Welcome to AlloVir's virtual investor event to discuss the opportunity for posoleucel in multi-virus prevention. I'm Sonia Choi, AlloVir's Senior Vice President of Corporate Affairs and Investor Relations, and your host for today's call. During the call, AlloVir's Chief Executive Officer, Dr. Diana Brainard, will provide a clinical overview. After which Dr. Sanjeet Dadwal, Chief of Infectious Diseases and Professor of Medicine at City of Hope, will walk us through the final data from a phase II multi-virus prevention study of the investigational virus specific T-cell therapy posoleucel. These data were presented at the American Society of Hematology annual meeting over the weekend. Following Dr. Dadwal's presentation, Dr. Brainard will host a fireside chat with both Dr. Dadwal and Dr. Joseph McGuirk, a hematologist, oncologist, and transplant specialist at University of Kansas Medical Center.
During the fireside chat, we will discuss the unmet need and prevention approach for posoleucel in allogeneic hematopoietic stem cell transplant patients. After the fireside chat, we will open the call for Q&A. Vikas Sinha, AlloVir's Chief Financial Officer, will join our presenters and will be available for questions. If you'd like to ask a question, please use the text box below the presentation slides on your screen. Before I turn the call over to Dr. Diana Brainard, I'd like to point out that we will be making forward-looking statements on this call, which are based on our current expectations and beliefs. These statements are subject to risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in AlloVir's SEC filings for additional detail. It's now my pleasure to turn the call over to AlloVir's CEO, Dr. Diana Brainard.
Thank you, Sonia. Good afternoon, everyone. Thank you for joining us. I'm thrilled to talk to you today as both the CEO of AlloVir and as an infectious diseases physician. AlloVir is a leader in the development of allogeneic off-the-shelf virus-specific T-cells or VSTs. AlloVir's VSTs are designed to address a critical unmet need to prevent or treat life-threatening viral infections and disease in immunocompromised patients. Transplantation, immunomodulation, chemotherapy, and even the extremes of age can all create vulnerability to viral infections that wouldn't necessarily pose a problem for someone with a competent immune system. Most of these viruses have no approved or effective therapies. Cumulatively, they have a devastating impact on patient outcomes, from prolonged hospitalization to end organ damage to death.
At AlloVir, we develop investigational therapies that restore the T-cell deficit that is leading to disease in the first place, we target multiple viruses simultaneously to enable both treatment and prevention in high-risk patient populations. The lead clinical candidate in our portfolio, posoleucel, targets six viruses that commonly cause disease post-transplant. They include adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and JC virus. Posoleucel is derived from healthy donors that are identified to be seropositive for each of our target viruses. We use a proprietary algorithm to select donors that give us breadth and depth of HLA coverage for at least 95% of our target patient population. Once we receive an apheresis product from a donor, the peripheral blood mononuclear cells are exposed to viral antigens and a proprietary cytokine cocktail. Over an approximately 14-day period, virus-specific T cells are selectively expanded.
After potency to our target viruses is confirmed, this mixture of virus-specific CD4 and CD8 T-cells is then cryopreserved, stored, and can be available for administration to a patient within about 48 hours of a request coming in to AlloVir. posoleucel is designed to provide an immunologic bridge for immunocompromised patients between the time of immunosuppression and the restoration of the patient's own immune system. Patients undergoing allotransplant receive a conditioning regimen prior to their transplant, which results in the elimination of their own immune system, shown schematically on this graph as the declining black line on the left. This conditioning enables the donor transplant to successfully engraft in the future, but it also leaves recipients in a severely immunocompromised state. The first 100-180 days post-transplant are a particularly vulnerable time.
This is the time period when the patient's own immune system has been ablated and the new immune system is not yet reconstituted. It's in this window of time when reactivation of one or more viruses most commonly occurs. For 90% of allo-HCT patients, their suppressed immune system allows viruses that were previously in a latent state to reactivate. More than 60% of HCT patients experience reactivation of more than one potentially fatal virus. As shown with the red line here representing viral load, reactivation of these viral infections can be associated with substantial morbidity as well as a documented increased risk of non-relapse mortality that rises with the number of viruses that have reactivated.
The progression of viral reactivation to clinically significant infection, including end organ disease, occurs in approximately 70% of high-risk allo patients. It's in this 1st 100-180 day window of susceptibility that we see the greatest need for new options to not only treat these viral diseases, but prevent them from occurring in the first place. Posoleucel has the potential to significantly reduce this risk of clinically significant viral infections in this high-risk post-transplant period. In contrast to the previous slide, we see here a scenario in which posoleucel is administered soon after transplant. Viral reactivation, when it occurs, triggers an expansion of the relevant posoleucel virus-specific T-cells. As VSTs increase, viral replication is then controlled, and progression to clinically significant infection is prevented. The data from our phase II open label study that Dr. Dadwal will summarize in just a minute support this mechanism of action.
Posoleucel is currently being evaluated in three ongoing phase III studies in allo-HCT patients. These include the prevention study, which we're discussing today, as well as two treatment trials, one in viral hemorrhagic cystitis and the other in adenovirus infection. Multivirus prevention could be the most transformative for patients, as posoleucel has the potential to substantially reduce or prevent virus-associated morbidity and mortality and dramatically improve patient outcomes.
With approximately 41,000 allo-HCT patients per year globally that could potentially benefit from posoleucel if approved, this also represents a blockbuster market opportunity of over $1 billion in peak sales annually. With that, I'd like to turn to Dr. Dadwal, who was an investigator in the phase II multivirus prevention trial that served as the basis for progression to our ongoing phase III multivirus prevention trial, where he's also an investigator. Dr. Dadwal, could I please ask you to introduce yourself and provide a brief overview of the phase II study results?
