Good morning, everyone, and welcome to AlloVir's virtual investor event to discuss the top-line final results from our phase 2 randomized double-blind placebo-controlled study of posoleucel in kidney transplant recipients with BK viremia. I'm Sonia Choi, AlloVir's Senior Vice President of Corporate Affairs and Investor Relations, and your host for today's call. During today's call, AlloVir's CEO, Dr. Diana Brainard, will discuss the study findings and talk about next steps. Following her presentation, we'll open the Q&A section of our call. Dr. Brainard and Dr. Anil Chandraker, Director of Renal Transplant Medicine at Brigham and Women's Hospital and Principal Investigator of the Posoleucel BK treatment study, will be available to provide additional context for the need for new treatment options in this patient population and answer questions about the study results. Vikas Sinha, AlloVir's Chief Financial Officer, will also be available for questions.
If you would 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. Brainard, I would 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 morning, everyone. Thank you for joining us. I'm thrilled to talk to you today and share the exciting and positive results of the posoleucel phase 2 study for the treatment of BK viremia in kidney transplant patients. These data demonstrate the therapeutic potential of posoleucel for BK virus treatment in kidney transplant patients, and more generally, support continued investigation across our 6 target viruses in solid organ transplant patients overall. We now have the opportunity to potentially bring posoleucel to an important new population of immunocompromised patients beyond the stem cell transplant patient focus in our ongoing posoleucel phase 3 trials. Before I dive into the details from today's announcement, I'd like to provide a bit of background to ground everyone on AlloVir's focus and where we are today. 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 treat or prevent life-threatening viral infections and disease in immunocompromised patients. We have 3 ongoing phase 3 registrational trials with our lead candidate, posoleucel, for 3 first-to-market indications. Enrollment in these studies is expected to complete this year. Our approach to multi-virus prevention in allogeneic hematopoietic cell transplant patients has the potential to transform the stem cell transplant field. allo-HCT patients are highly vulnerable to potentially devastating viral infections, particularly in the first 100-180 days post-transplant. The downstream effects of these viral infections can be life-threatening, and there are few treatment options. Preventing the progression of viral reactivation into clinically significant infections or disease and avoiding these devastating consequences would be a significant advance in the management of allo-HCT patients.
We presented compelling phase 2 trial results at ASH, both in 2021 and more recently in 2022. With the enthusiasm and engagement we're seeing from leading transplant centers around the world participating in the prevention phase 3 trial has enabled us to accelerate our estimates for trial completion and data readouts. Additionally, we ended 2022 with just over $234 million in cash to support our development programs. Our VSTs are a clinically validated approach to treating viral infections in immunocompromised patients. Transplantation, immunomodulation, chemotherapy, and even 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, ranging from prolonged hospitalization to end organ damage to death.
Our approach at AlloVir has been to develop investigational therapies that restore the T-cell deficit that is leading to disease in the first place and to target multiple viruses simultaneously to enable both treatment and prevention in high-risk populations. Our manufacturing is streamlined for a cell therapy. There's no gene editing and only a single round of expansion. Our cells are generated from healthy donors with immunity to our target viruses. Cells from unique donors undergo expansion in the presence of peptide and cytokine cocktails that generate T-cells with a high degree of polyclonal and potency across our target viruses. This process can prospectively produce cell banks that cover more than 95% of the population from a relatively small donor pool. Long-term stability enables us to cryopreserve these cells and deliver them to patients in need within 48 hours.
The lead clinical candidate in our portfolio, posoleucel, targets 6 relatively ubiquitous viruses that lie dormant in most people with healthy immune systems. They are adenovirus, BK virus, CMV, EBV, HHV-6, and JC virus. Posoleucel is truly a pipeline and a product with blockbuster franchise potential. As a multi-virus specific DSD, we can pursue multiple indications for posoleucel across multiple patient populations. This is truly unique, and it's a differentiated approach, supported now by 3 promising phase 2 studies, 2 in allo-HCT patients, and the third, which you'll hear more about in a moment, in kidney transplant patients. That backdrop, I'm thrilled to move to the positive top-line results for posoleucel in our phase 2 randomized double-blind placebo-controlled BKV study. I want to first share some context on why this study is so important.
