PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

Greetings, and welcome to PDS Biotechnologies Post 2022 ASCO Call and Webcast. [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Gabby DeGravina of CG Capital. You may now begin.

Good morning, and welcome to PDS Biotechnologies Post 2022 ASCO Conference Call and Webcast. With me today from the company are Dr. Frank Bedu-Addo, Chief Executive Officer; Dr. Lauren V. Wood, Chief Medical Officer; and Matt Hill, Chief Financial Officer. Before we begin, we want to remind everyone that on today's call, the company will be making forward-looking statements regarding regulatory and product candidate development plans as well as research activities. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. A description of these risks can be found in PDS Biotech's most recent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this conference call. Except to the extent which required by applicable law or regulation, PDSB undertakes no obligation to update the forward-looking statements included today to reflect subsequent events or circumstances. With that, I would now like to turn the call over to Dr. Frank Bedu-Addo. Frank?

Thank you, Gabby, and thanks to all of you for joining us this morning. Before we get into the details of our ASCO post presentation, we thought it would make sense to set the stage around the data that we've presented and, of course, highlight the market being addressed by both clinical programs presented at ASCO. PDS0101 is designed to treat HPV16 associated cancers, including head and neck, cervical, anal, vaginal, vulvar and penile cancers. In the VERSATILE-002 trial, PDS0101 is being evaluated with KEYTRUDA in head and neck cancer. In the National Cancer Institute-led trial, PDS0101 is being evaluated in a triple combination across the full spectrum of HPV16-related cancers. We estimate that these markets could create an aggregate market potential of $5 billion to $6 billion. PDS Biotech is seeking to make significant advancements in the treatment of cancer by overcoming the major limitations of current immunotherapy treatments. These limitations include limited induction of an adequate CD8 killer T-cell response, and secondly, limited ability to broadly overcome immune suppression beyond what checkpoint inhibitors are capable of achieving. To date, we have been able to show the utility of our Versamune platform in promoting the body's ability to generate the right type of killer T-cells and also the right T-cell potency and quantity as well as the ability to generate memory T-cells to enhance the durability of response. Importantly, we have demonstrated the potential to generate T-cells that have high specificity to the tumor, therefore, promoting the potential for potency while mitigating serious systemic side effects. This combination of potency and safety, we believe, could be transformational in cancer treatment. Also importantly, as we will see with the triple combination data and as filed in our patent family #5, we may be seeing evidence of Versamune's potential in combination with cytokines to overcome other immunosuppressive mechanisms that are independent of immune checkpoints such as myeloid-derived suppressor cells. We have now established proof-of-concept for Versamune, with clinical studies of PDS0101 as a molecularly targeted cancer immunotherapy that has demonstrated potential to be agnostic to the location of the cancer in the body and thus have the potential to treat a range of cancer types. We also have pipeline candidates in preclinical development with various antigens that generate similar levels of tumor-specific polyfunctional killer T-cells in the body. This establishment of proof-of-concept was initiated with a Phase I human clinical trial of PDS0101 monotherapy in subjects with pre-cervical cancer lesions. We confirmed induction of CD8 T-cells in the blood and also a retrospective demonstration of lesion shrinkage in 80% of patients with complete elimination of lesions in 60% of the patients within 3 months of treatment. Analysis of T-cell induction 3 months after treatment demonstrated that the PDS0101 monotherapy induced a memory T-cell response. The memory T-cell response is necessary for durability or long-term efficacy of the disease-specific immune response, which in the Phase I study correlated with the lack of lesion recurrence over a 2-year evaluation period in the patients. This monotherapy trial suggests that PDS0101 may induce durable and clinically relevant CD8 T-cells. With regards to the ASCO data, first, we will review our VERSATILE-002 Phase II trial, which is studying PDS0101 in combination with Merck's anti-PD-1 therapy, KEYTRUDA or pembrolizumab, in patients with HPV16 positive, metastatic and/or recurrent head and neck cancer. This trial has 2 study groups, checkpoint naive patients and checkpoint inhibitor refractory patients. Note that based partly on the data we will be reviewing today, PDS Biotech has received FDA fast track designation for development of the combination. In this trial, PDS Biotech is seeking to improve clinical benefit over that seen with KEYTRUDA monotherapy with a goal of approximately doubling the published objective response rate of 17% to approximately 33%. In addition to improved tumor shrinkage and overall survival, we believe that a significant treatment advantage will be achieved if enhanced clinical benefit is attained without compounding or increasing the toxicity profile over what has been reported with KEYTRUDA monotherapy. Please note that no controlled clinical studies have been conducted to compare checkpoint inhibitors and PDS0101. When thinking about the VERSATILE-002 data, it's important to understand the current treatments available for patients. In the KEYNOTE-048 study published by Merck, an objective response rate, which is greater than 30% tumor shrinkage, was reported in 17% of checkpoint inhibitor naive head and neck cancer patients who were treated with KEYTRUDA. The overall survival rate of these patients was 49% at 12 months. At 12 months, 17% of the surviving patients had ongoing or continued therapeutic responses without disease progression. It was also reported that about 17% of these patients treated with KEYTRUDA monotherapy experienced Grade 3 or higher adverse events, also called severe side effects. With