Yes. Thank you, Diana. My name is Dr. Sanjeet Singh Dadwal, and I'm the Chief of Infectious Disease at City of Hope National Medical Center in Duarte, California, where we perform about 800 hematopoietic stem cell transplants a year, and about a half of those are allogeneic hematopoietic stem cell transplants. Can I have the next slide? Here, as Diana mentioned, I was the investigator in the Allo-sponsored phase II trial of posoleucel for the prevention of clinically significant viral infections in Allo HCT patients. I just presented complete overview of the data from this trial earlier at American Society of Hematology this past week, and will briefly provide a high-level summary here. Regarding the phase II study design, it is a single-arm, open-label phase II study which enrolled high-risk Allo HCT patients.
posoleucel administration was initiated between days 15 and day 49 post-transplantation after patients demonstrated engraftment of the transplant. posoleucel was given every two weeks for a total of seven doses. The primary endpoint was the number of new onset clinically significant infections through week 14, with a secondary endpoint of number of new onset clinically significant infections through week 26. Clinically significant infection was defined as having either evidence of end organ disease due to one of these viruses or initiation of treatment for cytomegalovirus, adenovirus or Epstein-Barr virus in the setting of high level viremia. The safety tolerability data which was presented in this 26 patients who were dosed in the study, posoleucel was generally well tolerated.
Acute graft-versus-host disease grades two through four was reported in 5 out of 26 patients, which is 19%, which is a rate that is consistent with or even lower than what has been reported in literature for these high-risk patients. All four deaths were related to relapse or progression of the underlying hematologic disease and was assessed as not related to posoleucel. There were no events of cytokine release syndrome. The only one case of secondary graft failure was assessed by an investigator as not related to posoleucel. In this trial, we observed the expected rates of viral reactivation based upon data which has been reported in literature from allo-HCT patients. 85% of the patients reactivated at least one virus through week 14. 10 out of the 14 patients who were aviremic at baseline also reactivated while on the study.
Despite high levels of reactivation of the virus, only three cases of clinically significant infection were observed through week 14, which was the primary endpoint. Additional 4 cases of clinically significant infection were observed between weeks 14 and 26, which was the secondary endpoint of the study. Now, this slide shows on the biomarker data, and it clearly shows the recognition and expansion of virus-specific T-cells in response to viral replication with subsequent control of viremia. The squares on each graph represents the interferon gamma producing virus-specific T-cells, which is pre-infusion and labeled as pre at the bottom, and then there's post posoleucel infusion, but they had to be within the primary endpoint time period, which is 14 weeks.
The circles depict the change in viral load from a peak, which is prior to posoleucel dosing, to the level at week 14, which is the primary endpoint. You can clearly see a very nice correlation between T-cell expansion and reduction in the viral load for each of the target virus shown here. In the next 2 slides, we will show some more granular data from some representative patients. The patient on the left-hand side experienced CMV reactivation shortly after initiation of posoleucel treatment. Following viral reactivation, CMV-specific T-cells expanded as measured by interferon-gamma ELISpot with subsequent control of CMV viremia. A similar pattern was seen in the patient on the right-hand side who had HHV-6 reactivation that was again controlled with the expansion of HHV-6-specific T-cells.
This particular patient reflects the expansion of virus-specific T-cells in a patient with Epstein-Barr virus infection. In the next slide, this one, as you can see here, the dots, which is the rounded circles, is the viral load which is going up and this patient also had post-transplant lymphoproliferative disorder in the setting of high-dose steroids. Despite the steroids, you can see here, the T-cells, when they're given, they expanded and the viral load also resolved. In conclusion, in this trial, we saw low rates of clinically significant infection or end-organ disease in allo-HCT patients. 7 doses of posoleucel over 12 weeks was well-tolerated. The risk of graft-versus-host disease was similar in frequency and severity to those expected in high-risk allo stem cell transplant patients based upon published data.
Viral control was associated with the presence and expansion of reactive T-cells. What we did not show you here, but which was presented at the full ASH meeting, was the data on the biomarker. Sorry, one second. I have a little glitch here. I apologize. Thank you.
Thank you, Dr. Dadwal. Dr. McGuirk, I'm so pleased to have you join us today as well. You're a recognized leader in the field of bone marrow transplantation, and I'm hoping that you would please introduce yourself at this time and describe your role at University of Kansas Medical Center.
Of course. Thank you, Diana. I very happy to be part of this discussion today. It's critically important to our patients and their families, our team. My name is Dr. Joseph McGuirk, and I serve as Division Director of Hematologic Malignancies and Cellular Therapeutics, and I'm the Medical Director of the Blood and Marrow Transplant Program at University of Kansas Cancer Center.
Thank you. As many of you know, The University of Kansas Cancer Center is one of the most highly distinguished comprehensive cancer centers in the country. Stem cell transplants are a fundamental component of the treatment armamentarium available for hematologic malignancies. Given that the initial patient population we're targeting with posoleucel is the allogeneic stem cell transplant population, maybe you could start, Dr. McGuirk, by describing this patient population in a bit more detail and the trends that you're currently observing in transplant medicine, particularly in Kansas.
Certainly. As you know, Diana, patients undergoing stem cell transplants from the time of the transplant to several months post-transplant are among some of the most immunocompromised people in existence. For these patients, we eradicate their immune system and then repopulate it with a donor immune system. It takes months to repopulate that immune system and mature the different components. During that time, these patients are greatly compromised and highly vulnerable to infections, particularly viral infections. One trend we've been seeing in transplant medicine over the last 15 years is an increase in the number of alternative donor sources. As you know, most patients in need of an allogeneic stem cell transplant as a curative approach, don't have a brother or sister who's HLA identical.
