Good morning. Really appreciate everyone's attendance, and it's been really enjoyable seeing everyone in New York enjoying this conference. My name's Akash Tewari. I head our firm and biotech efforts on the research side for Jefferies, and we have the pleasure of hosting the Enanta management team, a company that is heavily embedded in small molecule drug discovery across different disease areas, and a lot of products that I think are going to become increasingly important. Jay, why don't I hand it off to you for some intro remarks, and we'll get started.
Sure. Thank you, Akash. Before I begin, I want to remind you that I'll be making some forward-looking statements. For a summary of the risks associated with these statements, please see our filings on SEC.gov and on our website. Where would you like to start? We can dive in on the RSV side.
Yeah.
We can go into, yeah, start there?
Let's start with RSV. I know right now you have some really interesting data with your N-protein inhibitor, the question is really, how does that molecule get developed, when are you going to phase III? Let's start with really even powering in these trials, because this is really precedent setting. We've never had success on the antiviral side in RSV, then you're also a mid-cap company, these are sometimes large, burdensome clinical trials. What have you learned in the field in terms of what the right trial design is for an antiviral in RSV in an adult population?
What we've learned, I would say it's getting to the right patient and at the right time. You're dealing with an acute respiratory virus. We all know what COVID's like, I think by now. Everybody knows sort of what flu is like. You probably may or may not know what RSV's like, but everybody in this room, I guarantee you, has had RSV multiple times. I found out with one of those little home diagnostic test kits that I had RSV two months ago. I wasn't expecting it to light up, it lit up, and it felt like one of many bad respiratory tract infections I've had over time. What you want to do is make sure that you're getting to the right patient.
When I said getting to the right patient, I think the key is focusing in on who are the patients that are at highest unmet need and it's the patients who do really poorly when the respiratory virus strikes. It's either the very young in the ped setting, the very old, immunocompromised patients who have CHF, COPD. There's a whole bunch of different risk categories, but if you really want to see the most dramatic effects, such as what we saw in our most recent study, you need to get into that high-risk patient population to see it. You don't want to wait around for a week.
Yeah.
Or more to try to get a drug on board. I think we know flu drugs, typically, you need a drug on board within 48 hours. I think COVID is within five days. Probably three days is better than five days for COVID, and I think that's probably the same case with RSV. I think those are the learnings. Pick the right severe population and get there as quickly as you can. I think the test kits are going to actually help that a great deal.
Understood. When we think about next steps with your N-protein inhibitor program as a monotherapy, I know there's also the potential to go with a combo approach as well. What are the landmarks? Is there a partnership opportunity available? Can you update us on any of those discussions, if there's anything that could be imminent? Number two, if you're to think, "Hey, this is the cost we would need to run this clinical trial," just help frame that for investors. What's the size and time scope of one of these studies?
Yeah. Maybe starting with the second question first. We are looking at a registration path. Again, we've been obviously having a lot of discussions with FDA. Post our RSV HR dataset really to define that registration path, because one doesn't exist. I think that's the good news and the bad news. You get to map it out with the agency for the first time. We'll give a more fulsome update on the discussions and alignment with the agency this month. I guess we targeted Q2, we're in the last month of Q2, stay tuned on that front.
Clock is ticking. Yeah. Okay.
What I think, ultimately, you're looking at some sort of a study design. It's not like a vaccine study. You're talking about hundreds of patients. You're talking about a pathway too, that not everybody has explored. I think Enanta's got probably one of the best teams in the world based on having developed two drugs in RSV, having looked in a variety of different patient populations, high-risk adults, peds, challenge studies on multiple different drugs. I think we've got the right team in place to be able to either progress this thing in the context of a partnership or without a partner. I think under any circumstances, any company probably in the world would need to rely on the insights and experiences and stuff that the Enanta team has developed here over time. We're exploring multiple different pathways.
