We're going to go ahead and get started. Thank you everybody for joining us this morning at the Citizens Life Sciences Conference.
Happy to be joined next by Enanta Pharmaceuticals. Here today with us is CEO Jay Luly and Tara Kieffer, the Chief Product Strategy Officer at Enanta. Welcome. Jay, maybe I'll just turn it over to you to give a quick intro and an overview of Enanta.
Sure. Thanks very much for the invitation. Before I begin, I want to remind you, I'll be making some forward-looking statements. For a summary of the risks associated with these statements, see our filings on SEC.gov and on our website. For those of you who are less familiar with Enanta, we are a drug discovery and development company based in Watertown, Massachusetts.
We have a specialty in small molecule drug discovery. More particularly, we got a strong start in infectious disease and namely virology. We came up through the ranks in the hepatitis C days looking for oral cures for hepatitis C. We came up with two protease inhibitors that when we teamed up with Abbvie got across the finish line.
The first one was VIEKIRA PAK, and we came up with a next-gen product called MAVYRET. To this day, it's the only 8-week cure for chronic hepatitis C and also acute hepatitis C. We've cured between 1 and 2 million patients on a global basis. It's been a gratifying story seeing that from discovery all the way through cures to many people.
We've worked in other viruses both in the liver and the respiratory arena. I think our current focus now in virology is in respiratory viruses, and we got into that space before the pandemic, focused on human respiratory syncytial virus. It's still an elusive virus in terms of having a treatment. To this day, there are no approved treatments for RSV.
Though there have been some advances in prophylaxis, a couple vaccines got approved a couple years ago. Although with far from ideal adoption and penetration. There are still a tremendous number of infections around the world, both in peds at one end of the age spectrum and high risk adults at the other end of the spectrum.
We aim to come up with the first ever treatment for respiratory syncytial virus. I'm sure we'll be talking more about that. We've got a couple of programs in that arena. We couldn't not work in the pandemic when it came along, so we did some more protease inhibitor work against SARS-CoV-2. Have some nice Phase two data there.
I think we're looking for probably further regulatory clarity in terms of how one advances one.
Mm-hmm
At the state of today's virus backdrop.
Yeah.
With that in mind, we broadened beyond virology. We got into immunology a couple years ago, a few years ago, actually. We disclosed our first program, I think, two years ago, at the beginning of the year on KIT, looking for small molecule drugs targeting KIT.
Well, I'm sure we'll talk about that. A year ago, at the beginning of the year, we announced our second immunology program, STAT6, where we're going after sort of an oral Dupixent, if you will. Early this year, we announced our third program in MRGPRX2, which is another mast cell target focused on different inflammatory disease states.
We continue to have discovery efforts and continue to want to build out further, but the nice thing is we've started to advance that I&I platform to the stage where we'll be moving to clinical data sets, hopefully later this year.
Great. Maybe let's start with RSV, zelicapavir. Can you just give us a broad overview of the program mechanism and the data that you've generated so far?
Sure. With RSV, we have two different mechanisms, and they're in contrast to a third mechanism. The third mechanism that many others approached was an approach going after viral entry.
This was targeting the so-called fusion protein of the virus. We elected not to do that. We reasoned that by the time people present with an active ongoing infection, there's already been viral entry that's occurred. Now you've got massive unchecked viral replication. Our approaches are replication inhibitors, shutting down the replication of the virus. We have an N protein target and an L protein target. Currently, both have made it through Phase I healthy volunteers.
They both made it through human challenge study data, where you infect a patient with the virus with your left hand, you wait a few days, and you treat them with your right hand with the drug.
Each of them performed incredibly well and the first one that came through the gates is published in The New England Journal of Medicine. We've got another one, again, another very successful study with our second molecule, EDP-323. Now the more advanced of the two, just based on the timing of when we discovered the drugs, is pointed toward a Phase III study in high-risk adult patients.