Increased utilization of what we call alternative donors, such as, utilizing umbilical cord blood, stem cells, stem cells from haploidentical or half-matched family members, mismatched related or unrelated donors for patients undergoing allogeneic transplant have greatly increased. This is a really, a really, great development, very important because it's increased availability and of stem cell transplantation as a curative approach for many underrepresented populations. Hence, the total number of transplants being conducted have increased remarkably in the last 15 years as well. However, a great deal more immunosuppression is needed in these patients to improve the chances of successful transplant using these alternative donors. We must be very aggressive with the immunosuppressive regimen, otherwise, the patient is at risk of rejecting the graft or experiencing non-engraftment, which is disastrous if it occurs.
Fortunately, it's, it's, it's quite unusual with the regimens that we use. With these regimens, the patient's T-cells are depleted very aggressively. Their immune response is greatly compromised for months, as I mentioned, after transplant. Unfortunately, this rigorous immune suppression increases the likelihood of infection quite significantly. Among the infections our patients have to contend with, viral infection is common. Many transplant patients, more than one virus may activate together. If one reactivates, others oftentimes come along for the ride in this very profoundly suppressed immune systems.
Thanks, Dr. McGuirk. I'm wondering if you've described these high-risk transplant scenarios. Could you also describe the characteristics of the patients that you see that are at highest risk of developing a viral infection after transplant and whether there's any way to predict which patients will get reactivated and with which virus?
Absolutely. Very important question. The risk of infection can increase based on several different factors, such as the type of transplant a patient's receiving. The alternative donors, for example, being somewhat more vulnerable, as I mentioned, the nature of the immunosuppressive regimen they're receiving or other comorbidities or drugs they're taking. Viral infections are a big issue for patients who are receiving T-cell depleted transplants. T-cell depletion, as you know, is a strategy to prevent graft versus host disease, but the price our patients pay is a greater vulnerability to viral infections. This is particularly the case in ex vivo depleted patients who are at highest risk of graft versus host disease, thus necessitating a T-cell depletion, as well as patients receiving haploidentical or mismatched unrelated donor transplants.
The immunosuppressive regimens that are given to deplete a patient's own immune system have changed quite a bit and can also be problematic for patients. The use, for example, of cyclophosphamide depletes T-cells and leads to high reactivation rates of viruses, in particular adenovirus, cytomegalovirus, Epstein-Barr virus, HHV6, all too common. More rarely JC virus, but when it reactivates, we're in a boatload of trouble. We don't have effective therapies established other than cellular therapy. These are all endogenous viruses that many of us harbor, and they reactivate during the period of highest risk during the first 100-180 days after the allogeneic stem cell transplant. All centers have protocols in place to screen patients prior to transplant to understand what their vulnerabilities are likely to be.
Despite these screening and diagnostic tools that are currently available in our programs, we cannot predict which virus or viruses will reactivate or progress to cause clinical signs and symptoms of these viral diseases.
Thanks, Dr. McGuirk. Now, Dr. Dadwal, maybe I'll turn to you. The City of Hope is well known for treating some of the highest risk transplant patients. Can you talk a little bit about the viruses that you most commonly see reactivating in your transplant patients and the current standard of care used to treat or prevent those infections at your center?
Most certainly. Thank you, Diana. We certainly do a lot of high-risk transplants at City of Hope. Actually we also is one of the known centers doing in elderly patients, which adds another sort of element to the immunosuppressed state in the post-transplant setting. This is one of the reasons I'm also quite excited about not having to worry about viral diseases in the future as a complication in post-transplant setting. Just to give a context, cytomegalovirus historically has been the most common infection we see in the post-transplant setting. In the context of newer, better drugs which are available in diagnostics, particularly prophylactic treatment with letermovir, CMV end organ disease is relatively rare. However, letermovir is not foolproof. Patients can have side effects which can lead to its discontinuation.
There are times when we see breakthrough infections, mainly as a result of severely suppressed immune system, which is not boosted by this drug. It basically prevents viral replication. It doesn't have to do anything with the, you know, immune reconstitution. Our own internal data shows that the reactivation rate in haploidentical stem cell transplant can run around 30% despite letermovir prophylaxis. I would like to highlight, haploidentical transplant has really taken off in the U.S. and across the globe as well. There's a increasing burden from cytomegalovirus in these patients. Reactivation then introduces the need for preemptive therapy. Those are drugs like ganciclovir and foscarnet.
Ganciclovir is a myelo-suppressive drug, and it is very well known that there's dose-dependent suppression of bone marrow causing neutropenia, which has downstream effects of increasing risk of bacterial and fungal infection and also increased mortality. As far as foscarnet is concerned, it can cause renal injury, so kidney injury, as well as multiple electrolyte abnormalities, requires intravenous infusion, and that means prolonged hospitalizations. That is another one big thing. That could be a huge issue in patients who are elderly who already have impaired renal function. As far as letermovir, it's also a pill burden added to other pills. It's a pill taken every day.
There's a concern for GI toxicity with nausea and vomiting and intolerance in some patients, which could be contributing to either discontinuation or suboptimal absorption and therefore CMV reactivation and need for preemptive therapy. At times it's difficult to also distinguish whether they're having these side effects due to letermovir with intractable nausea, or this is due to graft-versus-host disease. You know, we have seen that some patients report significant improvement in nausea once it is discontinued, and lo and behold, few weeks later they may have CMV reactivation. Also because letermovir is given for 100 days, there's a potential impact on delay of immune reconstitution against CMV. With delayed immune reconstitution, it does not abrogate the risk of developing reactivation. It just pushes it out later.
Overall, despite having letermovir available as prophylactic approach, CMV infection is still exacting a toll on our high-risk patients. If we can prevent that by avoiding drugs which have toxicities and provide patients an immunologic bridge until their own immune system is reconstituted and taken over, I think that's going to be a big breakthrough in the field.
Thanks, Dr. Dadwal. Dr. McGuirk, did you wanna add anything to some of those comments, particularly around CMV and the use of letermovir?