BKV is one of the most feared transplant-associated viral infections due to the lack of available, effective antiviral therapies and its profoundly negative impact on transplant outcomes. Approximately 80,000-100,000 kidney transplants are performed each year globally, that number is expected to grow to over 100,000 by 2030. Due to the long-term immunosuppression required to prevent graft rejection, solid organ transplant recipients are at high risk for reactivating common viruses that are typically controlled by the body's natural immune system. Uncontrolled, these viruses can have devastating consequences. BK viral infection poses a significant threat to kidney graft survival. The majority of patients who reactivate BK virus will then go on to develop high level BK viremia, putting them at significant risk for BKV-associated nephropathy or BKVN, which leads to decreased kidney survival and a return to end-stage renal disease and dialysis.
Consensus groups, including the American Society of Nephrology and the American Society of Transplantation, consider BK viral load of greater than or equal to 10,000 copies per milliliter to be presumptive BKVN. There are no approved or effective antiviral treatments for BK viremia. The only approach to managing BK viremia is a reduction in immunosuppression to allow the body's immune system to fight the virus. This is typically initiated with a viral load of greater than or equal to 10,000 copies per mil. However, this reduction in immunosuppression can also lead to graft rejection, putting the success of the kidney transplant at risk. We initiated our BKV study in kidney transplant patients after having first demonstrated efficacy with posoleucel against BKV in a phase 2 treatment study in allo-HCT patients.
At the end of last year, we added to that body of evidence with data from a second phase 2 study in allo-HCT patients, this time as a prevention therapy. On the left-hand side of the slide, you see results from the CHARMS phase 2 treatment study. In this trial, we saw rapid resolution of macroscopic hematuria among patients with BK viremia and hemorrhagic cystitis, which is shown in purple. In the same chart, we show natural history data in gray, and we see a consistent, substantially shortened time to resolution of macroscopic hematuria in patients who received posoleucel when compared to what was observed in the natural history study. These data support posoleucel receiving RMAT designation for the treatment of virus-associated hemorrhagic cystitis, and we're now globally enrolling our registrational trial for this first ever indication.
On the right side of the slide, you see data from our phase 2 multivirus prevention study. Here, we're looking to prevent the development of clinically significant BKV disease in this population, e.g., hemorrhagic cystitis. Of the 26 patients treated in this study overall, none developed treatment emergent hemorrhagic cystitis. Importantly, among patients who reactivated BK virus, we observed an expansion in BKV-specific T cells and subsequent BKV viral load declines. These data support the efficacy profile of posoleucel against BKV and provide a strong scientific basis for demonstrating activity against BKV and in the solid organ transplant population as well. This slide shows the design of our BKV treatment study of posoleucel. This was a randomized, double-blind, placebo-controlled phase 2 trial that enrolled 61 adult kidney transplant patients with BK viremia. Patients were randomized 1 to 1 to 1 to receive 1 of 2 dosing regimens of posoleucel.
Weekly administration of posoleucel for three weeks, then every two weeks. Later on, we'll refer to this dosing group as biweekly dosing or weekly for three weeks, then once a month. We'll refer to this group as monthly dosing or placebo over a period of 12 weeks. Following the dosing period, patients were followed through week 24. The primary study endpoint was safety and tolerability of posoleucel. The key secondary endpoint of the study was change in BK viremia. Shown here are the select patient demographics and baseline characteristics.
As you can see, there's little difference between the posoleucel and placebo groups in regard to age, race, ethnicity, years from kidney transplant to day 1, median eGFR, and BK viral load. Importantly, in this study, we enrolled an intentionally heterogeneous group of patients with a broad range of viral loads and time since kidney transplants, and we were able to successfully match all patients screened to a posoleucel cell line. The median time post-transplant at study entry was just over 1 year, with a range from 4 months to 14 years, and the baseline viral load ranged from 250 copies per milliliter to over 7.8 million copies per milliliter.
