Good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz , one of the Biotech Analysts here, and it's my pleasure to introduce Diana Brainard, CEO of AlloVir. Before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, we can dive right into Q&A. Diana, thanks for being here. We really appreciate it. Maybe to start, if you could just give us an overview of the platform, maybe for people who aren't familiar with it.
Yeah, I'd be happy to. Thanks, Mike. It's good to be here. AlloVir, we are a Platform company, and we have Allogeneic, off-the-shelf, multi-virus specific T-cell therapies for immunocompromised patients. We have our lead program in phase III right now.
Maybe you can talk about your initial focus is sort of applying your platform to stem cell transplant. Maybe, you know, walk us through, you know, where the opportunity is there in terms of, you know, how the patients progress after they get a transplant and what the risk is to viral infections.
Yeah, absolutely. With posoleucel, we're targeting viruses that are ubiquitous and in somebody with a normal immune system would generally not cause disease or problems. In patients such as stem cell transplants or solid organ transplant recipients, they don't have the immune system to keep these viruses in check. As they go through the transplant procedure and receive immunosuppression, viral reactivation and then the consequences of that viral reactivation turning into viral disease can really derail their recovery process and lead to complications such as prolonged hospitalization, worsening graft-versus-host disease, even organ failure or death. What we're doing with T-cells is replacing the immune deficit that they have, replacing those T-cells that they lack to enable them to control the infection.
This is an approach, virus-specific T-cell therapy, that's been around for a couple of decades, but has always been limited to small academic centers. We've really, through advances in the technology, that we in-licensed from Baylor, have been able to turn that scientific principle into a scalable platform.
Yep. Maybe you can just talk about some of the viruses you can target and you know the advantages of maybe targeting more broadly.
Yeah, sure. With posoleucel, we're targeting six different viruses: adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, HHV6 virus, and JC virus. Some of those, many people have heard of, some of them, maybe are less well known. What they all have in common is that, these are the six most commonly reactivated viruses in this post-transplant period for patients. We can, by having a single product that targets all of them, develop a therapy that can be used broadly, and many of these diseases actually have no currently approved treatments. We can also then take a preventative approach, where instead of waiting for people to get sick from these diseases, after the virus reactivates, you just can cover patients through their high-risk period and prevent them from ever getting these adverse consequences to begin with.
This is a reasonable approach because we know from epidemiology that about 90% of Allo stem cell transplant patients will reactivate at least one of these viruses in the first 100 days after transplant, and nearly two-thirds will reactivate two or more viruses. You never know which one. Having a multi-virus specific product really can help address that uncertainty as well as the unmet need.
Just in terms of like complications of a viral infection, are there certain viruses among those six that are more problematic than others?
I'd say the most common are CMV for sure, which can really affect any organ and lead to substantial morbidity and also BK virus. BK virus is most commonly in stem cell transplant patients associated with hemorrhagic cystitis. It's got no approved therapies, is very difficult for patients in terms of terrible pain and symptoms, but very difficult to also treat medically because of profound bleeding, damage to kidney function. Again, like I was saying, there's no care except for supportive care such as IV therapy and bladder irrigation.
When we had our phase II data, which I know we'll get to, and targeting these 6 viruses, and we're then thinking about next steps, BK virus came out as very much at the top of the list in terms of what transplanters were looking for in terms of getting something into their toolkit that they could use for their highest unmet needs.
Great. Maybe we can just keep talking about sort of what you learned in the phase II CHARM study, which you were sort of referring to there, and maybe high-level takeaways.
The CHARM study was a phase II treatment study. It was done at Baylor College of Medicine, and took patients who had refractory or relapsed viral infections, viral diseases that had failed other treatments or, for whom they were intolerant to the available therapies. They received posoleucel, and then were followed for up to 12 months for safety and efficacy. What this study showed, firstly with regard to safety, is that the cells were very well tolerated, with no cytokine release syndrome. These are non-engineered cells, so they're not associated with some of the adverse events commonly associated with CAR- T therapy. Also rates of graft-versus-host disease were low and consistent with what you'd expect as a background rate in this population.
When it came to efficacy, again, these were the patients who had failed all other prior therapies, and the response rate was over 90%, across all 6 viruses. Importantly, among the subset of patients who had multiple viral infections, that response rate was 100%. Very compelling data, and really enabled us to then take the next step looking into getting into phase III registrational trials for treatment.
Yeah. You're currently in 3 different phase III trials. I thought maybe we could just, you know, walk through each. You know, the most advanced, I believe, is your hemorrhagic cystitis study. Maybe you can give us an update on where you are there.
