Okay, why don't we go ahead and get started? My name is Chris Raymond. I'm one of the senior biotech analysts here at Piper Sandler. It's my pleasure to introduce our next company, AlloVir. We have with us Diana Brainard, the CEO, and also in the audience is Vikas Sinha, who's the president and CFO of the company. So, just to go over the format, this is a fireside chat format. We have an informal, you know, Q&A format that we have here, but let's just try to keep this as informal as possible. If anybody has any questions in the audience, just raise your hand. I'll make sure it gets asked and answered. If you don't want to do that, just email me.
I'll be monitoring my email as we go through this, and I'll make sure anybody, if anybody has any questions, that we'll get those handled. So we have about 20 or so minutes of Q&A. But before we do that, maybe I'd like to ask Diana to sort of walk through the setup and the premise on the AlloVir story, and then we'll jump into Q&A.
Great. Thank you, Chris, and great to be here for another year. Let me give a quick overview of AlloVir. We are a late clinical stage, single and multi-virus specific T-cell therapy company, and our product are allogeneic, off-the-shelf, partially HLA-matched. We're a platform company. Our lead program, posoleucel, is in three phase III studies right now for both the treatment and prevention of devastating viral infections that affect immunocompromised patients. I'll stop there, and let's just jump in.
Great. So you've got a lot of things going on with posoleucel. I want to jump into the specifics of the trials and the development programs and the timelines and the sort of catalyst flow for next year. But maybe before we do that, let's just talk about the field. So donor-derived virus-specific T cells have been, you know, around a while. Docs have been utilizing this in various forms for years to treat viral infections. But, you know, that's been mostly in an academic setting. You guys are the only company in the space, you know, really targeting multiple viruses with one product.
Maybe just talk about the premise and the setup and why this makes sense to commercialize, you know, something that's been, you know, done sort of, yeah, I wouldn't say homebrew, but in sort of an academic setting, you know, with various different approaches over time.
Yeah. I think homebrew is pretty, pretty apt, actually.
Yeah.
So you're right. So the field of VSTs started with donor-derived VSTs, meaning that the transplant recipients, the donor who gave them the transplant, could be a source of T-cells if the patient became sick with one of these devastating viruses that can cause so much morbidity and mortality. The problem with that is that, number one, the donor's not always available. Number two, you have to make the cells, which can take two to four weeks in which time the patient can have numerous complications and even die. And number three, that expansion was not always successful. So one of the key scientific advances in the field that helps support AlloVir and what we do, is the recognition that you don't need to have a full HLA match to have effective and safe virus-specific T-cells.
This idea you can do third-party or partially HLA-matched, VSTs and still retain efficacy through the HLAs that are matched, it's partially HLA-matched, was really important without any, undue safety signals. And, and then the second piece, which, has also been demonstrated, at Baylor College of Medicine, from where we've, licensed our technology, is this idea that you can target multiple viruses with one target. And that's important for a number of reasons. Number one, because some of the viruses that we're going after are, very devastating, up to 50% mortality, but are rare. And so individually, it might be difficult to justify an entire development program for such a rare condition. On the other hand, when you start going after multiple different viruses, with the same therapy, that opens up a range of possibilities.
Also, it is not uncommon in the immunocompromised setting for patients to have one or more of these viruses at the same time. So by having a multi-virus product, you can treat multiple infections should they coexist, and you can even start thinking about preventing infections, which is something we're also very excited about. Finally, what I'll say is that the scalability piece is really important for us, and so that comes in when you talk about a product that's not gene edited, where we've developed a process to identify donors and have a patent-protected algorithm for identifying donors with HLA types that give us a broad and deep HLA representation with the smallest number of donors to really have a strong bank. We can get those cells to patients within 48-72 hours.
And you start to see something that can really have an impact globally for patients, beyond just small homebrew-type academic shops.
So you mentioned the scalability and the, you know, obviously there's the manufacturing side with Elevate and the, you know, the relationship you have there. But maybe talk a little bit more about the front end, the donor identification, donor recruitment, and that aspect of it. I think this... It's always been a question that's come up with investors-
Yeah.
how do you find all these donors?
Yeah.
-that are seropositive?... and keep them. And so just walk through that if you would.