that, let's turn to the data from the VERSATILE-002 trial that were presented at ASCO. The highlights from the VERSATILE-002 Phase II clinical trial include 17 out of 19 patients for efficacy with available imaging data and 19 patients for safety. The objective response rate we've seen thus far was 7 out of 17 patients or 41.2%, which compares favorably to the published result of 17% seen in KEYNOTE-048. Additionally, 2 of the 7 patients had no evidence of disease or complete responses. Please note that these data include both confirmed and unconfirmed responses. Stable disease was reported in 6 out of the 17 patients or 35.3%, with 4 out of these 6 patients or 66.7% of them experiencing tumor shrinkage of less than 30%. Clinical efficacy, which is the objective response rate plus stable disease was seen in 13 out of 17 patients or 76.5%. Progressive or ongoing disease was reported in 4 out of 17 patients or 23.5%. At the time of data cutoff, patients have received a median of 4 out of 5 doses of PDS0101 and 9 out of 35 doses of KEYTRUDA. When we look at safety, it's important to note that there were no treatment-related adverse events greater than or equal to Grade 3 in the 19 patients. Additionally, no patients required dose interruption or reduction on the combination treatment and no patients discontinued the combination treatments. We also want to point out that median progression-free survival and overall survival have not yet been reached. The overall survival rate at 9 months of follow-up was 87.2% and the progression-free survival was 55.2%. So this almost 88% response and 55% rate is in contrast to 49% and 17%, respectively, for KEYTRUDA monotherapy in the published KEYNOTE-048 study. Overall, 89% of patients treated with PDS0101 in combination with KEYTRUDA were alive at the median of 9 months, suggesting survival benefits. While the data presented at ASCO are preliminary, we are encouraged by seeing enhanced clinical responses, specifically shrinking tumors extending survival without treatment-related Grade 3 and 4 toxicities thus far. It is important to emphasize that these are relatively small numbers. However, the responses when compared even with published results for KEYTRUDA plus chemotherapy, which have an objective response of 36% and overall survival at 12 months of 55% are encouraging. With the published results for KEYTRUDA plus chemotherapy in KEYNOTE-048, it is reported that over 70% of patients had Grade 3 or Grade 4 adverse events. At this time, the outcomes for PDS0101 in combination with KEYTRUDA appear to be trending at least in alignment with the historical efficacy figures for KEYTRUDA plus chemotherapy without the toxicity. Let's now move from the dual combination therapy to discuss the National Cancer Institute-led triple combination. In this trial, we are evaluating PDS0101 in combination with bintrafusp alfa, a bifunctional checkpoint inhibitor and M9241, also known as NHS-IL12 to investigational immune modulating candidates owned by Merck KGaA. By combining these 3 agents that activate antitumor immune response by complementary mechanisms, our goal is to generate cancer targeting killer T-cells while overcoming the immunosuppressive tumor environments. The triple combination is being evaluated across the range of HPV-positive advanced relapsed and refractory cancers, but are well documented to be extremely difficult to treat and for which more effective therapies are desperately needed. It is important to note that, historically, checkpoint inhibitors have been evaluated in the treatment of advanced HPV-associated cancers. In published studies, objective response rates have ranged in checkpoint inhibitor naive patients from 13% to 24%. Unfortunately, the majority of patients who receive checkpoint inhibitor therapy will continue to progress and become checkpoint inhibitor refractory. Historical median survival rates for checkpoint inhibitor refractory patients is only 3 to 4 months, and objective responses have historically been less than 10%. For most patients with checkpoint inhibitor refractory HPV-associated disease, there is no clear effective standard of care. A significant data package has been generated by the National Cancer Institute since the presentation at ASCO last year. Some important key pieces of information were presented at the Sears meeting. First, the durability of the responses. We now have evidence that the high objective responses may be durable and provide potential survival benefit. Secondly, the data suggests that all 3 agents may contribute in a clinical setting towards the promising outcomes seen to date. This has already been demonstrated in preclinical studies. Let's start with studies that demonstrate the potential roles of PDS0101 and M9241 in checkpoint inhibitor refractory patients. These are the patients who have failed all treatments, including checkpoint inhibitors. On the left plot, we see the results of studies evaluating high and low dose M9241. We see with high dose M9241 an objective response, meaning to much more than 30% in 63% of patients. On the other hand, with low-dose M9241, we only see an objective response rate of 7%. As a result of these data, all patients are currently receiving the high dose M9241. Now on the right-hand side, we see an evaluation that was done in HPV16 positive and HPV16 negative patients, which shows the role of PDS0101. Here, we see that even with the high dose M9241 when patients who are HPV16 negative received the triple combination, not a single patient experienced any tumor shrinkage. In the patients who are HPV16 positive, however, almost 70% of patients saw tumor shrinkage. This study suggests that even with high dose M9241, the right type of killer T-cells are necessary to induce tumor shrinkage. The role of the checkpoint inhibitor bintrafusp alfa in this population has already been confirmed and published. Now on this slide, we see waterfall in spite of plots that were presented by the National Cancer Institute. We are pleased by the overall responses we're seeing in each of the various cancer types across both checkpoint inhibitor naive and refractory patients. The data presented includes 30 cancer patients made up of 9 cervical, 2 vaginal and vulva, 6 anal and 13 head and neck cancer types. In these plots, we are seeing responses in all of the HPV cancer types treated