Recognizing the potential for differences in responses according to viral load, we stratified patients by low, less than 10,000 copies per milliliter, or high, greater than or equal to 10,000 copies per milliliter BK viral load. We did see an imbalance in the proportion of patients undergoing significant immunosuppression reduction prior to randomization, with 5% of patients in the posoleucel group and 21% in the placebo group having had a significant reduction in immunosuppression in the month prior to study entry. We define significant as a reduction of greater than or equal to 50% in any of the major immunosuppressive medications. Immunosuppression reduction to such a significant degree in such a short time frame prior to randomization would be expected to precipitate significant changes in T-cell function and corresponding potential BK viral load decline that could not be attributed to on-study interventions.
We therefore removed these 6 patients who received significant immunosuppression reduction immediately prior to study entry from our efficacy analysis so their viral load declines would not confound our ability to see a potential treatment effect. The key secondary endpoint of the study was the change in BK viral load in patients receiving posoleucel versus those receiving placebo. We're excited with the strength and consistency of the data showing that posoleucel achieved greater viral load reductions versus placebo. Antiviral responses to posoleucel increased over time, with the greatest differences between posoleucel and placebo observed at the end of the study, week 24. Overall, more than twice the percentage of posoleucel-treated patients achieved a greater than or equal to 1 log reduction in viral load as compared to placebo-treated patients. One of our goals with this study was to look at 2 different posoleucel dosing frequencies.
We observed a consistent efficacy signal greater than placebo in both posoleucel treatment groups, but we also noted consistently higher activity in the more frequently dosed treatment group where posoleucel was given bi-weekly. In this arm, more than three times the number of posoleucel-treated patients had a greater than 1 log viral load decline as compared to placebo patients. In addition, the median viral load reduction was nearly 1 log, and 85% of patients had at least a 50% viral load reduction. With respect to kidney function, this remained stable over the course of the study, and we saw no meaningful differences between groups, as we expected with a study duration of only 6 months.
As I mentioned earlier, patients with BK viral load of over 10,000 copies per milliliter are at the highest risk of graft loss. This degree of viremia is deemed presumptive BKVAN by multiple medical societies. We started enrollment of this study back in 2021 in low viral load patients in order to confirm safety in a lower risk group. Based on the early safety findings, we were able to accelerate opening enrollment to higher viral load patients where the unmet need is substantially higher. Seeing viral load reduction efficacy in this group is particularly exciting and meaningful.
In this pre-specified high viral load stratum for patients with a screening viral load of greater than or equal to 10,000 copies per ml, again, posoleucel patients overall were more than twice as likely to achieve a greater than or equal to 1 log viral load reduction than patients in the placebo group. Again, bi-weekly posoleucel had 3 times more viral load reductions of greater than or equal to 1 log than placebo patients. The difference in median viral load reduction is particularly striking as well, with a median 1.4 viral load decline for posoleucel-treated patients that's over 3 times higher than the less than half a log seen in those receiving placebo. Similar to the overall study population, we did not see a big difference in eGFR across groups.
Immunosuppression reduction was allowed during this study if patients had a BK viral load of greater than or equal to 10,000 copies per milliliter. This decision was made by the treating physician and guided by general principles laid out by our medical advisors in the protocol. Significant immunosuppression reduction of greater than or equal to 50% occurred in 12% of patients in the posoleucel group and 16% of patients in the placebo group over the course of the 24-week study period. Among the 5 posoleucel-treated patients who had significant immunosuppression reductions, 2 patients had a greater than or equal to 1 log BK viral load decline, which importantly preceded the significant immunosuppression reduction. Three patients did not have a greater than or equal to 1 log BK viral load reduction. We feel confident that on study immunosuppression changes did not impact our study results.
The primary endpoint of this study was safety and tolerability of posoleucel versus placebo. We're pleased to report that posoleucel was generally well tolerated, with balanced safety across the posoleucel and placebo groups. The incidence and severity of adverse events were consistent with the underlying patient population and background immunosuppression these patients receive. Headache was the most frequent treatment-related adverse event, occurring in 7% in the posoleucel group and 16% in the placebo group. No grade 3-4 AEs or SAEs were assessed as related to study drug. 1 patient in the posoleucel group discontinued treatment due to an adverse event, which was renal tuberculosis. 1 patient each in the posoleucel group and placebo groups had an infusion reaction. Both cases were mild and resolved.
