Good afternoon, everyone. Thanks for joining us at the Morgan Stanley Global Healthcare conference. I'm Mike Ulz, one of the biotech analysts here. It's my pleasure to introduce Diana Brainard, CEO of AlloVir. Just a reminder, the format for today is a fireside chat. But before we get started, I just need to read a quick disclosure. "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." And with that, Diana, thanks for joining us, and maybe I'll just turn it over to you for a brief introductory comments, and then we can get in the Q&A.
Great. Sounds good. Thanks, Mike. Great to be here representing AlloVir, and just as a quick introduction, at AlloVir, we're a late clinical stage biotech company with a platform to develop virus-specific T-cell therapies for patients suffering or at risk for one or more viruses due to an immunocompromised state. Our cells are allogeneic, off-the-shelf, not gene-edited, which enables us to manufacture them in a streamlined and lower cost of goods path than what people typically think of for cell therapies. We're in phase III, and I'll look forward to answering more questions as we go along.
Yeah, maybe we can just start with, you know, giving your focus on viral infections, maybe talk about how those infections are treated today, and, and maybe in terms of your strategy, where do you see the opportunity in terms of the high-risk patient populations?
Yeah, absolutely. So where virus-specific T cells have traditionally been used is in the stem cell transplant setting. And that's a place where patients, in order to receive a new immune system from a new donor, typically have their own immune systems ablated. And so in the waiting period before that new immune system sets in to become effective, they're at extremely high risk for viral infections. And the viruses that we're targeting with our lead product, posoleucel, are viruses that are typically caught in childhood and lie dormant in the body and are controlled by our own immune systems and kept in check. But in the setting of stem cell transplantation, these viruses can reactivate and cause a lot of problems, and many of these conditions have no approved therapies.
Posoleucel targets adenovirus, no approved therapy. BK virus, no approved therapy. CMV, which does have treatments approved, though those treatments can be toxic and resistance can develop, as well as Epstein-Barr virus, no approved therapies, but rituximab is used off-label often to treat with varying degrees of success. And then HHV-6, human herpesvirus 6, which has no approved therapies, and finally, JC virus also has no approved therapies. So as you can tell, a lot of unmet need to target these individual viruses, and with our product, posoleucel, we target all of them. So that really creates a unique opportunity to address a wide swath of unmet need for these immunocompromised patients, again, initially in stem cell transplant, but also with a vision towards other types of immunocompromised individuals who also may be at risk.
Yeah, so you have broad coverage of several several viruses. Are there some that are more frequent in stem cell transplants versus organ transplants? What does that look like?
That's right. So, depending on the nature of the immunosuppression, that can change the risk. A stem cell transplant is a great example where there's a very high risk for a relatively short period of time, 3-6 months after transplant. Solid organ transplant is a different type of setting where immunosuppression is lifelong. And so while the intensity of the immunosuppression may not be as great, it's longer lasting. And these patients do suffer from viral infections, though the manifestations can be different. And for example, BK virus in kidney transplant patients replicates in the transplanted kidney. And so that's a very different clinical picture than when you see BK reactivate in a stem cell transplant patient, where you'll often see virus-associated hemorrhagic cystitis, which is really a disease in the bladder.
And many of the infections can look a little bit different in solid organ, but we believe that posoleucel can address all of the different clinical syndromes caused by these viruses.
Got it. Makes sense. Maybe you can talk a little bit more about your platform in terms of where the source of the cells, how you select those cells, how you expand the cells, et cetera.
Yeah, it's a great point because our manufacturing process is a similar approach, irrespective of the viruses we're targeting. So we can use posoleucel as an example, but it would really be the same, for example, for our respiratory virus product targeting four different respiratory viruses. We look for donors who have immunity to the target viruses in question. And so in the case of posoleucel, those are the six viruses I mentioned. Again, it's just these infections are very common and acquired in childhood, so many adults have immunity to all of these viruses. Because we're off the shelf and we're partially HLA-matched, we look to create a cell bank that has a diversity of HLA types that can cover over 95% of the population with the smallest number of donors.
And so we have a p roprietary computer algorithm that helps us select the HLA profile of the desired donors. We test them to make sure they have strong immunity to the viruses. We make sure they don't have the things we don't want, other types of infections, et cetera. And then we collect an apheresis product, and from that apheresis product, we expand the CD4 and CD8 cells, again, in a proprietary mix of cytokines and media to promote the development of virus-specific CD4 and CD8 effector memory and central memory T cells by expanding them in the presence of select overlapping viral peptides from immunodominant epitopes. And after a single round of expansion, what we have on the back end are cells that are polyclonal targeting each of our viruses.