in the trial. And secondly, the majority of responders who have either stable disease or tumor shrinkage received high-dose M9241. An objective response was seen in 7 out of 8 patients or 88% with checkpoint inhibitor naive disease. And 7 of these 7 -- and of these 7 who had objective responses, 4 out of 7 or 57% of the patient's responses are still ongoing at a median of 17 months. In checkpoint inhibitor refractory disease, these patients were evaluated with both high and low dose M9241 as discussed. Among high-dose M9241 patients, 5 out of 8 or 63% had an objective response. To put this in context, the historical objective response rates in these patients has been less than 10%. If we look at the patients treated with both high and low dose M9241 combined, tumor reduction was seen in 10 out of 22 patients or 45% with checkpoint inhibitor refractory disease. Additionally, of the 6 patients who had an objective response, 4 of the 6 or 67% of the patient's responses are ongoing at a median of 12 months. In these patients that were treated with a high or low dose of M9241 despite the differences in objective responses between the 2 groups, survival outcomes were similar with a p-value of 0.96 by Kaplan-Meier analysis. At a median of 12 months of follow-up, 7 out of 22 patients or 77% were alive. To put this in context again, these are patients who are usually going into hospice and historically have only 3 to 4 months survival. In the checkpoint inhibitor naive cohort, 6 out of 8 patients or 75% were alive at a median of 17 months of follow-up, again, suggesting promising durability of the immune response. We see clinical responses across all types of HPV-positive cancers, which is encouraging. Now turning to the preliminary safety, 13 out of the 30 patients or 43% experienced Grade 3 treatment-related adverse events, with 7% experiencing Grade 4 adverse events. There were no Grade 5 treatment-related adverse events. We discussed the safety profile of checkpoint inhibitor plus chemotherapy and the fact that in KEYNOTE-048, over 70% had Grade 3 and 4 adverse events. In this case, we see potentially enhanced therapeutic benefit with fewer adverse events. Now a key question is how is the triple combination working to achieve the reported results. We believe that the combination of the Versamune platform and NHS-IL12 or M9241 is overcoming additional immunosuppressive mechanisms that do not use immune checkpoints to evade T-cells, and therefore, are not overcome by checkpoint inhibitors. PDS Biotech has demonstrated and owns U.S. patent number 10 828 364, covering the combination of Versamune and growth factors such as GM-CSF and cytokines such as IL-1 through IL-18 to reduce the population of myeloid-derived suppressor cells, also called MDSC. Importantly, this effect is independent of antigen inclusion. However, in the presence of antigens, Versamune also promotes a powerful tumor-specific killer T-cell response in addition to overcoming immune evasion. This slide depicts what we envision may be happening. For example, with the combination of PDS0101 in KEYTRUDA, we overcome immunization primarily in tumors that evade attack using the immune checkpoints. However, with the targeted T-cell attack promoted by PDS0101, we see an objective response of about 41%. With the triple combination, we may overcome immune suppression in a broader population of tumors that evade immune detection using multiple mechanisms. This larger number of exposed tumors are then killed using a targeted T-cell attack generated by Versamune, and now we see an objective response of 88% in checkpoint inhibitor naive patients. What this suggests, therefore, is that the combination of Versamune and cytokines may provide a proprietary platform that overcomes a broad range of immune suppressive mechanisms and may help advance the field of cancer immunotherapy, leading to more effective treatments. We expect to apply this platform beyond PDS0101. This clinical study is a demonstration of what has already been predicted by our preclinical studies and patents. In wrapping up this section, the results presented today suggest, in agreement with the published preclinical studies as well as clinical data, that all 3 drugs may contribute to the clinical outcomes. It is also the first clinical demonstration of the potential synergy between Versamune and NHS-IL12. These results, combined with the previously reported data from this trial, suggests that this novel combination has the potential to provide improved clinical outcomes and overall survival for patients with refractory HPV-associated cancers. And based on the data generated in both trials, we expect to have conversations with the FDA in the coming months to align on a pivotal trial regulatory pathway and strategy for both programs. With PDS0101 in combination with KEYTRUDA, this will be driven by the already received FDA fast track designation. We recently announced approval to expand our VERSATILE-00 trial into Europe. This expansion may enhance recruitment efforts and the efficient execution of a larger trial if initiated. Performing our pivotal trials in the United States and Europe will be important in getting both U.S. and EU product registration. As you may expect, these approvals take several months from start to finish. Clinical expenses associated with this expansion are already accounted for in our previously announced forecast. The data presented at this year's ASCO in both poster presentations, we believe, is promising. In our view, these data presented provide proof-of-concept for the Versamune platform as a CD8 T-cell activator and also as a platform to overcome tumor immune suppression. To summarize concisely, our VERSATILE-002 study has shown the potential to improve long-term clinical benefit without the severe side effects of chemotherapy treatment for those suffering from recurrent or metastatic HPV-positive head and neck cancer. Additionally, our triple combination has the potential to progress immunotherapy beyond what can be achieved with checkpoint inhibitors and may allow for clinical benefit to be achieved in a broader patient population, importantly, including the checkpoint inhibitor refractory patients. In closing, we are pleased with these data that were presented and would now like to open up the line to take your questions. Thank you very much.