There was no GVHD or CRS in either group, and there was a similarly low incidence of de novo donor-specific antibodies in the posoleucel and placebo groups. 3 patients who received posoleucel were reported to have acute rejection per biopsy report by a central reader, as per our protocol pre-specified definition. 1 who was clinically diagnosed with and successfully treated for renal tuberculosis and did not receive clinical treatment for rejection. 1 patient who had rejection on a biopsy prior to posoleucel dosing during the screening window, which then continued over the course of the study. 1 who developed rejection at week 22 of the trial. None of these cases were assessed by the investigator as related to posoleucel. To summarize, regarding the primary endpoint, safety and tolerability profiles were consistent between the posoleucel treatment groups and placebo.
We had no grade 3 or higher AEs, SAEs, or episodes of acute rejection that were assessed as related to posoleucel by the treating investigators. From an efficacy perspective, we're immensely gratified with the consistency of these data as they show posoleucel outperforms placebo across both dosing cohorts and viral load levels. The data are only strengthened with more frequent posoleucel dosing and in the highest BK viral load patients. Overall, posoleucel patients had more than 2x the rate of greater than or equal to 1 log BK viral load reductions than placebo patients. This difference increased to 3x for posoleucel over placebo when looking at the bi-weekly dosing group. Absolute median viral load reductions of 1.4 and 1.5 logs were seen in the high viral load posoleucel groups, again, over 3x what was observed in placebo patients.
This efficacy and safety profile in kidney transplant patients is highly supportive of continued investigation in kidney transplant patients and solid organ transplant patients more generally. We look forward to presenting further study results at a scientific conference later this year, as well as engaging with regulators on potential next steps. With that, I'd like to now turn to Q&A, and I'm so pleased to welcome Dr. Anil Chandraker, who is Director of Renal Transplant Medicine at Brigham and Women's Hospital and an international expert in the field of transplantation, and who is also the principal investigator of this posoleucel study. Welcome, Dr. Chandraker.
Thank you. Okay.
Great. I want to remind those of you who are listening that you can submit your questions in the text box below the presentation slides on your screen. While we wait for some additional questions to come in, maybe I'll start off with our first question for Dr. Chandraker. At the start of this call, I touched on how common BK viremia is in kidney transplant patients. I'm wondering if you could elaborate on the unmet need and also talk about the challenges in managing these infections and the impact of these infections on patient outcomes in your clinical experience.
Yeah. Thank you very much. You know, very excited to see these results. Yes, BK is the commonest viral infection that we see after kidney transplantation. It affects, you know, between 15%-25% of all kidney transplant recipients. They all have some degree of viral reactivation. At our own center, it's close to around 20%. You know, the current management of these patients is really the reduction of the immunosuppression. You know, that's a double-edged sword. Patients are on immunosuppression to prevent rejection. If you reduce the immunosuppression, there's always a risk of rejection. In this, the degree of rejection has varied in studies of BK therapy.
You know, what we would predict would be around up to 20% of patients who have their immunosuppression reduced may have some rebound rejection. Of course, there are a whole category of patients in whom reduction of immunosuppression is even riskier because they either are pre-sensitized, meaning they have a much higher risk of rejection following transplantation, or they have been desensitized in order to allow them to receive a transplant, which means removal of anti-HLA antibodies prior to transplantation. In multi-organ transplant recipients, for example, patients who have combined heart and kidney transplants where, you know, it's very difficult to reduce the immunosuppression without putting the heart at risk. If you reject a kidney, you go back onto dialysis. If you reject a heart, unfortunately the patient dies.
You know, there are still very significant unmet needs in terms of treatment of, BK, nephropathy and BK viremia in our kidney transplant population.
Great. Thank you. There is a question that's just come in from Anupam Rama at JPM organ. He's asking, and this is a question we've heard before. Can you put into context what a 1 log viral load reduction means from a patient perspective and how you as a clinician approach treatment and what good looks like?