Can you talk a little bit about the, thoughts on trial design there? Where are you in terms of your FDA dialogue on aligning on trial design?
You want to take that too? Sure.
The Phase three in adults would likely reflect the population in our Phase two study where we saw the most robust results. We call that the HR3 population, which includes people that are over 75 years of age, those with COPD or congestive heart failure.
We'd be looking at a primary endpoint around symptoms, so looking at the time to complete symptom resolution as measured by a tool called the RiiQ, and we'd be looking at the 13 RSV symptoms there. Probably on the order of maybe say 600-700 patients. We're aligning with regulatory agencies. I think more communication will be coming out around that in Q2.
How do you think just at a high level about the product profile that comes out of that? What are good results?
Obviously, something that's robustly statistically significant and safe, but just from a from a business perspective, what's the right product profile or target product profile?
It's a 5-day dosing period. It's been very safe and well-tolerated in the studies so far. In terms of efficacy, in our Phase III study, we saw a
Phase II.
Phase II study, we saw a reduction in symptom duration of about seven days. That's about three weeks that we saw in patients on placebo, and then it shortened to two weeks in patients that were treated with zelicapavir.
We also looked at a number of other endpoints. We looked at a second PRO called PGIS and saw statistical significance there in our Phase II. Importantly, we saw a reduction in hospitalization rate. That will be something in our Phase III that we'll be looking at as a as a secondary endpoint. We saw in Phase II about a 50% reduction there.
Maybe let's switch over to the L protein program, EDP-323. Just where are you in that development process?
Yeah. As I mentioned, that's our second RSV molecule. Again, at the beginning, we knew we wanted a replication inhibitor. There were only so many different ways you might approach that problem. We started with N, and then we picked another one, which is L, which is the viral polymerase. That one's really interesting because it's super potent.
We had the luxury of maybe dialing down our second molecule to an even finer degree of potency. It's a picomolar inhibitor of that polymerase. It also has outstanding human PK. When you have a viral target that you're going after, it's about having super potent molecule, having really good sustained exposure over a 24-hour time period, and that checked both of those boxes very well in healthy.
As we took it into the challenge model where you again will infect a patient with RSV, wait for the viral loads to start to build, and then you come in and you treat. When we did that, we were hoping everybody was asking, "What are your hopes? What are your expectations?" We just wanted literally to see as good a data as we had already seen with our other molecule, zelicapavir.
There are some interesting aspects with EDP-323 that looked in some ways even better, and that was that it seems to attack the virus even faster. Those viral loads, when you measure them in culture, get completely obliterated within 12 hours after the first dose.
Mm-hmm.
That's about almost a day faster than what we saw with zelicapavir. If you think about it, time is of the essence when you're treating viral infections. If you wait too long, it's not going to work.
Yeah.
we know that. That's true with flu, it's true with COVID. The sooner you get to somebody, the earlier in the infection you get to them the better the outcome is likely to be. We recruit patients in our Phase II adult study within 72 hours of symptom onset. You have a drug that can work even faster, there's the potential for even better efficacy in theory.
We have to test that, of course. We now have that human challenge study data on our second molecule in our back pocket while we're advancing zelicapavir toward Phase III.
Do you see both products being commercialized, and how would approach that? You've obviously been very successful in hepatitis C with a partnership. just how do you think about the RSV opportunity?
Yeah, there's different ways you can think about it. You can have first is do no harm and keep zelicapavir moving as fast as possible and get to the market, and we have the chance to be the first ever treatment for RSV. That would be great, and we don't want to jeopardize that leadership position. At the same time, we have that intriguing observation of the rapidity of, or the speed with which EDP-323 acts.
You owe it to yourself to kind of explore that in the next step, so you could do at least a comparator trial or a trial that cross-trial comparison of one drug versus the other to see if there truly is benefit there. The other way you can think about it, I'm sorry.