[Operator Instructions] Our first question has come from the line of Louise Chen with Cantor Fitzgerald.

This is Carvey on for Louise at Cantor. Congrats on the data presented. We just have a few questions. First, how was decision feedback at ASCO on the data you presented? Second, any updated thoughts on the market opportunity for PDS0101 afternoon presentations? And finally, on the VERSATILE-002 study, what are the expectations when looking at the CPI refractory patients?

Carvey, could you repeat the last question, the last portion of your question?

Yes. My last question on the VERSATILE-002, you guys started expanding on the CPI refractory setting last year. So we're just thinking about the expectations going in, we're looking at those data.

Okay. Okay. So I will start answering and I'll give you some of the answers, and then I will hand over to Dr. Wood to also give you some of her impressions. So in terms of the market opportunity, I think one of the key things that we are looking at over here is our strategy of evaluating different combinations in specific HPV cancer indications as well as in all HPV cancers and also at very different stages of disease. It's really designed to effectively understand what cancer treatments complement or synergize with PDS0101 or with diverse-based products, right? So here, this is also designed to determine which indications the various combinations may work best in and also at what stage of the disease. So this really enables us to determine what combinations and indications should be progressed into our pivotal trials, right? And this is really what has been facilitated. Our partnerships have actually facilitated the strategy of really understanding how these work -- could potentially work in the different indications. So for example, with the triple combination. We're seeing really outstanding data in checkpoint inhibitor refractory patients who really have no other alternatives, right? So for example, with a triple combination, we envision, once we talk to the FDA, potentially moving forward first in the checkpoint inhibitor refractory patient population. Just because of the data we've seen to date, the potential to become much broader immunosuppressive mechanisms and also to prolong the survival of these patients where we've seen 77% of these patients alive at 12 months, whereas traditionally, these patients should be dead within 3 to 4 months, right? So we believe that's a significant opportunity to help these patients and potentially to get this moving rapidly to address those patients. Now when we move over to the checkpoint inhibitor naive population, again, we see a significant opportunity there to really enhance what we've seen currently with checkpoint inhibitors in that population while potentially also eliminating a lot of the serious adverse events. And I'll let Lauren talk to you more about what oncologists view about the safety of these products, but I think that's really how we would see the market opportunities. We believe the market opportunity is still really significant for both the triple combination as well as the dual combination. I'll hand over to Lauren to give you the feedback at the conference as well as talk a little bit more about the VERSATILE-002 at and triple combination and the safety and clinical responses there that we're seeing. Lauren?