Yeah, so yes, I think there are, you know, 1 log viral load means, you know, a reduction of 50% in the viral load. In a, yeah, log rating is what's commonly used by infectious disease doctors. In transplant, you know, for transplant nephrologists and transplant surgeons, we normally just look at the overall viral load and see a decrease in the viral load as it goes down. If it starts at 1 million and it goes down to 500,000, that is seen as a very significant decrease and exactly what we would want to see in a patient responding to any sort of therapeutic maneuver.
Great. Thank you. We have another question from Mani Foroohar at SVB, and he's asking about the rejections in the study and the noted that they were all in the treatment group and asking for any potential explanation for the imbalance.
Yeah, I think going into the study, I think one of the major concerns that was raised is that, you know, if you take a T cell population, a polyclonal population, is it possible that these T cells can have an off-target effect and actually cause rejection within the transplant? I will note that there were 42 patients in the treatment group and only 19 placebo groups. There is an imbalance. None of the patients who were actually noted to have rejection by the central reader, the histology read-reader, were actually thought of as having rejection at a local center. If these patients weren't in the study, they wouldn't have been designated as having rejection, and none of them received treatment for rejection because of that.
Specifically, I believe that one patient was an exit patient at our center, had rejection prior to being treated within the study. It's quite likely that they already had a propensity to having rejection episodes. The second patient was a patient who had renal tuberculosis, which is very unusual. Again, I think that speaks to the fact these patients are immunocompromised and therefore open to other infections as well, which makes them difficult to treat. Again, that was assessed as being rejection at the local center. The third patient had rejection, I think 10 weeks after completion of the posoleucel. You wouldn't expect that it would be the posoleucel, if it's happening that far out following transplantation following treatment.
Again, none of those were actually viewed as being related to the drug, by the site investigators.
Thank you. Just for additional context from a study perspective, that was really helpful, clinical perspective. The only factor, baseline factor that we balanced intentionally across the arms was screening viral load, and so we stratified based on that. We did not look to balance on other factors that could have put patients at risk for rejection. Okay, we've got a bunch more questions that have come in since this one. Maybe we'll go to Christopher Raymond at Piper Sandler. He was asking about based on today's results showing the greatest antiviral effect in high viral load patients and bi-weekly dosing, asking if this is the only patient subgroup that we would evaluate in a future phase 3 trial, and would we confirm this dosing regimen?
What I'll say there, I'll take that one, so that's more a strategic question about next steps, is that we're thrilled to see the data today. What we're particularly excited about is the consistency of the efficacy. We see efficacy in the posoleucel overall groups as compared to placebo, where you see, you know, 2-fold higher response rates in percentage of patients experiencing at least a 1 log viral load decline. You see significant differences in median viral load declines. Then those differences are amplified as you and we have noted in the high viral load patients and in the bi-weekly dosing.
What we do with that and where we go with that, I think we set out as an objective in this trial to define the patient population with the highest benefit and to assess whether or not there were differences that would we could tease out between the dosing groups. I think we do then see that that's the biggest impact. How that translates into the next step will be putting our heads together with the transplant community, again, on the backbone of this disease having no approved therapies, and in discussions with regulators to determine what a next step or next trial could look like. Okay. I think that other question is around statistical significance and have we provided stats for this trial?
What I would say is because this is a phase 2 trial that we designed in an intentionally exploratory way, in bringing in a heterogeneous group of patients with respect to viral load levels, time since transplant, eGFR at baseline. A lot of the analysis we've shown you today are post-hoc analyses. In our top line press release, we didn't provide any P values. We've got a P-value with statistical significance in one of our slides. I think overall, in general, we really have de-emphasized the importance of achieving statistical significance and more focused on looking at places where we see consistency of the data across the board, because that's really what this study was about, rather than a phase 3 study where you're really trying to hit a single P value.
All right, couple more questions. Here's one for Dr. Chandraker. How receptive would solid organ transplant physicians be to adopting this type of treatment modality? I think what that means is using a cell therapy in the solid organ transplant population. Maybe you could speak to that.
Yeah. That was really one of the most exciting parts to this. I think, you know, the solid organ community is really interested in utilizing cell therapies and, you know, because there are other potential therapeutic approaches, such as the use of regulatory T cells that the community is very interested in. You know, with this study, what was so interesting was that there were multiple sites. Each site managed to get the cells in. The actual study itself was quite straightforward in that the cells were shipped, and they were thawed, and then they had to be infused into the patient within a short period of time. That was done very successfully across very different types of transplant centers from very, you know, high functioning academic centers to smaller transplant centers.