I, you know, I'll just reinforce basically what Sanjeet just articulated, and that is that this issue with regard to figuring out whether patients have active graft-versus-host disease or letermovir induced nausea, vomiting, and diarrhea in the early post-transplant period is a major daily challenge. In our transplant programs, it's not unusual that these patients end up being submitted to upper and lower endoscopic evaluations, biopsies to look for viral cytopathic effects. It's not an easy drug to use. It doesn't universally prevent the reactivation of CMV in our patients. As mentioned, often it pushes things out... Excuse me.
No problem. I'm gonna give you a break to get some water and get back to Dr. Dadwal. Maybe Dr. Dadwal, you could comment, outside of CMV, what the other viruses are that are concerning for you.
Surely, yes. I mean, CMV, you know, has always been known as the troll. There are other viruses as well which play a significant toll on the patients. One is human herpesvirus 6. It's a very common virus. More than 90% of human population is infected by the time they are teenagers, and it stays with us. In the post allogeneic stem cell transplant patients, according to literature, 40% of these patients can reactivate, and 1% of those can go on to develop severe encephalitis, which is often deadly. There's really not a good cure, and there's no good predictive methodology that if somebody reactivates HHV6, who is going to develop disease. That is the biggest challenge.
Investigators in Japan have done open label studies in recipients of cord blood transplant, which is the highest risk. They did not find any benefit of foscarnet on prevention of encephalitis when it was given prophylactically or preemptively. They actually did a study where they looked at HHV6 PCR from the blood. They treated with foscarnet versus observation. They did not see any sort of impact of the medication in preventing disease. Other viruses, Epstein-Barr virus, unchecked proliferation of Epstein-Barr virus, especially in patients who've had T-cell depleted transplants, can lead to post-transplant lymphoproliferative disease, also known as PTLD. We can monitor these patients with PCRs when it happens.
Oftentimes, centers have their own thresholds when to give rituximab, which basically eliminates B cells where this virus replicates, and the infection can just blow through that or patients can actually develop graft-versus-host disease as a result. We have also used rituximab in patients preemptively who are at very high risk for PTLD, but also for treatment of PTLD. As I mentioned, it has downstream effect on the immune system. A smaller proportion number of patients can develop adenovirus infections. Again, these are mostly immunocompromised patients, high risk, as studied in the current phase II trial and being studied in the phase III trial. Those who have graft-versus-host disease are taking high dose of steroids. This virus is more common in children compared to adults.
This can be a devastating disease in both children and adults, leading to death. Once somebody develops disseminated adenovirus infection, mortality is very, very high, and there are no effective or approved therapies for adenovirus. BK virus is also problematic in the post-transplant setting. It belongs to a family known as polyomavirus. It causes significant morbidity in patients who develop hemorrhagic cystitis, which is these patients have severe pain on urination, have profound amount of blood in the urine. As the case with adenovirus, there's no effective treatment for BK virus, and this infection can lead to long hospital stays. There's a significant cost to the healthcare system. These patients require IV hydration. They require catheterization of the urethra into the bladder irrigation, urologic consultations.
Similar to BK virus, JC virus can cause the same disease, and rarely, JC virus can also involve brain. It can cause brain infection. In summary, for these six viruses that posoleucel targets, approved therapies exist for only one virus, and it can present additional challenges for some patients. Definitely we need better ways to treat, and more importantly, prevention is a key part. One thing which I did not mention, some of the viruses have a bi-directional effect in increasing the risk of graft-versus-host disease. If we can prevent these infections, again, I mean, this has to be shown in the trials, is there going to be any impact on graft-versus-host disease?
Great. Thank you. Those are really good points. Dr. McGuirk, one of the points that Dr. Dadwal mentioned was around the cost that these viruses have on the healthcare system, and I'm just wondering if you could comment on the impact that these viruses have on patient quality of life, on their families, on the cost to the healthcare system overall.
Oh, certainly. These are really highly pertinent issues. These endogenous viral infections exact not only a significant toll on patients in terms of morbidity and mortality, as Sanjeet just very well described, but additionally can have an enormous financial impact. Every infection that a patient experiences adds more than $150,000 to the cost of transplant. We have outliers, of course, that end up in the intensive care unit, and that can go up by 5 to 10-fold. Patients and families experience significant financial costs as well. Issues such as transportation back and forth from home to the hospital, lost work for the caregiver. Just simple things like being able to buy groceries and pay the electric bill can become real challenges for our patients and their families.
The these add up and are major challenges not just to patients and their families, but patients who incur higher costs during their transplant care are also less likely to survive, which is devastating, first and foremost, to families. It's also demoralizing for the medical team to have beaten an underlying aggressive blood cancer with a transplant and then lose the patient to a viral infection, particularly a simple cold virus like adenovirus. If we had a tool to prevent these viral infections in the first place and be able to avoid all these negative impacts, that would be optimal. We have prophylactic approaches with CMV now that you've heard Dr. Dadwal describe, but we need these for other viruses as well.
As we have discussed, the drugs used to prevent or treat CMV have significant toxicities, and a risk of resistance. As a matter of fact, many patients in the current era, when we lose them from infections after transplants, there are secondary infections after the treatment of CMV because it's caused profound bone marrow suppression, and they're greatly vulnerable to fungal and bacterial infections. If we had an immunologic bridge that could help prevent infection while also allowing us to avoid the use of these drugs, with these severe, potentially life-threatening, side effects would be greatly helpful to the field.
Well, that's the perfect segue back to posoleucel. Each of you has had experience treating patients with posoleucel. Dr. Dadwal, as you mentioned before, you were an investigator in the phase II open label study and are an investigator in the phase III ongoing trial. Maybe you could start with a little bit of your perspective on the safety and efficacy profile of posoleucel that was observed in the phase II trial. Dr. Dadwal, you may be on mute. We can't hear you.