great. Thank you so much, Frank, and good morning, everyone. So just for everyone's recall, the poster presentation for the NCI triple combination that Frank has reviewed in HPV-related cancers was presented on Sunday morning. There was a lot of interest in the poster. I was not there for the entire session, but I want to highlight for all our listeners that this poster was also selected for the poster discussion session that followed that day after the session concluded. There was also reportedly a yellow sticky note left on the poster that said, "This should be submitted to the Journal of immunotherapy for cancer.' The disclaimer is I didn't see that yellow sticky, but reportedly, it was there. The VERSATILE-002 poster presentation was yesterday afternoon, and there was a significant amount of interest in the poster. I would say that the focus of the discussions were twofold. One, on the demonstrated waterfall plots demonstrating the achievement of objective responses and 41% of the subjects that we had presented in the CPI naive cohort and how that compared favorably with the historical data. The other thing that really seemed to impress individuals was the relative lack of treatment-related adverse events greater than or equal to Grade 3 that we've seen in the study with the combination, specifically that there was no dose discontinuation of either PDS0101 or pembrolizumab. And the other highlight was the fact that the median progression-free survival and overall survival had not been reached for the cohort. This is significant and again compares favorably because we know from historical published data on KEYNOTE-048 that in patients who have a composite score, PD-L1 tumor score greater than or equal to 1, the median progression-free survival for pembro monotherapy in that cohort of patients was reported to be approximately 3.2 months. And then when pembrolizumab was delivered with chemotherapy or extreme chemotherapy was delivered, the progression free for survival was approximately 5 to 5.2 months. So the fact that the 9-month PFS rate of 55% and the overall survival rate of 87% to this point in time is catching individual's attention. As it relates to the recruitment of the CPI refractory cohort, we did begin enrollment in that cohort, and we are close to completing enrollment in that cohort hopefully within the coming weeks. The Stage 1 of the refractory cohort requires that we enroll 21 patients. I can confirm that we have 17 patients that have been enrolled and dosed, and we actually have remaining 4 patients that are in screening to complete enrollment of that Stage 1 cohort. And hopefully, that will be accomplished before the end of this month.

Our next questions come from the line of Leland Gershell, Oppenheimer.

I wanted to ask a couple of questions. First, I know the trial is ongoing, but wondering if you've had a chance in VERSATILE-002, just in looking at patients who responded versus those who didn't, if you've looked at any characteristics in terms of their -- mounting of their CD8-positive killer T-cell response or perhaps other factors that may have differentiated between those who did respond and who didn't in the CPI naive. And also I want to ask, maybe I missed it in the slides, but if you could just elaborate on the number of the Grade 3 events and what those were in VERSATILE-002.

Great. Frank, do you want me to go ahead and take that question?

Yes, Lauren, why don't you go ahead and take it. Thank you.

