking.
Your previous study, which is not statistically significant on viral load or symptom reduction, but that was run in a healthier population.
It was in a healthy adult population, a young healthy adult population.
Right. How confident are you guys this time that you have the right types of patients to show kind of a delta? Can you kind of compare and contrast the patients that were in that prior study versus the one you have here? I am sure you have some sense of the baseline as well.
Yeah. In terms of enrollment criteria, instead of the open enrollment to otherwise healthy adults that happen to contract community RSV, we got them in within 48 hours of symptom onset. You remember that back in the day.
Yeah, absolutely.
Because we were like, "We have to try to get these people as early as possible. They're otherwise healthy." What we found was that wasn't early enough. You have to get them impossibly early if they're in an immune-competent state. Even at the 48-hour time point, by the time we gave them the first dose, their viral loads had already peaked and were coming down. Their symptoms had already peaked and were coming down. It's just impossible to show a drug effect on that tail. In contrast, these are adults who are elderly. They're at least 65, but we capped the population that was between 65 and 75 because we didn't want just otherwise healthy adults who were north of 65.
Age discriminatory.
We skewed it to people who were over 75, and we skewed it to people with COPD and congestive heart failure and other risk factors.
What percentage is that of the total population of above 75 or with some of these meaningful comorbidities?
We capped people who were just sort of basic asthmatics who were 65 to 75 at 20%.
Wow. Okay.
80% of the study is in a higher risk category. This is exactly the patient population that the agencies indicated in their guidance that they should be sought for approval.
Tell me about the viral kinetics there because the other population I know you guys had trouble enrolling was patients post-stem cell transplant, like this very niche population where it would have been more of an orphan drug. That was one of the only indications. I think this was the old arrow compound where it was a similar benzo backbone from you guys, but that was one of the rare instances where you were seeing, at least in a subpopulation, a signal with an antiviral. It took about five to seven days to get to peak viral load, right? When you think about the viral kinetics and time to peak load with an immune-compromised elderly population versus that kind of niche in-hospital stem cell transplant population, are they more similar? Are they different? What has your work suggested?
The stem cell transplant recipients are very different. That study, RSV Tx, was our transplant study. I think we were trying to recruit that thing in the pandemic. We had bone marrow transplant recipients who were incredibly—I mean, it's an incredibly cautious group anyway. In the pandemic, these people are double-masked. They're not going out. Nobody's seeing anybody. It was a really, really hard time to recruit that study. I think we got around a dozen or so participants and decided we have to really concentrate our efforts and get these two studies that I'm talking about, the PEDs study and the high-risk adult. We knew that those would be the faster paths to market anyway. We just doubled down and concentrated on them.
In terms of viral kinetics, though, in somebody who's sort of devoid of an immune system, it's very different. We had a 21-day dosing period in there. Probably that's the exact place where you would be thinking about using both drugs if you had them at your disposal so that you didn't have time for the virus to make mischief in an immune-compromised host with mutations, et cetera, et cetera. It's hard to really kind of compare that population. All I can say is that in the adult high-risk setting, we tried to skew the risk factor in a very real-world way, but also in a way that tried to capture, concentrate those high-risk adults.
All right. Good.
Just to add to that, both of those populations, Jay is talking about the high-risk patient population in the current study and the immune-compromised, are very, very different in terms of viral kinetics and symptoms as the patient population in RSVP, which were otherwise young, healthy adults. The viral loads tend to be much higher in these higher-risk patients. They have.
Like seven to eight log?
Yeah. It depends on the exact assay that you use and when you catch them. They are definitely higher. More importantly, they are more prolonged. They do not come down as quickly.
Yeah. That seems like the angle because I have a hard time believing that an elderly person is, again, time to symptoms, I don't think is going to be particularly different. You're still probably going to be catching these patients within two to three days of them having symptoms. Then it's like, "Okay, this is really getting bad. We have to go to the hospital." My guess is you're still probably catching them as they are either approaching or at peak viral load. It seems like that's going to be hard to do. The angle here is that the clearance of those patients is going to be more prolonged. That's where you see the difference.