The key thing we want to do is make sure that we see this thing moving ahead, because it's not often that Spire has been kicking around for 70 years. Nobody has been successful to get it to the stage where you have a global registration study with a mechanism that could potentially be the first in a brand new category. You're talking about a market where you have on the order of seven million outpatient visits a year just in the U.S. alone. Big unmet need. We're just really excited to see this thing moving ahead.
Okay.
We'll figure it out one way or the other.
Jay, this is pretty provocative. Let's hit on this, because you've had data for a while. Sounds like, okay, you're having an additional discussion with the FDA. Your study, the initial data you've published has been, I think, a year at this point. Am I?
No. I don't know when that was.
Months?
Last fall.
Last fall.
Yeah. If it's a biotech, two years.
It's been a while, right? It's been a while. It's really interesting because there is an administration that might take a more forward-looking approach in terms of therapeutics. There's a lot of difficulties running clinical trials, and if you have a safe medication, this would be something where I feel like there could be a more lenient stance in terms of clinical development. I just want to make sure I understand that. This does seem like a bit of a tone change from our prior conversations here. What is your perspective? What are you trying to propose to the FDA about the clinical development path, ideally with this molecule? Are there scenarios where you could actually get a path forward where you wouldn't have to look at an external partnership, your team would be able to run the trial internally?
Well, like I said, I think all these possibilities are on the table. What we're always trying to figure out is what is the most efficient pathway. That's just the nature of the business. We're no different than any other sponsor. You're always trying to figure out what's the most efficient way and how do you align on a constructive pathway that you can articulate and that the agency agrees with such that you can get this thing out there and done. I think, again, we'll have more to say this month on that.
We're just excited by the prospects of getting this thing moved ahead. We've certainly, as you well know, Akash, because you've been following RSV for a lot of years, it's a seasonal thing, right? We've been just planning for success, not only with our left hand having discussions with regulatory agencies, but also with our right hand doing everything to enable a study to get off and going even later this year. Drug supply, getting protocol figured out.
Yeah.
Those sorts of things. We haven't taken our foot off the gas at all.
As a reminder, I think prior, you've expressed the idea of partnering that asset out instead of running the phase III separately, or is this something that you've always stated you wanted to go internally develop?
I think where I would draw the line is we certainly have thought about a partner for the later stages of this and certainly for commercialization. Coming into an area where it's a new product category, doing a global launch, multiple different patient populations and so forth to really maximize the opportunity. I think that's what pharmas do incredibly well.
Sure.
As I mentioned, we do some of the development incredibly well. Anybody out there would certainly be wanting to understand what regulatory clarity looks like and also having the right execution team to get something done. Those are the things we're focused on.
Understood. I'll even put this more even simply. Is it fair to say that your team is markedly more excited about the opportunity of a constructive clinical trial design proposal with the FDA than, I remember last year when we talked about it, this wasn't something that I think you were proactively bringing up. Is that a fair read?
Well, we're further down the track, right? We've had discussions, and again, so we didn't have the data all that long ago. Working up further analyses. We wanted to take the full complement of everything we had to the agency, show them all the signals that we found in the various readouts. In the aggregate, I think it's an incredibly compelling story. We saw, and I can personally vouch for this, symptoms in this, to get to the degree of complete resolution is around three weeks i n a high-risk patient population. We cut that by a week. We had another readout, the PGIS.
Yeah.
We saw stat sig 2D improvement there. Importantly, in hospitalization, the attack rate for RSV in this population was about 5%, which is pretty significant. In fact, we had one of our placebo patients die of RSV in this study. We cut that down in the drug treatment group. There was basically no RSV-related hospitalizations. It's 5% versus a very, very low percent.
Okay.
We had obviously no deaths on zelicapavir-treated people.
Sure.
Only in the placebo group. The fact that you're getting a dramatic shortening of the time to complete symptom resolution.
It's one or two days. That is significant.
No. Well, it was, again, we saw a week.
A symptom resolution. That's right, okay.
Yeah.
Yeah.
It was about a week, in terms of that, using the RiiQ, the patient reported outcome.
Right. No, you're right. Yeah.