Wonderful. Thank you. Leland, that's great. Those are great questions. So as you all may be aware, we are specifically planning on characterizing the HPV16 specific both CD4 and CD8 T-cell responses that are associated with the combination therapy on VERSATILE-002. We are collecting those specimens, and they've been archived. And so our plan is to do that first analysis of specimens from both the CPI naive and CPI refractory patients who were in Stage 1 when we have at least preliminary data not only from baseline, but after they've received at least 4 cycles of therapy. We do plan to examine those specific responses at 3 time points. So we have not yet done that. We are planning on using multiparametric flow cytometry and specifically the IsoPlexis IsoCode Chip platform so that we can confirm the presence of antigen-specific polyfunctional T-cell responses, again, in both the CD4 and CD8 T-cell populations, but we have not yet done that. That's going to be done on batch when we do the analysis. And we hope that we will be able to pursue that before the end of this year. When we look at this preliminary cohort of Stage 1 patients, there does not appear to be any differentiating baseline characteristic that highlights the responder versus the nonresponder based on absolute lymphocyte count, CD4 percent or absolute CD8 percent or absolute counts, even Vitamin D levels, which I'm very interested in because it's a very critical peptide hormone receptor involved in immune-based reactions and immune responses. So right now, as of our preliminary analysis in this very small cohort of patients, we don't really have anything that highlights and differentiates or predicts those individuals who appear to have had responses versus those who have not responded or just had stabilization of disease. Can you repeat your other question for me? I'm sorry.

Laura, on the safety, the Grade 3, what those were and how many of those patients had them.

Right. So if we go back to the Slide 7 in the presentation, only 5 out of the 9 subjects had Grade 3 AEs. And that there were 5 subjects, the number of events, and that was not attributed to either pembrolizumab or PDS0101 or the combination.

Okay. And then one more question, if I may. Given the profound efficacy we've been seeing in the triple combo and also given your patent estate with respect to including cytokine-based therapies in -- as part of with the Versamune platform, wondering if you have any contemplations around future studies of other cytokine-based agents aside from bintra and M9241 that could be -- that could pair well with the Versamune.

Thanks, but...

Yes, I was going to say...

Laura, I'll go quickly and I'll hand over to you. There's something I want to go back to Leland on it, I'll hand back to you quickly. Leland, going back to the question you asked, actually, this -- what you just brought up with the triple combination is actually very important and correlates with the earlier question you ask in terms of what are the characteristics of the responders and nonresponders. So one of the key things we're seeing now potentially is that there are a number of factors involved where their patient response or not, one of them being the immunosuppressive mechanisms and by what mechanism are those tumors hiding from T-cell attack or from immune surveillance, right? And so what we envision could potentially be happening here is that in the patients who are responding to that checkpoint inhibitor plus PDS0101 therapy, their tumors are most probably hiding using the upregulation of immune checkpoint mechanism. However, there will be a number of these advanced tumors that are still not visible to their T-cell attack because they're probably hiding using other mechanisms. What we are able potentially to do with combination with -- of Versamune and cytokines is overcome some of those additional checkpoint inhibitor independent immunosuppressive mechanisms, and therefore, see a much larger or a much greater response rate in those patients by more or less unlocking those tumors and allowing the generated T-cells to go in and more efficiently kill those exposed cancer cells. As I said in the patent, the patent actually covers both growth factors and a broad range of cytokines. And so what we see today is really the first clinical demonstration of that effect that has already been demonstrated in preclinical studies. And so we do envision that based upon the proprietary platform and the potential to use these approaches, IL-2, IL-12, GM-CSF that these are things we will be evaluating and selecting the best combinations as we move forward into PDS0102 and PDS0103. But the patent definitely gives us that flexibility to select which ones may work best. And we also believe that NHS IL-12, based upon the data we've generated to date, appears to provide good synergy with Versamune. And so that's something that we will also look at as a platform moving forward into the other indications. Lauren, sorry, I'll hand over back to you.

Sure, Frank. The only thing that I would add and highlight for our listeners is that, again, Frank has highlighted the IP and the potential to combine the Versamune platforms with multiple growth factors and cytokines. And exactly which cytokines to pursue and what combinations would be best? There is really an expansive potential of possible combinations. But what I think is going to be key in driving this is really well vetted preclinical data and investigation in terms of optimizing what those combinations may be. I do want to highlight for everyone the fact that the very impressive data that we're seeing in the clinical study of the triple combination was really informed by well-informed preclinical studies performed by the laboratory of Dr. Jeff Schlom at the National Cancer Institute and published in June 2020 in the Journal of Immunotherapy of Cancer. And specifically, the doublet combinations of PDS0101, bintrafusp alfa and NHS-IL12 were examined as well as the triple combination as well as the monotherapy of these individual agents in preclinical animal modeling studies. And it was clearly demonstrated that it was the triple combination that resulted in superior tumor regression and specifically induction of both CD8 and CD4 in the tumor microenvironment. And that's what informed this clinical trial. And I think we would want to pursue that kind of aggressive preclinical vetting in our combination studies with impending future Versamune-based products as well as with other cytokines. I think that's what leads to the kind of impressive preliminary clinical success that we are seeing.