You have a wider window to try to.
Is that the way to think about it?
Yes. Absolutely.
That's really interesting. I've always asked you guys this question. Sometimes the issue with Enanta is like, "Do you have a study that's powered to hit that signal on?" That's what a lot of investors are going to ask. What is your level of confidence that you are--and let's put it this way--what is the primary endpoint? Is it viral load reduction? Is it symptom reduction? I just want to be clear. Number two, are you powered? If you show a one-day benefit, is that statistically significant? I just want to make sure.
Yeah. In a study of this size, a one-day is likely not. I mean, you'd have to see—you'd have to see what the placebo looked like at first. The placebo would have to be incredibly short. You can see in these phase III studies where they were powered to show a day, there were around 500 to 700 patients, whether it was flu, two different sponsors with flu, a different class with COVID. I think to see stat sig on a day, that's the kind of phase III range.
Reasonable for a phase III. And then also on the.
Down here, that's the last bullet point on this slide. And so you'll define the effect at 180. I mean, we could have done 500, 700 patients, but it would take us a few more seasons, right?
Right.
The key here is get the proof of concept, get the directional thing, see if you can find about a day. It may not be stat sig on 180 patients, but you look at it in the context of, did you see virology line up? Did you shorten the time to symptom improvement?
What about viral load reduction? What are you guys expecting there?
Yeah. I think viral load in these patient populations is being compared to placebo, which is also declining. In our PEDs study, we saw about a log, over a log at the end of treatment. That's something reasonable.
COVID drugs, again, people took me a while to get my head around because I was coming from the hep C world where you see five, seven log reductions. In these acute infections, as Tara mentioned, the placebos are coming down. Paxlovid and SARS-CoV-2 protease inhibitors, when they show an antiviral load or an antiviral drop, it's about 0.8 logs, maybe a log, something like that.
Yeah. I mean, just for this study, the point of it was twofold. We wanted to get confidence around the compound and moving forward in this program. We'll get that with the many endpoints that we're looking at and then also to see what a treatment effect size might be to enable powering a larger phase three.
Lastly, on RSV, and then we definitely want to hit on the other stuff. On the L inhibitor, you mentioned that you're seeing something that you haven't seen with previous compounds. Talk to me about what you're seeing in terms of speed of onset of viral load reduction.
In the strategy deck, we do not have that slide. Even in our current corporate deck, which we have on our website, you have to go back to the challenge study data set where we have all the slides in there. What you will see is it is incredibly fast at knocking down infectious virus. If you look at not just viral load reduction, which is a PCR-driven assay, you are looking at live and dead virus fragments and stuff. It looks very good there. When you look at cultured virus, within 12 hours after the first dose, I think all but two patients in the study had where the virus was gone. zeli was good. We have seen other challenge studies that were not bad, but nothing knocked it down like 323.
Imagine if you can take that virus down about a day faster, even if you're getting whatever it is.
Wait. So did you overlay the challenge curves and said one? Because I remember you used to give me grief on that, on the N inhibitor. And you're like, "Oh, you shouldn't be looking at this." Are you saying that now maybe that is what you're saying?
Again, you can't.
I'm kidding. I'm kidding.
You were pointing to a toxic molecule that got ultimately.
It was lumicitabine. Right, right.
Yeah. It was a nuke or a non-nuke. We didn't want to get into the nuke polymerase game, but it's a non-nuke. It's super potent.
I'm interested in seeing that. I think there is an angle there for sure. Okay. Maybe stepping back to KIT. Obviously, one of your peers was recently acquired. Here's the thing, the way I kind of think about it. There are games you can play in terms of knockdown on trip days. You can say 80% is actually 100%. There are error bars in terms of some of these heme markers. You can have high baseline hemoglobin. You can have males versus females. To me, I'm skeptical that any of these compounds are not going to have on-target heme toxicity, frankly. All these compounds are relatively selective as well. When I think about what would differentiate any of these drugs, I think it's the clinical development plan that actually doubles down on it being oral.