I think there's a great deal of excitement. You know, I still constantly get calls from colleagues asking if the study is still open because they have patients they would like to enroll into the study. I think there is a lot of interest in this area. I think it would be very receptive.
Great. Thank you. let's see. here's a question around to you, Dr. Chandraker, around what do you see as the potential benefits of using virus-specific T cells for this disease and as compared to going after other mechanisms of action?
So I think, yes, it's very inter-- You know, one thing I would say, and it's not something I think that's been touched on, is that it is not easy to do these studies, because, you know, you have reduction of immunosuppression, and in this study, the site PI uses immunosuppression as is clinically safe. To set up studies like this are very difficult because you essentially have a moving target. To get a significant signal is actually very interesting. There are other potential treatments that, you know, we've trialed a number of these treatments in the past. None of them have so far come to fruition. I think prevention is a great strategy, potentially, but I think, you know, you'd have to be able to show clinical efficacy.
Great. Thank you. I think there's another question around from Anupam Rama at J.P. Morgan asking around our next steps. As you look at the totality of data today, are you committed to moving forward with this indication with next steps focused on determining study endpoints, duration and sample size? I would say this is a very similar response to the one I provided earlier in terms of we're digesting these data. We're really thrilled to see such a consistent signal. We're really excited to have identified the patient population who benefits most from posoleucel as the population with the highest unmet need, those with the highest viral load. We see that as being a really important finding.
We're also pleased to, you know, have an understanding that there is a bit of a dose response here in terms of increasing the frequency of posoleucel, again, leading to increases in responses. In terms of committing to moving forward this indication with next steps, I think what we need to do is we need to gather input from the community in parallel to engaging with regulators. We're really excited to do that and to determine what our next steps are gonna be. We haven't gotten to that point yet. It looks like there's one more question for Dr. Chandraker. How receptive would the solid organ transplant physicians be to adopting this type of treatment modality?
This is also, similar to the prior question in terms of, are physicians open to using cell therapy in solid organ transplant patients?
I mean, I would say that absolutely. I mean, we had a future transplantation meeting that was run by the American Society of Transplantation a couple of years ago, where we had one section on use of cell therapies in different aspects of solid organ transplantation. There seems to be resounding interest in this area. I have not met any transplant physicians or surgeons who are saying that this is a bad thing. I think the concern and the right concern is, you know, is this safe? I think, you know, having strong safety signals from a study like this will only enhance the interest in this area.
Great. Thank you. Sonia, I think we're done with the questions in the queue. Is that correct?
That's correct. There are no further questions, so we can hand it back over to you, Diana, to close out the call.
Great. Thank you. I do have one more slide just to round things out. We're very excited about these results from our first study to evaluate a virus-specific T cell therapy in solid organ transplant patients. As I mentioned before, it's the consistency of posoleucel's safety profile and efficacy profile in these kidney transplant patients, emphasizing that those at highest risk for BKV-associated graft loss seem to have the highest antiviral responses to posoleucel. Because of these cumulative data, we really see this as an important and compelling milestone moment, not just for AlloVir, but also for the kidney transplant community and solid organ transplant community more generally. We're looking forward to working with regulatory authorities and transplant specialists on our clinical development strategy in kidney transplant patients and beyond.
That brings us back to posoleucel overall and how we really do have a franchise within a single product. The positive data from this phase 2 study paves the way to build into solid organ transplant patients on the back of what we're already doing in stem cell transplant patients, where we have our 3 ongoing phase 3 registrational trials. There, we're really excited to be on track to complete enrollment of all phase 3 studies by the end of this year, having data readouts there over the course of 2024. As we look to those data readouts, preparing for commercial readiness, fast regulatory filings, and advancing our pipeline as well to have a large impact across the broad and changing landscape of immunocompromised patients who could potentially benefit from this novel approach to treating viral infections.
With that, I'll conclude. Thank you for your time, and thank you for your interest in AlloVir.