The hospitalization, we weren't necessarily expecting to see that in such a small study, but.
It sounds like the agency, and this is quite important, is looking at the totality of your data.
Yeah.
Right? I think that's one of the reasons I think we got more bullish on that data set too, was it's not just, "Hey, you have a log drop." It's like the log drop correlated with the symptom reduction, which correlated. There's not one that's randomly trending the wrong way. Is that?
There was a super high degree of alignment of a bunch of different signals.
All right. Jay, leading up to this, give me something. No, this is interesting. How do you do this in a capital efficient manner? In my mind, I'm thinking a couple of things. A, do you run a trial where you have a synthetic comparator arm? You look at historical rates of hospitalizations because it's unethical to run a trial where patients aren't getting access to drug, especially these are elderly individuals. The size of your study could dramatically decrease. You could run a study maybe for you could power it for mortality. You can power it for symptoms. You can power it for symptom resolution. You can power it for viral load reduction, right?
For a company that has capital constraints as Enanta does right now, what is the right endpoint that you feel like, A, puts your drug in the best position to succeed, but then, B, also allows you to run the trial efficiently?
Well, I think they're not all mutually exclusive. I think some of the key readouts we're aiming to ultimately get, it would be wonderful if you could power for the most far-flung endpoint that would give you the best possible overall profile. I think just drilling down on symptoms and hospitalization and looking at those kinds of things has the potential to be a fairly manageable proposition.
Okay.
We're going to be looking at hospitalization anyway. Yeah, we would.
Jay, to maybe just to put a fine print, because I couldn't agree with you more. Even your prior point is like, look, everything has to trend in the right direction. There needs to be consistency of the data. That makes sense. I'll give you an example. We cover Ionis and pancreatitis events, right? There's not that many pancreatitis events, but even a few, you show a trend, whether it's stat sig or not.
Right.
The point is like, well, the agency can say whether it's stat sig or not, there's 10 events on one arm, there's no events on the other arm.
Yeah.
Hey, there's a signal here." I can't help but think, forget stat sig or not, but just directionally, hazard ratio. If it was on hospitalization, you mentioned a 5% kind of underlying attack rate. If you were to say, more explicitly, let's say that you had an endpoint where it was more a hazard ratio on hospitalization versus symptom improvement, which again, has traditionally been used, and there's always going to be a larger N required there. Are you going to the agency and saying, "Look, our drug's going to be safe. We're going to show the trends on the symptoms. But we think we're going to see de minimis hospitalizations with our drug, and there's going to be an underlying rate, and that's really our primary endpoint." Is that the approach you're going to take here? Or hospitalization, sorry.
Yeah. I probably can't get out in front of our planned discussion on this this month. All of those things are very much on our mind. We've even done a lot of testing with payers on different profiles and what that could look like, what kinds of data would be important in the minds of payers and also physicians. We've done a lot of market research here. We built that into our thinking and into our proposals for endpoints to the agency. That's about what I can say today.
Okay. I'm still going to keep trying. On hospitalization, is the sense that you would need something statistically significant or an obvious trend? There's nuance between the two. How should we think about a strong trend on a hard endpoint for a smaller study?
Yeah.
Compelling? Is that the way we could think about it?
Right.
It doesn't have to be stat sig, but it has to be a strong trend?
Yeah. I think that's probably not unreasonable. Again, we saw a pretty strong trend even in a smaller study.
Can you remind us, in terms of hospitalization rates with your drug and then the placebo arm, what was the trend that we saw?
It's 5% placebo, and effectively, I think all-cause hospitalization was 1.7%. The adjudicated RSV-related hospitalizations was 0%.
Right. Interesting. How does that maybe change trial design size? If we're thinking about a more stringent, to your point, there's nothing more important than hospitalizations and deaths. These are really clinically relevant. When you think about traditional phase III studies in RSV versus, let's say, something where you can pick a trend on a incredibly important endpoint, are we talking about half the size? Are we talking about the same size? How do you power that study correctly?