Yes, I was on mute. My apologies.
Okay.
No, happy to comment on that. At the ASH presentation, we highlighted a patient on which I can provide more details at this time. This was a 61-year-old elderly male with multiple comorbidities, had chronic kidney disease too. He was treated for cutaneous T-cell lymphoma with a myeloablative conditioning, which is a pretty, you know, toxic conditioning prior to receiving an allogeneic hematopoietic stem cell transplant from a mismatched unrelated donor. This is one of the high-risk donors. Pre-screening, we found out this patient was donor CMV negative, but he himself was positive for cytomegalovirus, which is known to be the biggest risk factor for CMV reactivation. He was unable to get letermovir in the outpatient setting when he was discharged from the hospital.
He was enrolled in the phase II open-label study of posoleucel, and on the time we gave him first dose of posoleucel, he had reactivation of CMV, and his viral load increased to 1,000 copies per mL. At my institution, you know, historically, we did not treat until viral loads had reached 5,000 copies. This was back in 2010s. Subsequently became more, sort of, stringent and came down to 1,500 copies per mL. With this patient at 1,000 copies, we waited and did not treat. The local PCR in our own lab went up to 1,600 copies per mL. On discussion with the hematologist, we felt comfortable not to start ganciclovir because his graft was borderline, and we did not want to give him foscarnet because of kidneys, so we thought we'll wait.
Patient got the second dose of posoleucel, and subsequent to that, the viral load dropped significantly and stayed down through the remainder of the study period. I mean, there was a clear increase in the viral load from 1,000 to 1,600 copies. Had it gone further up, we would have done preemptive therapy, but with the posoleucel, the CMV PCR came down very nicely and then remained negative throughout the remainder of study period. This patient did complete 7 doses of posoleucel. Looking back at the biomarker data, that was the one thing I was unable to, you know, mention in the conclusion was that we noted presence of posoleucel both during the infusion period, and we detected posoleucel in the post-infusion period as far as long as 26 weeks.
Also in that slide, we showed that there was expansion of CMV specific T-cells which also persisted. In essence, we were able to prevent the toxicity of ganciclovir, which could have caused more myelosuppression in somebody who had a borderline graft function, but wasn't neutropenic, or we could have caused kidney damage if we gave this person foscarnet, and he would have been hospitalized for a prolonged period of time. By preemptively this is really like preemptively treating with posoleucel, we were able to avoid having to do any of these drugs with their undesirable side effects. Of course, more research, I mean, more research is needed, and that is why AlloVir is conducting phase III trials right now.
Wonderful. Thanks so much. That was a great example of the potential for posoleucel to control viral re-replication after reactivation has occurred and obviate the need to add on toxic antiviral agents. Dr. McGuirk, turning to you're very familiar with using virus-specific T-cell therapies in general and posoleucel specifically. Perhaps you could discuss your site's experience with the viruses that posoleucel targets.
You bet. Sanjeet spoke just now about a patient with CMV viremia. I'll add to that by talking about adenoviral infection. This is an absolutely devastating disease, as Sanjeet mentioned earlier, that can progress from an asymptomatic viremia, which is detect a virus, patient has no symptoms, to multi-or-organ failure in a matter of days in these incredibly immunocompromised patients. Adenovirus disease is a particular problem in children, it has no approved therapy. I can share a case with a 17-year-old young lady that I took care of personally. She was in remission from leukemia after a cord blood transplant, relatively early after a cord blood transplant. She developed a multi-organ adenoviral disease and was in our intensive care unit on a ventilator on maximum support, 100% FiO2.
I was having conversations with her family about end of life issues, and possibly taking her off the ventilator. We had made no progress. We were able to provide this patient with posoleucel through the AlloVir's compassionate use program. She got out of the intensive care unit in a couple of days, rehabbed over a couple of weeks. I'm very happy to say that she survived this infection and we had a successful outcome. She attended her senior prom six months later, which we of course, got many pictures of, as did some of our local press. It was just unprecedented. We've never seen somebody respond in that way, in a very long career in the field.
I'm highlighting this anecdote because it supports the promise of prevention for patients with such devastating viral infections. We need much better options to prevent clinically significant viral diseases, allowing us to move earlier in the continuum of care to either preempt or prophylact these patients in the first place, so that we never end up again in such situations.
Thank you, Dr. McGuirk. That's such a powerful example. Both of those descriptions of patients are really the motivators that keep us coming to work every day at AlloVir to deliver for these patients. As we look to the future, we're doing a lot of planning for the potential of our three phase III posoleucel trials to read out with successful results, ideally lead to regulatory approvals. I would just love each of you to comment on if this would be the case, how would you use posoleucel in your clinical practice? Perhaps Dr. McGuirk, you could start first, we'll turn to Dr. Dadwal for his thoughts as well.
Absolutely. As Dr. Dadwal and I spoke to, CMV continues to be, take an enormous toll on our patients, in spite of the current preventative and therapeutic options that were described earlier. BK virus, Epstein-Barr virus, HHV6 also commonly reactivate and progress to clinically significant infections in our patient population. As Dr. Dadwal said earlier, while HHV6 is less common, when someone does develop HHV6, it can be absolutely devastating. We had a patient earlier this year, as a matter of fact, that died from HHV6 induced encephalitis, but he actually had hepatitis, enteritis, and encephalitis at that time. We threw everything but the kitchen sink at this patient without success.
Considering the toll these infections have on patients, families, resource utilization, the cost of the healthcare system, if there's an option which prevents infection in the first place, it should be used aggressively and very broadly in the field.
Thanks, Dr. McGuirk. Dr. Dadwal, do you wanna, do you wanna comment?