Mm-hmm. Yeah. We use two different vendors for donor identification, and the viruses that posoleucel targets are adenovirus, BK virus, CMV, EBV, HHV-6, and JC virus. Even though many people have not heard of these viruses, they're ubiquitous and most commonly acquired in childhood, and in many cases are asymptomatic or associated with mild flu-like symptoms. They're DNA viruses, which are then latent in the body, controlled by our own immune system, and then only reactivate in the setting of immunocompromise. So when we look for donors, we screen patients or potential donors for immunity to these viruses, and it's not uncommon for people to have immunity across all of these viruses.
We'll test a potential donor to confirm that T-cell immunity, and if the donor has the immunity we're looking for, as well as doesn't have all the things you don't want, and there's a laundry list of things you have to test for from a regulatory standpoint, of course, would want to test for. Then we collect an apheresis product. So it's basically a very large blood draw, isolate the peripheral blood mononuclear cells, and then put those cells through a round, a single round of expansion with cytokines, as well as the overlapping peptides from two to three of the proteins for each target virus that confer the highest degree of protective immunity. On the back end of that approximate two-week expansion, you have a population of CD4 and CD8 cells that are virus-specific. They're polyclonal.
They're covering multiple epitopes across multiple HLAs. They're polyfunctional in terms of secreting interferon gamma, cytokines, perforin, granzyme, and they're primarily effector memory phenotype. We test for potency on that back end to confirm that we have expanded cells representing all of our target viruses, and then we can freeze those cells down and store them in the vapor phase of liquid nitrogen, and then ship them to patients in need within 48-72 hours.
Got it. Okay, thank you. And so maybe we'll just dive into the data and sort of your development plan to date. You've generated already impressive, you know, clearly proof of... at least in my view, proof of concept data in both prevention and the treatment settings. You know, sort of another question that kind of comes up is, you know, assuming success, you know, in both settings, how do you see those two indications sort of coexisting? Is it, is it, you know, sort of physician's choice? Is there a, you know, some other driver that you think would, you know, indicate or dictate maybe the uptake of one setting or the other?
Yeah. Yeah. So it is a good question that we consider a lot, and we've got three data sets in Phase II supporting both treatment and prevention, as you mentioned, and so feel like we're on solid footing for both of those paradigms. And there's precedent in the realm of virology for drugs that are used in both a treatment and prevention setting. This is not a novel concept. As long as you have potent enough activity and don't have trouble with resistance, which can be an issue for direct acting antivirals, we don't believe that's an issue. We haven't seen that as an issue for posoleucel and wouldn't anticipate it, because we're a polyclonal product, then you know, it's not unusual to be used for treatment and prevention.
But you're correct that the value proposition for these different approaches, treatment or prevention, is different. When you talk about treatment, you're talking about a smaller patient population overall and an acute unmet need with direct morbidity and mortality right in front of that patient and that physician. And you're talking about two doses, and so it's a little bit of a different equation than when you're talking about prevention, which is really a big picture. Let's look at a population of patients who are at extremely high risk for getting one or more of these viruses and having an event that then can derail the recovery process. And why wait for them to get sick? Let's get everybody on posoleucel who's high risk and then prevent the disease.
That's a dosing paradigm that is seven doses instead of two doses, and it's also demonstrating in a phase III trial, and then clinically, you're proving a negative. You're showing that something's not happening.
Mm-hmm.
Rather than showing someone's had something, and then you're making it better.
Right.
I think they require different approaches in terms of setting up access and payer structures, and we're working through how best to sequence those approaches to make sure we can have the best impact for patients overall.
Okay. And maybe just give us a top line, you know, I know you've already reported these data, but for investors who might not be as familiar, the top line, sort of, what you saw in the prevention and in the treatment setting-
Yeah. Great.
In phase II.
Yeah. So, I'll start with prevention. There we took 26 patients in an open label fashion, who were status post allogeneic stem cell transplant, high risk for developing infections, and we gave them seven doses of posoleucel over a 12-week period, so each dose separated by two weeks. And we followed them through the primary endpoint at week 14 to ask the question: If these patients are on posoleucel, can we prevent clinically significant infections across our six target viruses? And what we found at the end of that 14-week period was that there were only three infections in these 26 patients, leading to an infection rate of about 12%, which is very low and much lower than what we would expect to see if you look at the literature around how commonly these target viruses are occurring.