With that in mind, you could almost think of 323 as being like a next-gen profile coming forward in terms of lifecycle management. You could also imagine very difficult to treat patients that, for example, severely immunocompromised patients that don't have a working immune system to help eradicate the virus.
Mightn't two drugs provide greater benefit to that patient, maybe two drugs and even a longer dosing schedule to make sure that you can really get rid of that virus. Having two orthogonal mechanisms could be helpful. We've also shown with 323 in our challenge study that there is a way to use it potentially in post-exposure prophylaxis.
Okay.
We saw some effects there in that challenge study. Do you begin to position one drug in one way or one population, another in another? There's just a lot of different options, and so we'll be sorting through those with time maybe within a partnership.
When you think about what's the right way to think about timing of partnerships? Is it when do you get the most out of the asset? Obviously, if you run a Phase three program for zelicapavir, that's going to generate a lot of value.
Yep. It's always that trade-off when do you do it? We certainly know we've seen the benefits. There's just nothing like having a super strong and committed commercial partner. We saw that with AbbVie.
They have proven to be now over almost 20 years, just a terrific partner in terms of the commitment, the global reach. We did that partnership very, very early. It still provided us great retained economics over the last many years. I think the key, the most important thing is finding that right, committed commercial partner who can really maximize the reach and commercial value. When you do that is anytime between now and launch.
You're right, there is another value inflection to extract out of this with Phase three data. We're weighing all of that presently.
Just, before we switch to the I&I portfolio.
Yep.
Jay, you mentioned at the start you have had and have had a very successful and productive discovery engine. You're producing new molecules now on the I&I side, but how do we think about the discovery efforts on virology? Is that still an active focus?
Not so much anymore. We've explored many viruses first Hep C, Hep E, human metapneumovirus, RSV, COVID. At some point, we were finding fewer and fewer super compelling viruses to go after that would have substantial unmet need and could build a business around. That's why I would say the COVID pandemic stalled our entry into I&I a little bit, simply because that new virus landed on our plates, and we couldn't not work on it.
Exactly, yeah.
Otherwise, I think we were ready to build beyond just virology.
Got it. On the I&I portfolio, as you said you've now disclosed three programs, and you're moving into the clinic, and the first one is targeting KIT, as you said. Let me just ask the simple question of why did you decide to go after KIT? What was the the thinking behind that? Urticaria is the indication. Again, why KIT? Why urticaria?
We like the KIT target for a number of reasons. By targeting KIT, you're actually depleting mast cells. Any indication that is mast cell driven or mast cell related could be amenable to this type of therapeutic. We follow the antibody story closely. There are antibodies out there that target KIT, one from Celldex that is in Phase three currently.
The data that they've shown from their Phase two is what we consider best in disease efficacy. They are moving that in a Phase three trial. We'd be looking to replicate that efficacy with an oral small molecule. Potentially have a dosing strategy that might mitigate some of the on target tolerability that some of the antibodies have seen.
Yeah. Just give us the update where you are on that program and what's what's coming next.
Yeah. We've set a goal for IND in Q1 and Phase I data in Q4, and we're on track for that.
Is that the typical single ascending dose, multiple ascending dose data?
Phase I would be.
Yeah
typical SAD, MAD
Yeah
healthy volunteers. We'll get safety and tolerability, PK for dose selection, and then we'll also be able to measure biomarkers in healthy volunteers, such as serum tryptase.
Mm-hmm.
Which is a really good biomarker. Gives you an idea of mast cell activation, and mast cell burden. We'll be able to understand that in healthy volunteers and be targeting to see a depletion of about 80%.
What have the preclinical data shown so far, both in terms of what you'd expect from a PK profile, but also target engagement?
The potency that we've shown preclinically is quite good, so 2-3 nanomolar, in that range. Very selective against KIT. We've spent a lot of time thinking about our DMPK properties preclinically as well, so be QD dosing schedule.
Again, just looking further forward, product profile, how do you see the product being differentiated versus for example, if there are other drugs targeting to KIT on the market at the time?