Yeah. I mean, I completely concur with Joseph. I mean, in allogeneic stem cell transplant patients, you know, we see all these viruses, again, CMV is at the forefront, we see breakthrough infections as we discussed previously. The other five viruses with posoleucel targets, there's actually extremely limited options. We really don't have much. I mean, with HHV6, even if you have ganciclovir foscarnet, you're basically chasing the disease now because preemptive therapy doesn't work, prophylaxis doesn't work. Once the end organ disease has happened, encephalitis, mortality is high, like 90%. It would really those drugs are not helpful once the disease has happened. I would also like to add another point about the negative impacts of these viruses. Both cytomegalovirus and HHV6 are known to increase the risk of graft-versus-host disease.
There's also multiple papers show increased healthcare resource utilizations in patients who have cytomegalovirus infection. If we can decrease CMV, HHV6 infection rate, can we reduce GvHD rates? I mean, that is what the clinical trial can answer. We did see 20% acute GvHD in the phase II open label study of posoleucel, but this compares to rates of actually 30%-40%, which are reported in literature with this high-risk allogeneic stem cell transplant patient population. Given the number of the patients enrolled in phase II was small, we cannot draw definitive conclusions at this time. If that decrease plays out, that could be very important for the patients.
Wonderful. Thank you. I think we've got a few questions that are coming through. At this point, I'll ask either of you if you'd like to make any additional comments before we move to the questions from the audience. For those of you on the line, as a reminder, if you'd like to submit a question, please feel free to do so now through the chat function of the webcast platform. Doctors McGuirk and Dadwal, any further comments at this time?
Yes. Thank you for the opportunity, Diana. I just really appreciate the platform to be able to carry the flag for this field. This is long overdue. We've been watching the science unfold for the last couple of decades. The science is absolutely matured. We need to get these constructs to all of our programs throughout the nation and beyond, worldwide, and heading these things off of the pass, because I can tell you right now, it's a very busy time in our program. We have a 100-bed inpatient hematology oncology and stem cell transplant unit. It's full of patients right now. Probably 20%-25% of our patients are in the hospital right now because they're dealing with viral infections.
I'll just reiterate that the multi-virus approach of posoleucel is very important, critically important to our field. Many transplant-associated viruses reactivate together, as we've discussed, in parallel or in sequence. While screening and diagnostic approaches have improved, we still cannot accurately predict which viruses will reactivate in a patient and which will progress to clinically significant infection and disease. Transplant patients are severely immune-compromised and can be very fragile, particularly in the first 100 to 180 days post-transplant, as we've discussed today. Posoleucel infusion potentially provides an immunologic bridge that may help these patients, and I'm personally confident that it will help many patients infection-free, stay infection-free until reconstitution of their new immune system occurs. Historically, we've seen a trend where the number of patients eligible for transplant has increased over time. That trend continues.
This is due to prophylactic CMV therapy, better supportive care measures, better risk stratification, alternative immunosuppressive regimens, reduced intensity conditioning regimens, allowing us to transplant patients of advanced age well into their seventies. Reducing the risk of viral infection even further would help us continue that trend by making transplants safer and therefore available for more patients. It's a critical unmet need until posoleucel has shown up on the scene.
Thank you, Dr. McGuirk. I'm gonna transition to questions now. We've gotten a couple of questions which I'm gonna kind of bucket together 'cause they're similarly themed. I think you, Dr. McGuirk, you sort of started answering that question, those questions before they even came in. I'll start with Dr. Dadwal, if you could make a comment here. The question is, do you see a prevention approach being uniformly adopted, or do you see this as a specialized approach that only the leading transplant centers will be comfortable with?
I mean, this is. First of all, I want to say this is going to be a revolutionary approach in preventing viral infections. I think any transplant center which does allogeneic stem cell transplant center should be, you know, or would like to do this because that's one of the biggest complication in the first 100 days. I don't see there should be an impediment, whether it is a large volume transplant center or a small volume transplant center. As long as you have apheresis in a transplant center, one should be able to do it.
If I may, Diana.
Yes.
I'll just jump in here and say I absolutely, fully concur. Any transplant program in this nation performing allogeneic transplants is mandated to be FACT accredited and report those data to a central registry, as you know. These therapies are, they are complex in the development in your laboratories. They are not complex for a transplant team. The procedure of handling these cells, storing these cells, infusing these cells is a routine everyday event of the year for allogeneic transplant programs. There should be no barrier and no reason why every allogeneic stem cell transplant program should and will be able to and should be providing these therapies.
Great. Thank you. I'm gonna jump ahead in the question queue because this question is connected. It comes in as how much of a burden are infusions every two weeks for a total of 7 doses for patients? Are patients being seen that frequently anyway, or will it be hard for them to come back to the clinic for these visits? Dr. McGuirk, maybe you can comment on that, and then I'll ask Dr. Dadwal as well, representing City of Hope and other types of centers.
Absolutely. When our patients are discharged from the hospital, and that's generally in the 20-25 day range after transplant, they're coming to our clinic in our program three days a week for if everything is going well until day 35, and then two days a week out to day 100, and then on a weekly or every other week basis out to day 180. These patients are a captive audience. They're already with us. They're coming into clinic. They're getting blood levels checked of their graft-versus-host disease prophylactic regimens. We're watching for infections. We're looking for EBV and CMV, actively watching for respiratory viral and symptoms, et cetera.
We watch them like a hawk, as do our colleagues at the City of Hope, as Dr. Dadwal will speak to. It is not an undue or extra burden to our patients or their families or our teams for that matter. The undue burden to everyone is that these viruses should get out of hand, and that's when it's extraordinarily a burden for patients, their families, and our team. We're very bullish on heading things off at the pass for these patients.
Thank you. That's helpful. Dr. Dadwal, anything to add there?