Within that literature, in the first 100 - 180 days across those different target viruses, you might expect to see somewhere around 70%-75% of patients developing an infection. So this is a very big difference in what we observed versus what we would have expected. At the same time, we also saw that in this first setting of giving multiple doses of posoleucel over a 12-week period, that the safety was very consistent with the safety in the treatment setting with two doses. Which is to say, we did not see significant infusion-related reactions. We did not see any CNS toxicity. We did not see suggestions of drug-related graft rejection or any increase in the severity or frequency of graft versus host disease beyond what would be expected in an allo-HCT population.
And so encouraging safety, encouraging efficacy, and we got the green light to move to Phase III, where we're essentially replicating the Phase II, but with a placebo control-
Mm-hmm.
And, on a much grander scale in terms of numbers and geographic scope, now doing something globally. So that's prevention.
Yep.
When I talk about treatment, we had two treatment studies in phase II. We've got one in allo-HCT patients, which was a single-arm study in 58 patients who had a treatment-resistant or refractory disease to any one of our six target viruses. And they were then eligible to receive posoleucel one or two or even up to three doses, and they were followed for a clinical response and a virologic response. And in that study, patients were designated as having a complete response if they had both a clinical and a complete resolution of their viremia, or a partial response if they had at least a 50% reduction in their viral load and a clinical improvement in their signs and symptoms.
We saw over a 95% response in aggregate across all of our different diseases, including importantly, among a significant subset of patients who had multiple viruses at the same time. So again, very encouraging data in a patient population that had no other options available to them. And that study really was what enabled our two treatment trials in specific indications, one for virus-associated hemorrhagic cystitis, which is double-blind, placebo-controlled, and then one for adenovirus infection, which is also double-blind, placebo-controlled. And I do want to also just mention the phase II data we have in kidney transplant patients, where we have not initiated a phase III trial, but we're really excited about this study because it's the first placebo-controlled data we have for posoleucel, and really actually, I think the first placebo-controlled study done with VSTs.
In that study, we dosed kidney transplant recipients who had reactivated BK virus, which is a dreaded complication of kidney transplant. BK virus resides in the uroepithelial tract, and therefore, in the setting of kidney transplant, can reactivate in the transplanted organ, which is a relatively immunoprivileged site because it's transplant, so it's, it's foreign, and it can't necessarily be recognized as easily by the host immune system, which is also immunosuppressed to prevent rejection. So it's a major cause of graft loss, and it has no approved therapies. So the only tool available for physicians is to reduce immunosuppression, but that can, of course, engender a risk of organ rejection, which, you know, in and of itself is a big problem.
Yep.
So we studied posoleucel, again, given over a three-month period, every two weeks or once every month in these kidney transplant recipients with BK viremia, and our results were very exciting. We saw, number one, that as compared to placebo, posoleucel recipients had a higher proportion of patients with at least a log viral load reduction, up to three times higher in the subgroup that benefited most, which was, importantly, the patients with the highest viral load to start, so the patients at higher risk for progression to significant disease. And in, we had two different dosing arms in that study of posoleucel. We saw a dose response. So the patients that received more frequent posoleucel had the highest responses.
So we found these results to be very encouraging in terms of suggesting that posoleucel can impact this condition, but also in terms of having this placebo-controlled data, it enabled us to look at some really interesting and exciting biomarker immunology work demonstrating mechanism of action and proof of concept there.
Excellent. That, that was great. So you're now chugging along with your pivotal programs, and second half of next year, as you've sort of outlined, is sort of the moment of truth. Maybe walk through the design, and, and set-up and, and how you intend to sort of communicate the data.
Yeah. So, I mentioned all of our trials are double-blind, placebo-controlled, and they're being conducted globally. And, the studies are all continuing to enroll right now. And, we will, once we complete enrollment of at least one of our trials, we will, provide further guidance, I would imagine, by the end of this year, or the early part of next year, on, how, we will read out in the second half of next year. We're on track for each of these studies to deliver data in the second half of next year. And because each of these studies is a standalone supporting, registration of an independent indication, we see them as really individual readouts and important, you know, sort of card turnovers, if you will, to support posoleucel approvals, and as such, we'll report them each separately.
Mm-hmm.
Of course, they'll all be presented at scientific meetings. But you can expect to see top-line results as they come in for each of the three trials, and the cadence will establish once we get a little bit further along, with the enrollment.