Yeah. Great. That's a good place to start. As I mentioned before, hemorrhagic cystitis trial is the first phase III that we initiated based on the feedback we'd received from the transplant community. Hemorrhagic cystitis in this setting is mostly caused by BK virus, but also adenovirus can be causative. These patients have generally, again, profound pain. They've got blood in their urine from the inflammation and the reactivation of the virus in the urogenital tract. What we're looking at in terms of that study, it's double-blind, placebo-controlled randomized trial. It's actively enrolling 125 patients across North America, Europe and Asia. The primary endpoint is time to resolution of macroscopic hematuria or essentially blood clots in the urine.
That's a clinically relevant endpoint that correlates with generally symptomatic improvement and ability to leave the hospital and be off of supportive care. It's an important clinical endpoint and also corresponds to really positive data that we had from our phase II trial versus the natural history data that's out there.
When should we expect, you know, maybe data from that? Or when's the next update there?
We're on track to complete enrollment of that study in the first half of next year. There's a 6-month follow-up, then that would put us into having data towards the end of the year or into early 2024.
Gotcha. Maybe we can switch to the second phase III study. That's the treatment of adenovirus and stem cell transplants. Maybe just give us a, you know-
Yeah
Brief view of the prior data and
Yeah. Adenovirus is an infection that most people acquire in childhood. In pediatric populations, stem cell transplant recipients, it can really be very devastating with about 35% of pediatric stem cell transplant patients developing reactivation of adenovirus with high rates of morbidity and mortality affecting organs like the liver and the lung and the GI tract. Again, no approved therapies for this virus at all. Some people use off-label cidofovir, even though their supportive data don't exist just because there are no other options. There is a strong pull from the pediatric community to get this study started, and we initiated it last year. Again, it's also a double-blind, placebo-controlled trial in 80 patients, where it's open to both children and adults, though we anticipate probably the majority of patients will be children.
Importantly there, we've got a virologic primary endpoint, and that's relevant because it enables us to have a rescue treatment incorporated after the primary endpoint. That's really highly relevant for parents who would be consenting their children and to enter the trial. We're looking at the proportion of patients in the active versus the placebo arm who are virologically negative at day 28. Again, that study opened up at the very end of last year and is enrolling in the U.S. and Europe right now.
When might we see data?
Yeah, sure. That's a great, obvious next question. We're hoping to get that study completely enrolled next year. In terms of getting a little more clarity on that, we'll probably be able to give better timelines in the early part of next year in terms of when in 2023 it'll complete.
Yep. Makes sense. Maybe moving to your third phase III study, which is ongoing now. It's multi-virus prevention and stem cell transplants, but maybe you could just talk a little bit about the phase II data. You shared some data, I think, end of last year, if I remember. But maybe just walk us through that data and maybe put it in the context of, you know, what's a meaningful effect there.
Yeah. The taking the preventative approach is always the holy grail, right? Why wait for people to develop disease, develop organ damage, have the symptoms, get the complications, and then try to backtrack? If your therapy is safe and well-tolerated, then it makes sense to move up earlier in the disease and even take a preventative or prophylactic approach. That's exactly what we heard from physicians with posoleucel, because it is a multi-virus product, that it's really ideally suited for prevention in this high-risk window post-stem cell transplant. From the great treatment data we had supporting the safety and the treatment efficacy, we then conducted a phase II prevention study, which you were just talking about. We enrolled in an open-label fashion 26 patients who were treated from about 2 weeks post-transplant.
They could enroll anytime from about 2 weeks to 8 weeks post-transplant. They received 7 doses separated by 2 weeks over this post-transplant period and were followed for the development of clinically significant infection across all six of our target viruses with viral load measurements on a weekly basis through that primary endpoint, and then further follow-up out for 6 months. We presented a first data cut at ASH last year, and we were really excited by the data because first and foremost, we demonstrated that repeat dosing of posoleucel over the course of 7 doses was very consistent with the treatment algorithm, which is 2 doses. Generally well-tolerated, no observable increase in severity or rates of graft-versus-host disease. If anything, a numeric reduction, which we can talk about.
No new safety signals emerging with this prolonged dosing period covering this high-risk window. Then on the efficacy side, we had come up with a benchmark of about 70% would have been the expected rate across these six different viruses for what we might have seen should we just follow the natural history. What we landed was in the first through the first 14 weeks, we had three out of 26 patients developing clinically significant infections. A really strong reduction in the number we anticipated would have developed clinically significant infection. This data set back in December was what enabled us to have the regulatory discussions to lay out the design for a single phase III double-blind placebo-controlled registrational trial taking this preventative approach.