Not really. I think Joseph mentioned very nicely and eloquently that this patient population is being watched very closely. Similarly at City of Hope, in the first 100 days, our patients are seen twice a week, and then they're seen once a week till day 180. It is very personalized for each patient based upon their risk, how frequent they're monitored, so that should not be an issue. Our nursing staff, our transplant physicians are completely sort of, how should I say, conversant with cellular therapy. I mean, we do CAR Ts, we do other T-cell immunotherapies. I don't think there should be any burden from it. I think the experience from phase II trial I've had is actually patients wanted to be on T-cells.
When we presented the trial to the phase III, most of the patients want the cells. They understand the concept too.
Thank you. Let's go now to a question from Anupam Rama at JP Morgan. Dr. Dadwal, we'll start with you, based on the experience that you've published from City of Hope, and then ask Dr. McGuirk to comment as well. The question is, can you put the rate of clinically significant infections in the prevention study into context of what you would see with letermovir and CMV alone? How do you view the treatment angle of this product versus the prevention setting? I think that second part we may have addressed already is the need for prevention, but maybe Dr. Dadwal just commenting on, in this letermovir era, how common are you seeing CMV reactivation in your high-risk ALL patients?
When you define high-risk population, I mean, this is my response that in the high-risk population, we are talking about haploidentical stem cell transplant patients. We're talking about these as even of match unrelated donor who are getting post-transplant Cytoxan, which causes in vivo I mean, in vivo T-cell depletion. We have mismatched unrelated who get Cytoxan. We have cord blood transplant patients. We still, even in the era of letermovir, we are seeing 30% reactivation rate of CMV, which is pretty high. That is that. Beyond CMV, I mean, again, letermovir is only 100 days. Also there's been studies which have showed that there's polyfunctional T-cell delay in immune reconstitution, and that could be just against CMV, but other things too.
There's biological impacts also on CMV specific immune reconstitution and potentially other things. Yes, letermovir has been a great advance, there's no question, but it's not an answer in all. The major part beyond CMV is HHV6. We are seeing more HHV6 in patients who are getting these very high-risk transplants like cord blood, haplo, or mismatched unrelated, different age groups. We are still teasing out who is that person who is at high risk. Given the fact that 40% of patients reactivate with HHV6 and only 1% will get encephalitis and 90% of them may die, or 80%-90% will die, I mean, that's 1 death is too many for our transplant patients. Having something which is gonna cover everything, HHV6, BK virus is pretty common in the first 30 to 100 days.
Those patients who develop hemorrhagic cystitis, they are miserable. They're in hospital for weeks. They have Foley catheters and procedures. Similarly, adenovirus. I think the benefit is beyond CMV. CMV is one part, definitely in that high-risk population, but there's gonna be so much benefit for the other viruses. That would be my take.
Great. Thank you.
Yes, and.
Go ahead, please, Dr. McGuirk.
No, I certainly concur with that. I think, you know, when University of Kansas is one of the largest transplant programs in the nation as well. A lot of allo transplant activity in our program, about 45%-50% of all of our transplants, similar to the ratio at City of Hope. And what I can tell you, this is not meant to be a disservice to the men and women scientists who develop letermovir, I think from my perspective, it hasn't been a great advance. It has been an advance. I say that because of its side effects, the GI side effects, which are by far common.
If you look at their data, the high incidence of GI issues. Again, that really muddies the water in terms of is this graft-versus-host disease or is this letermovir? In addition, we too see about 30% reactivation of CMV despite patients being on letermovir, particularly in the alternative donor populations that Dr. Dadwal described, the cord bloods, the mismatched unrelated donors, the haplo transplant patients, even the unrelated donor regimens. Patients with post-transplant cyclophosphamide, which is becoming a standard of care now for graft-versus-host disease prophylaxis. It comes with a price. We analyzed our center data very recently, and looked at a large group of patients over the last several years in our program.
Over the last three years, 500 patients, unrelated donors represented about just slightly less than two-thirds, and haplo's about 1/3 of that population. What we saw was that we were pushing, and this has been reported in the literature as well, we were pushing CMV out later with letermovir. Not only does do a significant minority of patients reactivate CMV despite being on letermovir, but it's a quite significant % of patients reactivate later when we stop the letermovir. You know, from my perspective, and I, you know, I think, and I've always felt this way, I trained at Sloan Kettering, and my work in the lab in the 1990s was growing CTLs against CMV in the laboratory. This has been going on for a long time.
Biologically, it makes more sense, to give what we know is the active biological, way that we control CMV in humans, and that's three T cells, right? These people are only developing CMV because we're compromising their T cells. They've got high titers of CMV specific T cells, but we ablate them. We get rid of them, and then we give them the donor's T cells. The donor's T cells, if they've been exposed to CMV before, will eventually grow up and eventually control CMV, but it takes months, as we described. Some of the donors are not exposed to CMV before. The natural biological strategy to get rid of CMV as a problem for our patients is to give them CMV specific T cells. That's for CMV. Then, as Dr.
Dadwal just described, there's a much broader array of viruses that we've been talking about this afternoon, that our patients have to contend with in addition to CMV. The posoleucel helps us tackle this broad array. It helps us tackle the CMV problem that continues to exist despite letermovir. Again, it's been an advance. I don't think it's been a great advance personally, but that's just my opinion. It helps us deal with so much more beyond that.
Right. Thank you both for those really insightful comments. I will move on to our next question. We're running a little short on time, I'm gonna ask each of you to give a one-minute response each to a question from Mani Foroohar at Leerink. His question reads as, "In considering the use of posoleucel as preventative therapy, what clinical trial data or totality of data will you and your colleagues need for broad adoption? Do you think that there'll be variability in terms of adoption across different types of practice settings, patient populations, or even geographies?" Maybe Dr. Dadwal, I'll have you start again to give Dr. McGuirk a break and a sip of water.