We test and confirm that with a potency to each of our target viruses, and then we can freeze down those cells. And we can generate hundreds of vials from a single donor, so that enables us to then treat many, many patients from any given donor. And with about 10-15 donors, we can have the breadth of coverage as well as the depth of coverage and keep those cells stored in the vapor phase of liquid nitrogen, so that then when a patient is in need, we can get those cells to patients within 48-72 hours.
If we stick with posoleucel and stem cell transplants, specifically, maybe you can talk about the process a patient goes through to get a stem cell transplant, when, at what point your posoleucel gets sort of injected into them?
Yeah. So, typically, patients receive an allogeneic stem cell transplant for malignancies, often hematologic malignancies, leukemia, lymphoma being very common, but other hematologic conditions. They can have also primary immunodeficiency that's more common in children or other syndromes such as sickle cell disease. And in order to receive that graft, I mentioned they have to have their own immune system ablated, and that can be done usually with medications, sometimes radiation, to wipe out their own immune system so that it won't fight off the new graft coming in. They receive that stem cell graft and start engrafting, meaning those new cells start living in the bone marrow and sort of producing white blood cells, red blood cells, platelets, after about 2-3 weeks.
And at that point, that is when we would use posoleucel in the preventative setting to cover patients during the risk, the high-risk window period. Otherwise, if you use posoleucel for treatment, the patients remain at very high risk for infections in the first 90-180 days post-transplant. And so physicians are often monitoring them for viral reactivation and for signs and symptoms, and would use posoleucel when the patient starts to get sick or starts to have a very high, rapidly rising viral load.
So prevention sort of upfront before they hit that window, and then treatment when you start to see a rise in-
When patients start to get sick, yeah. And they're really two different philosophies, but the patient population is highly overlapping.
Maybe we can just focus on some of the, maybe the phase II prevention data. You know, you've shared some of that data. Maybe walk us through that and some of the key endpoints there.
Yeah, absolutely. So, we have data from three phase II trials, and focusing on the phase II prevention data, that was an open-label, single-arm study where we dosed 26 patients post allogeneic stem cell transplant with posoleucel, and gave them 7 doses of posoleucel, separated by 2 weeks, so dosing interval over a 12-week period. And what we looked for was signs or symptoms of clinically significant infection to any one of our target viruses, over to the primary endpoint at week 14. And we had expected to see anywhere between 50%-70% of patients developing a clinically significant infection based on what the literature tells us about how commonly these infections occur. What we saw was quite encouraging. Only 3 of the 26 patients developed clinically significant infection.
Two patients developed CMV, one patient developed an adenoviral infection. So this rate of about 12% was substantially lower than we would have predicted. And based on the strength of these data, as well as the compelling safety data demonstrating we saw no suggestion of cytokine release syndrome, which to date hasn't been an issue with VSTs. With the recurrent dosing, we didn't see any suggestion that there were worrisome rates of graft-versus-host disease. Again, rates of graft-versus-host disease with VSTs have not been a concern to date, but it's something we're always looking very carefully at.
So these 26 patients and that preliminary data enabled us to move directly to a phase III trial, which in many regards is similar to the phase II, but it importantly has the addition of a placebo control, as well as an expansion to 300 patients, and we're currently enrolling that trial, globally.
Can you maybe talk about what the reaction was to the phase II data, given the sort of dramatic impact it's-
Yeah. I mean, I think there's a lot of excitement seeing those data and recognizing that where the concept of virus-specific T cells has been really entrenched has been when patients get sick, physicians reaching for those cells where they're available at specific academic centers, where they might make their own virus-specific T cells, or even in some instances, transferring patients from a center without VSTs to a center with VSTs to enable access. But this idea of moving upstream and preventing infections created a lot of excitement because it enables physicians to avoid the adverse consequences of these infections that can derail patients.
There's been a lot of thought that once patients have infections, they have higher rates of graft-versus-host disease and other comorbidities that develop from either directly the virus or from the approved or experimental drugs used to address that virus.
Can you just talk about if a patient got a stem cell transplant, and they started to develop a viral infection, how long does it take to figure out what virus it is and how to treat it? You know, is it just by that time, is it way too late, or?
Yeah. Well, it can. It depends on the virus. And, you know, many of these patients are followed quite closely in the months following stem cell transplant. So they, they're generally, you know, coming into the clinic once or twice a week initially, and then every week, and then once they get past the three-month mark, it may be less frequent. But what can be difficult is that these patients have a range of symptoms and issues they're confronting.
And so, you know, that's been the attractiveness of a preventative approach, is that if you can take that risk off the table, you can allow the physician to focus on other potential complications, such as graft-versus-host disease, such as recurrence of malignancy, and potentially, you know, improve the overall care for the patient.