Okay. Let me ask you maybe sort of a question that maybe more pertains to the commercial opportunity. When I first started talking to you guys and looking at the story, you know, one of the things that sort of struck me as an interesting analogy was how matched related and unrelated donor transplants really inflected higher if you go back a decade, a decade and a half, with advances on managing GVHD. And this seemed to me to be something that could also, you know, sort of impact that. If you can, you know, address another major governor on the use of unrelated donor transplants, then you could potentially impact the market and grow it just by that innovation.
Yeah.
You've had some time with KOLs and talking to the docs far more than I've had the opportunity to do it. Is that still sort of, you know, out there as on the table? Is there any sort of nuance or detail to that, you know, you've learned over the last few years?
It's a really exciting part of our vision for what posoleucel can bring to patients and to transplant centers. So allogeneic stem cell transplant is growing annually at 3%-5% year-over-year growth. So the number of patients receiving allo transplant is increasing every year, and really, the limitation is the availability of a suitable donor. And that you spoke of opening up the potential for matched unrelated donors.
Mm-hmm
... is really unlocking a potential for the growth of allo transplants. And that is absolutely true, because it's sometimes hard to find a suitable related donor. Those matched unrelated donors bring an increased risk of graft versus host disease, which now can be managed more and more effectively, but generally, that's managed through more profound immunosuppression. And with more profound immunosuppression comes a higher risk of infection. Now, this is where posoleucel comes in. So if you have a drug that can effectively treat these complications, these viral complications that are heightened because of graft versus host disease, you then have a tool that can enable you to be as aggressive as you need to be to prevent one of the biggest complications of a matched unrelated donor transplant, which is graft versus host disease.
We do hear from physicians that there are patients along the margins, whether that's elderly patients, whether that's retransplant patients, whether that's patients with existing comorbidities, that still can find a center to transplant them, such as City of Hope, but where they're not considered great transplant candidates. This is where we think posoleucel could really help. If you could give people reassurance that this is not a complication they need to fear because there's a therapeutic option available-
Mm-hmm
... either as a preventative or as a treatment, then we do think we can boost that growth and make transplant available to a larger population of patients and, you know, and theoretically, move it out of only the highest risk transplant centers to even some of the medium and lower volume transplant centers may feel more comfortable doing these higher risk transplants, which would increase accessibility.
Okay, one last commercial question, if I may, and this is something I know comes up a lot when you talk to investors, and it's around the pharmacoeconomics. Obviously, you know, transplants are expensive. Allo transplants, in particular, are expensive, heavily, you know, involved processes and also relatively, you know, actively managed by managed care. And so this would, you know, imply another sort of level of expense. You're obviously providing the opportunity to avoid, you know, on the back end, a massive expense and massive complication. Just talk about the work you're doing, you know, pre-commercial, to sort of answer that pharmacoeconomic question and you know, sort of grease the skids as best you can with that payer equation.
Yeah, it is really important. And as you said, that work never stops, but it has already started, and some of it we've already published. So for example, in the treatment setting where the value proposition is very high for somebody who's already established disease, we know from claims analyses that we've done and published, that patients with hemorrhagic cystitis, as an example, even when controlling for graft-versus-host disease, which is a big driver of increased cost, if you have hemorrhagic cystitis, your claims for reimbursement are about $200,000 higher than if you don't have hemorrhagic cystitis. And that's largely driven by days in the hospital and days in the ICU.
So these are very expensive conditions, and having these data and getting these data out in the public domain is a really important goal of ours prior to launch and prior to payer discussions. And so we're doing that for adenovirus. And then when you get to the prevention setting, you know, it's a much larger population, and it's a slightly different equation. On the other hand, you actually get to look at all six of the viruses and say, cumulatively, there's a very high degree of cost associated with all six of these viruses. Now, any individual patient isn't necessarily going to get all six, but any individual patient is at risk for any one of these, and you don't know.
And if you can get the prevention on board, particularly if that payment can be spread out from the inpatient and the outpatient setting, which is something we're seeing in our studies, I think you have a pretty good recipe for having the transplant centers recognize the value that you're bringing to the table by taking these infections out of the equation for patients. And again, at the end of the day, clinical outcomes for patients will drive decisions because these centers rely on their outcomes to get center of excellence designations, and to negotiate contracts with commercial payers.
Okay, excellent. Great, we're out of time. A lot of moments of truth, I guess, coming up next, next year, so very exciting. Please join me in thanking Diana for that great, great talk.
Great.