Sure. I mean, in terms of, the use of prevention and what kind of data we need, obviously, number one, safety is important, tolerability is important. At least in the phase II trials, it was safe and it was tolerable. That is, I think, number one. Number two Is gonna be efficacy and how do you measure efficacy as, can you prevent clinically significant infections and end organ disease? End organ disease as such with CMV is pretty uncommon these days because of either preemptive therapy or even with the use of letermovir. I mean, the end organ disease is.
If I can even see reduction in clinically significant viremias, and if I can, you know, have those measurable endpoints rather than disease alone, that would be very sort of important for us in terms of looking at how to prevent. Also, if we see that we are able to prevent symptomatic disease from BK virus, you know, adenovirus, and also reactivation of HHV6, control of HHV6, those would be very important things for me in terms of the utility of posoleucel. In terms of the variability in adoption, I mean, you know, across the United States, each center develops their own guidelines, and there are multiple things which go into play. You know, the type of institution it is and which state is it in? What is the reimbursement structure?
All those things that go along. I think for the most part, when transplant centers come along and there is a intervention which is clearly beneficial for the patient, I don't think anybody's gonna shy away from that. I can certainly say that at least from my institution, we are very early adopters of anything which is going to help our patients.
Thank you. Dr. McGuirk, maybe you could comment specifically on the phase III trial for prevention and whether it's successful, that registrational trial will be enough for you and others to feel confident with using posoleucel for prevention.
Unequivocally. Yes, absolutely. I think that that will be a paradigm shift in the field. You know, from a transplant physician's perspective, foscarnet and ganciclovir, which are our preemptive measures, are very toxic. While we might not lose our patients with CMV to CMV disease because it's much less frequent these days, we do subsequently lose them to bacterial infections and fungal infections or graft-versus-host disease. Keep in mind, both of these drugs are toxic to the bone marrow. Both are toxic to the kidneys. There's a little differential between which is more toxic to bone marrow versus the kidneys. It's not uncommon. We have to hold the graft-versus-host disease prophylactic drugs because of patients developing kidney failure. These are not rare events in our transplant programs.
We need to get beyond these drugs in this preemptive approach. We need to head it off in the past in the first place to give these patients prophylactic therapy. I think the phase III registrational trial will bring about a landmark paradigm shift in our field. I think that there will You know, the big centers like Dr. Dadwal's and ours across the nation will adopt this right away. I strongly suspect that other centers will be on board relatively shortly thereafter. This is going to be a compelling therapeutic landscape change.
Great. Thank you so much. The last question that I'm going to answer and then ask if either of you guys wanna make any additional comments. It comes from Michael at Morgan Stanley, and he was wondering whether there are any specific high-risk patient groups that would not be a good candidate for receiving posoleucel as preventative therapy. The one that comes to my mind that we have talked about is the small proportion of patients receiving high-dose steroids, more than 0.5 milligrams per kilogram during that window, not getting them started on a cell therapy. Also those patients with really severe life-threatening graft-versus-host disease who are not included in our trials. Are there other patient populations that I've omitted from that list, either Dr. Dadwal or Dr. McGuirk?
In my opinion, those are the circumstances. It's not that, you know, patients are on steroids. It's that it will afford the efficacy of the T cells that we're infusing if they're on that high dose of steroids. That's the problem there. In a patient who has a very significant graft-versus-host disease, the conundrum, Dr. Dadwal, it'll be interesting to hear his thoughts on this. The conundrum that we have is that we have to obviously further immunosuppress those patients. Those patients are particularly vulnerable to reactivation of these endogenous viruses.
The strategy that would allow us to manage their GVHD, get that steroid dose down to a level as quickly as we are able, and we actually practice this way in the compassionate use setting, as you all know, get it down to a dose where we can be, have some level of confidence that the cells are gonna persist and help us get rid of the accompanying viral infections that we're dealing with with that graft-versus-host disease. Dr. Dadwal?
No, my thoughts are aligned with you. I completely agree with what you said. We see such patients. I mean, we have one patient with adenovirus, and we bump down the dose of prednisone as much as we can so that it reaches that threshold of being less than 0.5 milligram per kilogram. Yeah, I think it's in the era of also health economics, I mean, if you look at the preemptive therapy with either ganciclovir or foscarnet, there's some very nice papers which have come out in the last few years. There's a differential cost between somebody who does not have CMV versus somebody who has. It ranges anywhere from $70,000-$80,000 to $150,000.
You can add in GvHD or no GvHD, so there's along with significant therapeutic toxicity of these drugs, there's also financial toxicity. If you can cover all six viruses, I think that's the way to go.
Right. Thank you. That's a wonderful way to conclude the Q&A portion of our call. I wanna give a thanks to everyone for joining us today and in particular, a special thanks to Dr. Dadwal and Dr. McGuirk. I'll also close by highlighting the progress that we, as AlloVir, the company, have made in 2022. If we can advance the slide, that's great. I'll say we completed the phase II study of posoleucel for the treatment of BK viremia just this month in kidney transplant recipients. We're on track to have final top-line data from that study in the first quarter of 2023. Throughout 2022, we made great strides in advancing our pipeline of off-the-shelf multi-virus specific T-cell therapies.
Specifically across all of our phase III studies, we made significant progress, and we will provide more granular updates on that progress early next year. Please stay tuned for that. There was a question around that in the Q&A box that we didn't have a chance to get to. I would say that therapies to treat and prevent viral infections in the most vulnerable window post-stem cell transplant remain a critical unmet need, as you heard today. With posoleucel, AlloVir aims to address this need. It's a single off-the-shelf therapy that offers clinical and economic value for patients, providers, and payers. I hope you heard today that we're very excited to progress our three phase III studies and look forward to providing updates to you in the future. Thanks so much.