Yeah. There are no precedents.
Sure.
Right? This is where we're going in, and statisticians have spent a lot of time focused on that. Let us make the public disclosure in June, and you'll see a lot more granularity.
Okay. Maybe just lastly on this, because you said we had our data last year, and it sounds like you've already had some preliminary discussions with the agency. Talk to me. Obviously, we've seen paradigm changers in virology. Xofluza, I think is an important idea, where this idea of instead of a traditional vaccine, you have a therapeutic which can protect patients from flu, and there could be an expedited clinical development path that I think has been alluded to. Let's see if that actually plays out. When you think about the agency's view of antivirals for respiratory infections, and particularly under this administration, do you feel like there has been a more constructive stance than what you've seen historically?
I'd say we've seen a very constructive stance for multiple years. We've had lots of interactions over time. We have Fast Track designation for both assets and RSV. We've had the opportunity to engage and the group there, I think has been pretty even keel.
Pretty even keel. Maybe just lastly, in terms of viral load reduction versus, let's say, a symptom endpoint. You showed, to your credit, a trend on both. Is there one that you feel like, and especially in a larger global study, it might be a little more difficult? Is it symptoms? Is it absolute log reduction? If you were to have to pick another endpoint that you would think about for phase III, which one's preferable?
Yeah. Virology, I should let Tara talk about it. She's actually a virologist. I think virology, generally in acute indications, we saw it in COVID also, the agency puts less emphasis on virology. It's interesting. There were certain COVID drugs approved that didn't show anything on virology.
That is true.
You can only measure virology in your nose, right? Which is not necessarily where all the action is.
That's a good point. Yeah.
And so i t's interesting. It's supportive.
Symptom resolution.
Always good to see.
Yeah.
They're looking for other things, right?
Understood. Moving on from that topic, but still in RSV, obviously you have your L-protein inhibitor as well. Again, you think about could the agency take a more constructive approach here? I don't understand why you have to now go run a phase IIb with the L-protein inhibitor. If the drug's safe, and you've done your challenge study, and you have enough human data, why not take a combination approach in a phase III, put these drugs in the best position to succeed? Should we be thinking about potentially an accelerated path with the L-protein inhibitor in terms of getting that into a phase III, especially when you're thinking about it maybe as a combination add-on?
Yeah. You still ultimately need, I think, to show something in a real-world setting for c hallenge studies are great.
Yeah. They can drive.
They're incredibly powerful tool t o help you pick dose and show that you've got an antiviral, show that you can reduce symptoms. It's incredible, but there are certain practical limitations. The way that the studies are set up, it's not perfectly real world.
Yeah.
I think you probably need at least something in the real-world setting before you would jump in, so that you've demonstrated that in a certain patient population, you've got some sort of activity as opposed to healthy volunteers who you've infected.
Okay. Sorry, go on.
To follow up on that, I think most patients probably will do okay with one of our drugs. I think there are patient populations out there. You can think of the severe immune-compromised patients who potentially could benefit from a combo. Hit the virus orthogonally two different directions.
Yeah.
Two different direct acting antivirals, hammer it. Maybe potentially coming in a little bit later in the infection, but with two drugs, hammer it.
Right. For traditional adults.
Yeah. Those are different ways that you can think about leveraging EDP-323. The other way is, get zelicapavir to market, establish the market, be the first to market, and build that. Then lifecycle management, you can be coming through with something EDP-323-like, well, EDP-323, that would push it out even further. Meanwhile, you have the options of combinations, and we also saw in our challenge data, but it's compelling, post-exposure prophylaxis.
Yeah.
The data were actually very strong for that.
Doesn't surprise me. Maybe just last point on this. I can't help but think when you're running in an asymptomatic patient population, couldn't there be two arms, one arm with an L-protein inhibitor and then one arm with a combination of an L and N. Both of those drugs, given that you already have established safety data.
Yeah.
Is that possible that we can have the combination as early as once you get the challenge data in-house and you're going to now run a symptomatic population, you can already go with the combo then?