Gotcha. That 12%, clinically significant infections, can you just put that into the context of, you know, an antiviral in this sort of setting? Would you expect it to be in the same range or not quite?
Yeah. Well, I think that, in terms of what's available for patients right now, there, there is one drug approved for prevention of our target viral infections, and that's letermovir for CMV. And what letermovir was able to show, in high-risk patients was that it can reduce the clinically significant infections for CMV by about 40%. And that's, that's meaningful. And in high-risk adult patients, letermovir, at least in the U.S., is, is having considerable uptake because of that difference. But, it doesn't reduce the rate of infection to zero. It reduces the infection rate from, you know, above 50% to below 50%, and the exact numbers depend on the risk stratification of the patient, and it's only CMV.
And so for us, what's exciting to us about posoleucel is the idea of being able to treat infections, but also at the same time, having the ability to prevent these infections, which have no treatments and have no prevention as well.
Yep, makes sense. Clearly an advantage there. And in terms of, you know, assuming you have some positive data and, you're moving, you know, to, to approval, is this gonna be challenging to get physicians to adopt it? It seems like there's some excitement that, you know, you can treat them upfront and prevent it and worry about other issues these patients are having.
Yeah. I mean, I think that there's, there's always challenges bringing something new to the market. At the same time, we've tried to address some of that potential resistance by really casting a broad net with our clinical trials and the participating investigators. The stem cell transplant universe, in terms of centers conducting high-risk allotransplants, is highly concentrated in the U.S. and Europe. And so we're able to touch nearly all of those centers with our ongoing trials and give them firsthand experience with posoleucel, either through treatment or prevention, which we think will really, considerably accelerate the enthusiasm and uptake. And, you know, we also recognize that there's groundwork that needs to happen, to make sure that access is in place at the time of approval.
We hired a Chief Commercial Officer in June, Cintia Piccina, who's got a lot of cell therapy experience, both at large companies such as Novartis, as well as smaller companies, such as Bluebird, and really brings a lot of historical perspective on what it takes to go center by center to secure access to a life-saving cell therapy.
Makes sense. Can we just go back to the phase III posoleucel prevention study, and when do you expect to have data from that study? And remind us of the key endpoint. Is there any comments you can make around powering or expectations, things like that?
Yeah. I'm just gonna have a sip of water here. So all three of our phase three trials are continuing to enroll, and what we've communicated is that we are on track, and consistently have stayed on track to have data in the second half of next year. And we anticipate that once we get to a place where our first study completes enrollment, we'll most likely announce that and then have more clarity on the cascading trials and timelines. But suffice it to say that we will have readouts for all three studies in the second half of next year, and then look to, you know, what makes the most sense from a regulatory standpoint in terms of sequencing of regulatory filings and launches.
Of course, a lot of that will be data-driven as well. The primary endpoint for the prevention trial is around the number of clinically significant infections in the posoleucel patients as compared to the placebo patients. What we're looking to do is, you know, match the efficacy that was seen in letermovir, but do that across all of these different viruses, including CMV, where letermovir use is allowed. Because we think there's still room to improve, and not all patients are eligible for letermovir, such as pediatric patients and there are regions of the world and centers where it's not used. So looking to see a 50% reduction in clinically significant infections across the board is how we've powered this trial.
Got it. Can you just talk about the market opportunity in prevention versus treatment, maybe addressable patients, and just how to think about that?
Yeah. So, in terms of how to think about the market opportunities, I mean, it is fair to think about treatment and prevention somewhat separately, and they're both compelling opportunities. When you... Let's start with prevention. You've got a large population that could potentially benefit high-risk allogeneic stem cell transplant patients. And this is a growing segment of stem cell transplantation with about 3%-5% growth per year. And that's globally as well. And so you know, there are about, we estimate about 40,000 potential eligible patients for posoleucel in that setting. But of course, because you're going for prevention to prevent something that doesn't exist, that's not as maybe higher price point if you go after treatment. And so then the question is, what does treatment look like?
Treatment is compelling. It's a smaller patient population. We're talking about for hemorrhagic cystitis. We estimate between 10% and 15% of high-risk allos will develop hemorrhagic cystitis, severe enough to merit treatment with posoleucel, should our data be successful. In adenovirus, it nets out much more common in pediatrics than adults. Overall, it nets out to, again, around maybe 10% of stem cell transplant patients having adenovirus requiring adenovirus treatment. But there, again, it's a slightly different value proposition, particularly for adenovirus, very high mortality. So the pricing structure is a little bit different. Even though the patient numbers are smaller, the cost of goods is a little bit lower because you're doing 2 doses instead of 7.