We started that study at the end of March of this year. Really excited to have that going. Feel like this is truly the way to improve outcomes across the broadest high-risk Allo transplant population in terms of really reducing morbidity and mortality from these viruses.
Yeah. You mentioned sort of the benchmark of 70% on efficacy, and you were clearly way below that.
Mm-hmm.
You know, as we think about the next readout, if that number sort of increases, like at what point, you know, would you think it's like or what's the bar for meaningfulness?
Yeah.
Relative to that 70% ?
Yeah. It is a really good question in terms of what do people care about. We spend a lot of time because this is a new approach and a new way of thinking about preventing multiple viruses, what this could look like. The message we received is that, you know, if you can do for all six of these viruses, what letermovir has done for CMV, which has reduced the rates of infection by about 50%, then that's a home run. That's where we've set up our trial to be well-powered, even under more conservative assumptions than the efficacy we saw for ourselves in phase II and the 70% triangulation we had to be able to see at least a twofold reduction in the rates of clinically significant infection with posoleucel as compared to standard of care/placebo.
Again, that feels like it will be highly clinically meaningful. I would also say at the same time, we've really made the efforts to create the pharmacoeconomic arguments and evidence for why this would be a good investment for patients as well, recognizing that's always important to do in parallel.
Yeah. Makes sense. You mentioned GVHD, and you seem to be seeing a lower rate than you might expect. You know, any thoughts as to why that is?
Yeah. I mean, our study was certainly not powered around looking at a difference in GVHD, but it is interesting the relationship between graft-versus-host disease, one of the worst complications of stem cell transplant, and viral infections, also dreaded complications. There's an interplay there with graft-versus-host disease being a risk factor for viral reactivation, but also patients with viral reactivation generally having higher rates of graft-versus-host disease. This is thought to be related to the pro-inflammatory cytokine milieu that's created under either scenario that then becomes enabling for the worsening of the other condition. Therefore, it's a hypothesis, it's tantalizing that by reducing the rates of clinically significant viral infections, we can also improve the rates and even potentially severity of graft-versus-host disease.
In the phase III study with a much larger population and a placebo control arm, we really should be able to tease that out. It's something that has been demonstrated in the setting of other antivirals. There is precedent for potential optimism on that front.
Interesting. The phase II study, I think you're gonna give an update in the second half of this year. Can you maybe just talk about what the key endpoints are, what we should focus on and how we should think about those?
Yeah. As I mentioned, the study had enrolled 26 patients and they were treated over a dosing period of around 14 weeks and then followed for a total of 6 months. At ASH last year, we presented all of the data we had in hand, which was about 11 patients through the primary endpoint and safety data on a slightly higher number. We updated that dataset at the European Bone Marrow Transplantation meeting. What we look to do at the end of this year is present the complete dataset on all 26 patients through the end of follow-up. I wouldn't anticipate any surprises with that data.
I think directionally it's gonna be very consistent, but it will be nice to show, you know, everyone through the follow-up, the full safety, the full efficacy, and also some of the more interesting biomarker data around, how common we're seeing viral reactivation across multiple viruses, what kind of T-cell expansion we're seeing, to the different viruses and, as measured by ELISpot, and also persistence data, how long we can detect our T-cells in patients with and without viral reactivation over the course of the study. You know, more to come on that front.
Yep. Maybe just with the phase III study that you've mentioned you already started and just thinking about that in terms of any differences or notable differences from the phase II that could, you know, lead to a different outcome?
I think in large part we're doing things very similarly. The dose, the dosing interval, the duration of follow-up, the timing of the primary endpoint are all the same. We did broaden the enrollment criteria to allow matched-unrelated donor Allo patients into the phase III, and that was based on one, the request of the physicians participating in the phase II that we allow those patients to come into the trial because of their high risk for viral reactivation. After hearing that repeatedly, going back to the literature, really trying to drill down into those matched-unrelated donors and recognizing that their risk is also quite high for viral reactivation, infection, and subsequent disease. They've been added to our population, and that's important because they represent about 40% of all Allos.
That brings our inclusion criteria to encompass approximately 85% of all Allos right now, and so is a very broad and highly relevant population for the transplant stem cell transplanters.
Got it. Maybe we can just shift gears now to solid organ transplant and maybe to start just, you know, talk about, you know, the risk of viral infection there, and then sort of how that's managed today and why that's a big problem?
