Assembly Biosciences, Inc. ($ASMB)

Here at the bank. And with me on the stage is Assembly Biosciences and Anuj Gaggar, Chief Medical Officer. Thank you so much for joining us.

Thanks for having us.

Excellent. Well, maybe to start broadly for those less familiar with the Assembly story. Can you give us a quick overview of your work in virology?

Yes. Thanks. First of all, we're very excited to be here and share our story with everyone. Assembly is a company that's a clinical stage company that is really focused on patients who are still suffering from serious viral illnesses. We're a full R&D company, research and development, and we have a broad partnership with Gilead Sciences, who, as you know, is a leader in antiviral discovery and development. Over the past 2.5 years, we have brought 4 new molecules into the clinic and have generated really positive data on each of those molecules. Most recently, we've had 2 of those molecules, our HSV programs, optioned by Gilead Sciences on the strength of the Phase Ib data. And we're excited for the next year where we'll move our other programs into value inflection points as well.

Great. Maybe just to take a step back, how would you frame the unmet need in hepatitis B, hep D, HSV? Is this still a space that supports meaningful innovation despite the availability of both vaccines and antivirals?

Yes. In a word, absolutely. I think what we do at Assembly is we look for the places where there are still unmet needs for patients. And taking some of the diseases that we work on one at a time. For HSV, there is no vaccine. There's neither a prophylactic vaccine nor a therapeutic vaccine right now despite significant effort. Most recently, GSK and Moderna both had trials that did not meet their endpoints in patients with HSV-2 infection. And in the world of antivirals for HSV, we know that while there are treatments, still, there's a lot of efficacy that's remained to be gotten for patients. More than 2/3 of patients fail on chronic suppressive therapy for HSV-2. So we know that despite having significant effort from a lot of folks on vaccines and with the antivirals, we have room to go. Hepatitis B and hepatitis D, we look at that similarly where there's a great prophylactic vaccine. But for those patients who already have infection of which there's, globally, millions of patients, there are no effective therapies for curing hepatitis B or for really treating hepatitis D outside of bulevirtide, which is approved in the EU. So we look at those areas, too, and we see a lot of opportunity for patients to have better outcomes with better antivirals. So that's how we focus, how we approach diseases, and these are 2 where we think there's a lot to be added by what we're doing.

We got it. Let's pivot to the herpes simplex program. A recurring theme here is that current therapies may suppress outbreaks, but often fail to meaningfully improve quality of life for many patients. Beyond simply reducing the outbreaks, how does Assembly define a clinically meaningful outcome? And which endpoints best capture that?

Yes. For patients that are suffering from HSV-2 infection and recurrent genital herpes, there's really 3 areas that they look at for improvement for their outcome. So first are the lesions themselves. These are what really are psychologically impactful for patients. They're, of course, very painful, and many patients are having multiple lesions a year many times, even sometimes once a month. Currently, we know that the standard of care treatment, valacyclovir, has an impact on that part of their disease. But by their label also, 2/3 of patients at least have recurrences even while taking this medicine. So we know on lesions, there is room to go to make that better for patients. And what we think is going to improve that are medicines that have higher potency, easier to take, a little more convenient, and we think that's where our drugs fit really well. A second area that's very important for patients also is just the convenience. So we know right now because of the poor PK and lower potency of valacyclovir, patients have to take that drug every day to maintain their efficacy. By missing days, you risk of recurrence coming. And so for patients, that's very impactful on their lives, whether they're traveling, weekends away, they got to bring their medicines, get reminded of that every day. And what we've seen from the HIV world is that one way to improve adherence and, therefore, efficacy is to get treatments that are longer acting. So we see an impact there if we were to make those treatments more convenient. And I think one final component that is very important to patients is transmission. So a lot of these patients are sexually actually active. They have partners that don't have HSV. And so they're very concerned if they are going to transmit it to their partners or to others. And here, we know that what really leads to transmission is high levels of virus and many days with viral shedding. And so treatments that can impact that can impact that for patients as well. So we look at the molecules, 1179 and 5366 that we had developed and Gilead has now in-licensed as highly potent weekly dose medicines that are tolerated well. And we think that's something that can address all 3 aspects for patients.