So we really feel like we're positioned for success in both arenas and can be data-driven in terms of how we approach this, and also, you know, use this time as we're waiting for data readouts to really make sure we're doing our homework to set ourselves up for commercial success.
It makes sense. Maybe we can just shift to solid organ transplant. You had some data, I think it was last year now, if I remember.
Earlier this year.
Earlier this year. There you go. Maybe just talk about some key takeaways from that data set and, and maybe next steps or how you're thinking about next steps for that program.
Yeah. So but you, you're actually right. We presented in 2022, blinded data from our phase II study, and then this year, in February, press released our top line unblinded data from that phase II trial, and then had a scientific presentation in June at the podium to go into more depth. And in that trial, which we looked at posoleucel in kidney transplant recipients with BK viremia, and we were looking at two different dosing regimens, as well as a heterogeneous mix of patients with high levels of viral load and low levels of viral load. And what we saw was really consistent across the trial, differentiation from placebo-receiving patients versus posoleucel-receiving patients in terms of the numbers of patients with one log or more decline in viral load.
We saw that effect most strong in the patients who started the trial with a higher viral load. That's relevant because those patients are at the highest risk for progression to really substantive kidney disease and subsequent kidney dysfunction and ultimately higher rates of graft loss. So targeting these higher-risk patients makes sense. The other thing that we noticed was that in the two different dosing intervals, the patients who received posoleucel every other week versus once a month had higher responses. Again, a dose response there that aligns very nicely with how we're dosing in prevention in terms of every other week.
So again, we think the path forward for this disease that has no approved therapies and where there's just an enormous unmet need that we hear from physicians, but also saw in terms of the pace of enrollment of that study, is to go after the high viral load patients with this every other week dosing regimen. Over the course of the fall, we plan to pull in regulatory feedback, as we've done for our other three phase III first to market indications, working with regulators to establish what is that path to get to a registrational study? What does that look like? How can we work together to make that happen?
And you're, I know you haven't had conversations with, but do you think that's highly likely that you'll be able to figure out what the path forward is here and have some agreement? Or is there any area where you're particularly, I don't know, worried where the FDA might focus on or?
Well, I mean, I think that we have, we have a good batting average, in terms of, having successfully done this, with our other trials. You know, it's always a challenge when you're in a new area, and I think that, I have confidence we can get there. Sometimes it takes more than one conversation. That's fine. We can do that. We're committed to the, to these patients, and we also, I think, have a little bit more luxury because posoleucel is already in phase III for these stem cell transplant indications. We don't want patients to have to wait.
At the same time, we do think that demonstrating safety and efficacy with the drug in other clinical settings may help us in terms of allowing people to see a greater potential benefit for patients in other settings.
Yep. Got you. Maybe you want to just touch real quickly on some of your other pipeline assets.
Mm-hmm.
Or like, 106 or 107.
Yeah. So, as we head into respiratory virus season, it's a good time to talk about 106, which targets influenza, parainfluenza, human metapneumovirus, and RSV. And these are the four other... Outside of, not including COVID, these are the four respiratory viral infections that cause the greatest degree of morbidity and even mortality in immunocompromised patients. And, oftentimes, they'll even occur together at the same time in the most vulnerable patients. And no therapies approved except for influenza, in terms of treatment, and even there, the treatment tends to be more geared towards outpatient reduction of symptoms in otherwise healthy patients.
So really, a strong unmet need, and we are in the phase I-B/II-A trial with this study with this program, and completed the dose escalation component of the trial in patients. We were going into both stem cell and solid organ transplant patients for this trial, and we are hoping to present the results from that phase I-B dose escalation at the end of this year at a scientific meeting. Again, the focus will be safety, showing that you can give a cell therapy product to patients with upper respiratory viral infections, and you can do that safely without any concerns for exacerbation of the clinical course, and that these data will enable us to move into phase II-A portion, which would be more of looking for an efficacy signal to guide registration.
Okay. Maybe in the last minute, we can just talk about current cash position, your runway, and what sort of readouts does that get you through? Is that the full three phase III trials? Will we have the readouts for all those?
Yeah, we did, we did raise some money this summer with the intent of having cash to get us past our phase III readouts, and so our cash gets us into 2025. So we're well positioned to have our phase III readouts before running out of money, which, of course, is important. We're continuing to be very careful with our expenditures and anticipate really putting our resources into completing the phase III trials, getting those readouts, doing the activities necessary to have a successful BLA and then a successful launch. And, of course, that effort in particular would be augmented once we have positive data in hand.
Okay, great. Why don't we end it there, and thanks so much, Diana. I appreciate your time.
Thank you, Mike.