Yeah. I mean, solid organ transplant is also an area of really high unmet need for viral infections and a place where chronic immunosuppression is needed to maintain graft survival, but also comes at the cost of getting these infectious complications, which are well-recognized. How that looks in solid organ transplant recipients is a little different from stem cell transplant patients, because the immunosuppression is different. There are some similarities there. The same viruses tend in general to cause similar problems like CMV is a problem. BK virus is a big problem in kidney transplant patients, though it manifests as nephropathy rather than hemorrhagic cystitis. We can talk about that in our study in a second. Epstein-Barr virus can be a big problem, adenovirus as well, and rarely JC and HHV6.
There is a need for additional, you know, therapeutic options for these patients. For that reason, we've been really excited about getting into the solid organ transplant population. What I will say is that these physicians have less experience with cell therapy than the stem cell transplant physicians who are used to using CAR- T and thinking about cell therapy as a modality. It's our first task at hand in this group of patients is to demonstrate safety and help people understand the safety profile of our cells being administered and the safety with respect to the transplanted organ, which is their primary concern.
Yes. Earlier this year you showed some blinded look at a dataset in phase II BKV study. Maybe you can just, you know, talk about key takeaways there so far.
Yeah. We, our first study in the solid organ transplant patients, we decided to go into kidney transplant patients with BK virus reactivation. That's because BK virus-associated nephropathy is one of the worst complications of renal transplant. It leads to accelerated graft loss. No approved therapies for this condition. The only approach that these transplant nephrologists have is to reduce immunosuppression to help the patient's immune system control the virus. The problem with that is as that immune system starts to rev up to control the virus, it can also lead to increased rates of graft rejection. That's highly problematic, and they wind up in a really negative push-pull situation for these patients. Very high unmet need. No approved treatment options. In this study, we are looking at a couple of things.
One is looking at two different dosing intervals because this is a different population than stem cell transplants. Looking at every other week versus monthly administration after three consecutive weekly doses. Also looking at specific safety issues relative to the transplant, incidents of HLA antibodies, incidents of graft rejection, and then the usual other things, cytokine release syndrome, graft-versus-host disease, et cetera. We had the study enrolled faster than expected. Initially we planned to do an interim analysis, but because we were able to get to the other side of enrolling the trial, we just presented the blinded safety at the American Transplant Congress in June. The aggregate safety data is very encouraging.
None of these very worrisome events cropped up at all across any of the treatment arms. Encouraging safety data for repeat administration of posoleucel. We showed blinded viral load data. There's really no take-home you can leave with looking at blinded virologic data except to say, "Okay, there's a median trend of decreasing viral load that's consistent with the potential for an effect.
Yeah.
We'll see that unblinded safety and efficacy in the first quarter of next year.
Just how should we think about that unblinded efficacy? You know, is separation the key? How much separation do we need? Is there a threshold that you're looking for, a bar like?
Yeah, I mean, you know, it's a really good question, and it's one that we wrestle with because very little is understood about this condition and even this virus in terms of what's the connection between viral load and disease severity, and how much of a surrogate is viral load. I think there's a general appreciation that you don't get BK virus nephropathy without high levels of viral load, but no one's ever clearly demonstrated that by reducing viral load, you can reverse clinical outcomes, which is ultimately what you're trying to do. I think that our data with 61 patients will be one of the largest datasets ever made available in this disease. It's gonna be very informative, not just for us, but also for the field in general.
Because we enroll the heterogeneous population of patients with high viral load as well as lower viral load patients within a year of transplant, but also some patients one to three years post-transplant, we really should be able to tease out differences between active and placebo across these different groups, which will help inform next steps for not just BK virus nephropathy, which is really important, but also the broader solid organ transplant population.
Just beyond viral load reductions, any other sort of key endpoints to keep an eye on that might give us insights into the?
Yeah. I mean, I think ultimately what we're trying to do is get the virus in check so that the graft is not damaged, and you don't have that accelerated graft loss. Now, graft loss takes years to happen. You're not gonna see that in a six-month trial. It's possible. We'll certainly be looking at renal function, and it's possible in the highest viral load patients that we might be able to tease out a signal between, you know, posoleucel treated and placebo recipients if there were an effect. But we'll have to wait and see. It's hard to know because, again, we can't say, "Oh, treatment X does this, and we're gonna aspire to be the same or better." That there is no treatment X.
Yeah. Well, we're looking forward to the data and looks like we're just about out of time, so why don't we end it there?