Let's get into that a little bit further. Gilead licensed the helicase primase inhibitor program relatively early. And I guess, from your perspective, what aspects of the data or mechanism clearly signal the potential for differentiation?

Yes. Both Gilead and Assembly were working on this target prior to our collaboration. So I think we both independently identified this target as one that could make a meaningful impact for patients. And it has to do with the fact that it's -- there's no kind of host equivalent. You can make very potent molecules against it. And from our experience in antivirals, the more potent you can make a molecule, the more efficacy you can get out of it. So I think we started from a place where we shared the value of that target. And then it was just the data and the strength of the data from our Phase Ib programs. We exceeded our expectations even on multiple aspects, both on lesion reduction, shedding reduction, and high viral load shedding reduction. And I think on the strength of those data, that's probably what led -- I mean we can't speak for Gilead, but we think the strength of those data early really led to them making that option decision before we even completed the trials.

Got it. And then again, from a broader perspective, HSV therapeutics have historically received far less investment attention than areas like HIV and HBV. Why do you think that's been the case? And do you believe the commercial opportunity here has been structurally underappreciated?

Yes. We believe it is underappreciated. I think what has happened over the past 20-some years is there was a heavy focus on HIV therapeutics. And that dominated, I think, a lot of the attention in the antiviral world. And then there was a wave of hepatitis B, then hepatitis C, and then COVID. And I think what these things did is sort of drew attention, both industry attention, investor attention into clear areas of need that were demonstrated. Also, there had been a treatment valacyclovir, which was about 30 years ago now, and there was just assumption that things were going well. I think now what we are seeing when we talk with patients, we realized that there is an opportunity to improve upon what actually is a substandard drug. We would never accept it in those other areas. And this is the time now for we can see to address all those. So I think that we're kind of hitting a time where there's more awareness, slightly less stigma now. And there was a lot of stigma on these diseases before. And I think we've done a good job of erasing stigma for HIV, hepatitis C, hepatitis B, and I think now is the right time for HSV, now.

Excellent. Well, let's move to your hepatitis D program. While NTCP blockade has been clinically validated at this point, what do you view as the key translational risk when applying that biology to a small molecule oral approach like 6250?

Yes. So one benefit we have in hepatitis delta space is the knowledge from the bulevirtide program from Gilead. So that program, which is a peptide that targets NTCP has now been approved in the EU, and we expect soon, approval in the U.S. from them. And it has multiple years of data demonstrating safety, efficacy in a broad range of patient populations. So our molecule targets the same molecule or same protein, NTCP. One of the nice things about our program is that when you target NTCP, you have a pharmacodynamic readout, which is an elevation in serum bile acid, something that's seen with bulevirtide. And in our Phase Ia study, we're able to demonstrate not only our safety and PK, but we could look at levels of bile acids in the serum. And we saw a dose-dependent increase in bile acids that also was equal to and even greater than what was seen with bulevirtide. So for us, that's a very derisking Phase Ia study that lets us go straight to a Phase II program, which is what we're planning for the end of this year. I think for us, the remaining uncertainties or unknowns is just to equate all that with the antiviral efficacy. We have in vitro data in which we've tested multiple genotypes of hepatitis B and delta, so we know it works in vitro. We know we're hitting the target in vivo. And now just putting that together in the Phase II is the last kind of thing that we have to target.

Great. When you look at the clinical program, what specific signals from the Phase I add to your confidence that an oral NTCP inhibitor can translate the efficacy that you've seen from this peptide into the practice?

Yes. I mean I think we -- what we always wanted is a daily oral medicine that we know patients could take and have sufficient pressure on the virus every day. And that's something very important in antiviral development. And so the PK was really important from this Phase Ia study, which showed that we can dose every day and achieve levels of the drug that we think will lead to efficacy. And as I mentioned, that pharmacodynamic measure of bile acid elevation tells us we're not just getting serum levels, but we're getting levels on target in the liver itself. The fact that it has matched what we expected from the pre-clinical experiments, I think, is really good data for us to give us confidence. And now it's just a matter of, yes, generating the clinical data in delta patients.