Well, such a trial design could be contemplated. In fact, I think you would need almost that comparison to convince yourself that you are adding any benefit, because you have to be able to show utility in combination studies one's doing something.
Can I push back on that? I just don't get it because to me this is an issue I think you even dealt with, which is like, okay, I set my first population in healthy volunteers, then otherwise healthy RSV patients, and maybe that's not the patient population. In general, you want to hammer these viruses as much as possible to prevent. An early study's not going to do that. If you were to say how would you even know in, let's say, a regular adult RSV population, whether the combo would be better or not? You would have to run an immunocompromised trial, which is going to take forever to enroll. What would you even learn if, let's say, there's not a delta between the two arms in an RSV adult population?
Yeah. Again, you have to show benefit. I think that's one of the rules. We saw it in hepatitis C.
Yeah.
When Viekira launched, it was three direct acting antivirals. Each one had to play a role in that, show some benefit, and then we came up with MAVYRET with AbbVie. A two drug combo, there's no question.
Yeah.
That the two were powerful. Again, I come back to much as I want to maximize both assets.
You like your boys, yeah.
We also think that the majority of the patient population, we should be able, in an acute infection like RSV, one could be enough for most patients.
Understood. Running out of time, I want to hit on the STAT6 inhibitor. I think this idea of degrader versus inhibitor, but I think there's even within the inhibitor realm, a bifurcation between allosteric and orthosteric approaches. I think there might be a view like, "Hey, orthosteric might actually be better than allosteric, and we're not actually getting the same PK." Can you comment a bit on when you think about allosteric inhibitors themselves, is Enanta's drug an allosteric inhibitor? B, this idea that you can get complete target engagement with going with that approach, would you agree or disagree with that?
I think you can get complete inhibition with all of the above. It just takes the right molecule. When we think about it if you go back, I was working on JAKs and STATs in the early '90s and a different company back then, but they were difficult to drug targets in the STAT field. It made perfect sense, I think, at the beginning of STAT6 work, after failure in drug targeting, to come up with a degrader approach when it's difficult to drug target. That's no longer the case. Now that you can drug it, our attitude is, why use a degrader if you don't have to? If you can get complete inhibition with a well-behaved, potent small molecule that has good small molecule attributes, you've seen us make a lot of these things in the past.
I have.
Whether it's allosteric or orthosteric, I think at the end of the day it doesn't matter, especially you can prove so much of this stuff preclinically. We've shown DUPIXENT-like activity with an inhibitor, not only in atopic dermatitis models but also asthma. I think it all boils down to the specific molecule. There's lots of mechanisms.
I know we're running out of time. I want to sneak in this question. There's this idea, though, if you can target intracellular, you deal with receptor recycling and turnover and presentation in the cell surface, and sometimes that dynamic can happen when you're looking about an inhibitor. Sometimes if you can target intracellularly. One of the things I've noticed, for example, about the Kymera drug is that it works at very low doses.
Well, that's the nature of the mechanism.
Yeah, exactly. No, I agree. How do you think about dose response on an inhibitor approach? Again, I think there's probably a different dynamic there.
It's no different than anything else.
Yeah.
You want to have good coverage for the target. You want to be able to knock it down. Question that a lot of people had is, can you knock it down over a 24 hour period? Continuously, even though the answer is, and you know this from our virology experience, we're used to leaning on viruses hard.
Yeah.
Above the EC50 or IC90 or whatever we're looking at. You just need to have drug levels above that. As long as you have continuous drug levels with good PK, you're going to be fine.
I keep saying last question, but this is the last question. Plasma and protein bind it adjusted.
Yeah.
At the site of the lesion. Do you feel like you're going to be able to get to DUPIXENT? We're talking about IC99s. That's very hard with a small molecule drug.
We've done it in animal models already.
Okay. You feel comfortable in terms of drug distribution and plasma?
Yep. It's already done it.
Okay. On that note, this is one of our best ones. Thank you so much.