Right. The ones that are furthest advanced are antibodies, so we would certainly differentiate from route of administration. There is one other oral KIT molecule in development currently, from Blueprint Medicines.
Again, we selected EDP-978 as a molecule that we've hopefully optimized around all those parameters of potency, selectivity, ADME properties and hopefully generate a best-in-class molecule. We'll have to ultimately see what the clinical data look like. We'd be looking at urticaria, both CSU and CIndU as an indication, as well as other mast cell-related diseases, prurigo nodularis. Big indications, probably room for multiple players as well.
Got it. Moving on to EDP-3903, STAT6-targeted. I mean, it's really straightforward when you say, like, oral Dupixent, right? That's, that should be very obvious to people of the why. Just walk us through the evolution of this program as well.
yeah one of the interesting things is so Dupixent targets the IL-4, IL-13 pathway, but more at the receptor level. Downstream, the signaling funnels through STAT6. People have been staring at STAT6 for a long, long time, and it was viewed to be a very difficult to drug target.
It's among the reasons why degraders came in because they you know tend to slide into places where people think small molecule drug development with a classic inhibitor you know is challenging or impossible. I think the you know degraders have demonstrated you know some interesting activity in the space. There are certain companies out there that you know have done that quite notably.
We've come at it from a this is a druggable target angle, and we want to have sort of a classical non-degrader, just a very well-behaved classic inhibitor approach, small molecule. In order to do that, you need to have established a few things.
You need to be able to hit the target, show complete inhibition of the target, and show complete inhibition of the target over a sustained period of time so that you know you don't let it relax so much. We were I think well equipped and well trained to do that because we come at it from a virology angle, right? Where you have to hit that virus hard 24/7.
Mm-hmm
have a lot of drug pressure on it. We developed our candidates with that in mind, again, focusing on potency, selectivity for kit or STAT6 versus off-target kinds of considerations and, really developing that complete and sustained level of inhibition. We've shown that in animal models. We've also shown Dupixent-like activity in animal models of both atopic dermatitis and asthma.
Mm-hmm.
we think we've achieved many of the objectives we set out.
When we think about timelines relative to KIT, where are you?
KIT, we're expecting, as Tara mentioned Phase one data in Q4. We're on track for an IND filing in STAT6 in the second half of this year.
Okay. Third program you just announced, so do you want to-
MRGPRX2
Yep.
Tara, you want to take that?
Right. MRGPRX2 is our newest program. We are currently optimizing some prototypes. We've shared a little bit of data on those prototypes. We see really good potency there. Selectivity, again, is important here for that target. We've been able to show that we're potent across a number of different agonists for MRGPRX2. There, we'd be thinking about an indication also as a proof of concept in urticaria initially.
Mm-hmm.
There's a lot of different indications you could think about with MRGPRX2. Again, other mast cell-driven diseases, but also other things like migraine, because the receptor's expressed not only on mast cells but on peripheral neurons. There's some evidence that it could be important in these other indications.
Going back to that point about discovery productivity you're putting multiple programs into the clinic, large indications, large opportunities to move into other indications. How do you think about the partnering strategy around the I&I portfolio?
well it's kind of fungible, right? It depends what every other piece starts to do and how well capitalized you've made other programs. Right now, we have plans and have targeted the three I&I programs that we have now. We're hoping to have a MRGPRX2 candidate in the second half of this year and take them all through early clinical data sets. We have more discovery work going on in I&I as well.
Got it. Can you just talk about the the less interesting question, just financing? Just where is cash? What is funded today in the
All of the I&I is funded through clinical data sets. We had finished the last quarter with, I believe, $242 million in cash. That's a runway into fiscal 2029. The Phase III study will depend on how we play that. Is it in the context of a partnership or not?
Right. Okay, great. Well
Yep
Jay, Tara, I really appreciate you being with us this morning.
Indeed.
Thank you.
Thank you very much.