Got it. And just in terms of sort of, I guess, planning for catalysts, when should -- we can sort of expect these readouts to come?

So we've accelerated our chronic tox on that program because we want to do a longer-term dosing in patients with hepatitis delta. So the plan is to start those studies by the end of this year. And then we're expecting to have our data readouts by the end of '27 for this program to be able to look at and say what dose level would we like to go forward with in Phase III. Of course, that will be subject to discussions with regulators, but we're trying to design this Phase II to allow us to go to Phase III right afterwards.

At a high level, what do you think or believe 6250 ultimately needs to demonstrate in terms of efficacy and safety relative to -- what is likely to be the standard of care here? I mean, can you just win on convenience? Or do you need to be better in class?

Yes. So there's great competition in this space right now, not only Gilead's bulevirtide, but Mirum has an antibody that they acquired from Bluejay, and Vir has an antibody siRNA combination as well. When we look at all of these modalities, we think they all bucket into the same idea, which is preventing new hepatocytes from being infected. So they all are functional entry inhibitors. You can either do that at the level of the receptor as bulevirtide and our molecule 6250 do or you can do it at the level of the virus by removing the virus, which is what the antibodies are doing. So we think that in the end, they shall have -- should have at least similar efficacy when it comes to ALT normalization, which we think is the most important part of the outcomes for patients. In that setting, I think we think we can actually get maybe more efficacy because we can maintain our levels more consistently over time and may actually improve efficacy. But from a convenience perspective, we think there's a lot of value and convenience here. So all of the other modalities are injectables, either daily injectable in the case of bulevirtide, potentially weekly or monthly injectable with Mirum, and monthly injectables with multiple agents with Vir. And in a setting where patients are already taking a pill every day for their hepatitis B, the simplest thing from the patient is to take a pill for hepatitis delta as well. So we think, in this setting with similar efficacy, the convenience will have a major impact.

Maybe just to take a step back and look kind of overall broadly at your portfolio. What do you view as the biggest remaining uncertainties? Is it durability, efficacy, safety, commercial adoption?

One of the nice things about antivirals is that what you see in early-stage studies tends to track with later-stage studies. So we really work hard to design our early studies, so that they address as many questions as we can to derisk them for later studies. So for HSV-2, the Phase Ib studies that were performed really derisk it from efficacy and safety for future studies. Of course, the longer you dose patients, the more patients you dose, you have more confidence on safety. So I think that's one thing we always are looking for. Same thing for our delta program. The next study is meant to derisk it on the antiviral component, which we think should track really well for Phase III as well. So I think our uncertainties are not so much around that. They're really around the edges. So for HSV-2, are there other markets we're not considering or Gilead may have to consider that might expand the use of these molecules? So we've looked at recurrent genital herpes, but there's areas where you can think about subcutaneous injections every 3 months or monthly orals or oral herpes or other places where we can make an impact for patients. So I think there's some areas where I think some work needs to get done about what's the best way to impact patients. And then I think from a company side, we're just awaiting some development plan from Gilead on the HSV-2 programs. So what that lets us do as a company is opt in to a 40% profit-cost share, which gets us a little more value for the work that we put in already for the program.

Yes, makes sense. I guess in terms of next steps and looking beyond your current portfolio, what other viruses do you think might be very interesting targets?

So we have a program, which we haven't talked about today, ABI-7272, which is focused on transplant-related herpes viruses. The transplant space is one with more transplants happening and more immunosuppressed patients out there. These viruses are having kind of a lot of impact on those patients' outcomes. So how we address those is something that we're very interested in. So CMV being one that we think is very exciting and 7272 is a fantastic molecule that we think can be useful for that. And then beyond that, we're looking at what other or the implications on those patients for their outcomes and how can we address it. So we have a very active research group. We didn't stop research just because we were doing our development work. And so we're hoping to maybe announce even another candidate later on this year, but we're hard at work at finding out the next frontier.

Dr. Gaggar, sounds fascinating. Looking forward to the next steps. Thank you so much for joining us.

Thank you so much.