I would almost imagine a very clever titration scheme where you get to certain levels of trip days reduction and then stop. You look at where your kind of heme markers are. If you can have something clean there, that can really help in terms of strategic decisions going forward. How would you design, knowing what some of your peers have done, how do you design a phase one study that is generating more useful data to make a more informed decision? Again, how would you design it differently than some of your peers?
I think, and I'll let Tara comment on it too, but I mean, we're trying to distinguish ourselves certainly from antibodies of Celldex and Jasper with really long half-lives that become tricky even if you try to have a shorter half-life antibody. It's still multiple days, right? In this area, I think you're right. It's about how do you come up with a very clever dosing strategy that allows either sort of a knockdown and then a maintenance or intermittent dosing or basically figuring out what is the most titratable scheme that you can come up with. Suffice it to say, we imagined our program with that in mind. Some of the characteristics of 1421, I think, are going to allow for some very interesting flexible dosing designs.
Do you think maybe too long of a half-life is a bad idea, right? When is a half-life too long when it comes to a daily oral?
You know, we'll have to--it's hard to know. Multiple days is too long?
Yeah. 40?
Once a day.
Forty might be too long.
Possible.
Are you going for shorter? Are you thinking about 20? Put it this way. When you think about a daily oral, is it maybe a mistake to have over 40 hours of half-life because you get kind of a steady-state drug accumulation?
Yeah. The key is about being able to turn it off, right?
Right.
It's one thing about turning it on, and you do get accumulation, and then there's a longer tail and so on and so forth. It's impossible to know the answer to Akash in terms of what is too long. All I know is historically, we've just tried to find the right sweet spot for dosing. It may not be having a super long half-life is an advantage.
Got it. As we think, there have been compounds that have shown liver toxicity here. I think generally speaking, if you can avoid the daily rule of two or should, are you confident that you can get to, let's say, 80%-90% IC coverage at a dose that's below 100 mgs?
Yeah. I can't answer that today.
Okay. STAT6. I thought there was some really encouraging data. I do not know how to interpret it, to be honest with you. But I do think in terms of knockdown, you are seeing stuff that I have not consistently seen with a degrader. When you think about an inhibitor and you think about differentiation, because here is kind of my work, I do not understand STAT6 in terms of its correlation on clinical endpoints. I do not think anyone does. And when I look at the story of Entyvio, when I look at the story of even Dupy, it is not just receptor occupancy or IC coverage. There is, frankly, efficacy that is going—there is a dose response with some of these drugs that are well beyond simply pocket fit, right? You are getting complete target receptor occupancy.
When you think about STAT6 and amplification downstream, because it is an upstream target, how important is it to be hyper potent, right? Not just 90% knockdown, but 100% or more knockdown. Do you think you're going to be able to deliver that with an inhibitor program?
Yes.
Okay. Do you think you're going to be able to get levels of target knockdown or steady-state inhibition that is meaningfully higher than a degrader?
I think you don't need to be meaningfully higher than the degrader. I mean, you need to knock it all down. And as long as you can—as long as you're operating within a PK range where trough concentrations ultimately give you the knockdown you need, then you're fine. I mean, it doesn't—and so I feel very comfortable and confident in small molecule here.
Yeah. And then maybe lastly, because you are in a more constrained cash position right now, but you have programs that could be theoretically quite valuable to a strategic partner or for you guys internally. Would your team be willing to make a strategic decision on the STAT6 program before you have clinical data in symptomatic patients? Do you think if you can do something like healthy volunteer PK, PD, do you feel like that's a really meaningful card flip for you guys?
I think we saw this week that phase one data in healthies can be a big value creator.
How soon do you think we can get that? End of 2026?
We haven't guided that far out on STAT6 yet other than DC in the second half of this year. We'll refine that when we.
All right. Manoush wants to be in the trial.
Sorry?
Manoush wants to be in the trial. We'll do primary research. We'll enroll ourselves if you want.
Okay. There you go.
All right. Thank you. Really appreciate it. See you guys.
Bye now.