Our next question is come from the line of Jim Molloy with Alliance Global Partners.

I had a quick question on two things really. Has the -- the data you presented at ASCO, has that changed the character? Or how you could characterize potential partnership opportunities? Or is it still too early yet for that? And then second, are you able to narrow down the expectations on timing for end of Phase II meetings for VERSATILE or the triple combo?

Jim, thanks a lot for those questions. So for the first one, the data presented at ASCO, no, it has not changed our view of how we move forward with partnerships. So one of the things I mentioned in the presentation is the fact that we have -- we now believe we've generated solid proof-of-concept for the Versamune platform in terms of its ability not only to generate CD8 T-cells, but in combination with the cytokines to overcome broader immune suppression. That proof-of-concept is very clearly demonstrated today. We believe starting this process that based upon the field in which we are, that this would be necessary to make potential and prospective partners comfortable with the technology and the validation of the technology. And we just brought on our Senior Vice President of Business Development a few weeks ago, really to start this process of really aggressively look, pursuing those potential partnerships moving forward, right? We do believe that this is the time for it. The data has been generated that demonstrates exactly how Versamune is working and why it's working. And so that piece, we believe this data does not change anything. It actually solidifies our view in terms of the generation of proof-of-concept, and therefore, that is being pursued quite actively today. Right. In terms of the timing for end of Phase II meetings, we are planning to meet with the FDA hopefully sometime in the third quarter to start discussions on how we progress both programs into pivotal trials and what the FDA would want to see on our part to get that done. So hopefully, but sometime in the third quarter, we should have some more information on exactly how we're going to progress these moving forward. But our goal would be to move these forward as quickly as possible. Just based upon the data and opportunity we see and the unmet medical needs. As you can tell, we've already received a fast track of VERSATILE-002, which really highlights the FDA's view of the unmet medical need in that space. And we -- and the unmet medical need in terms of checkpoint inhibitor refractory patients is also quite severe. So we would definitely like to move these forward as quickly as possible, and we'll be discussing that with the FDA shortly.

Maybe a quick follow-up on that. So the expectation would be that the end of Phase II is second half of this year in the Phase II meeting, single Phase III trial design hammered out and started early next year. Is that reasonable? And then is current -- is a partnership necessary to run the Phase IIIs or maybe just preferable to defray some of the costs?

Yes. The partnership is not necessary. But in terms of the timing, I would probably hold off on the timing until we actually have those discussions with the FDA. So I think in the third quarter, we'll be in a position to give you much more definite date on when those things are happening, right? We definitely want to get in front of the FDA as quickly as possible because I think we would want to have some of those answers as quickly as possible too.

Our next question has come from the line of Joe Pantginis with H.C. Wainwright.

So you guys -- obviously, you had a lot of your updates in today's slides for the triple combo and also like the mechanism. So I was hoping to translate, no pun intended, my question to the 002 study and get some thoughts around the Versamune contribution from a mechanistic standpoint and what you feel is ongoing in the changes in the tumor microenvironment that allow for enhanced immune infiltration and what have you in this difficult head and neck population and when we think you might be able to show some translational data to further support that?

Lauren, do you want to go first?

Yes. Thank you Joe for the questions. So I think one of the things that we are observing with the VERSATILE-002 combination and the differentiating aspects of the Versamune activity is, is that we really know from our extensively well-vetted preclinical studies that Versamune, specifically when it's co-delivered with whatever the antigens of interest are and specifically with PDS0101, these are a mixture of HPV16 E6 and E7 antigens. What Versamune is able to do as a cationic lipid nanoparticle is really address several key issues that I think have been lacking in terms of this approach. One, it facilitates antigen uptake and endosomal processing and cross presentation to both MHC class I and class II pathways, depending on the size of the antigens that you deliver. This allows induction of antigen-specific CD8 and CD4 T-cell responses. And I just want to highlight for a moment, I think I'm coming at this from an immunology perspective, the critical importance of having induction of antigen-specific CD4 helper responses because we know that when CD4 help is induced, you really have the induction of superior CD8 T-cell responses in terms of functional ability and longevity, and that's what we're also going to seek to document when we do the characterization of these bank specimens from patients on the trial. The other thing that's critical is, is that these responses are induced in the context of triggering Type 1 interferons, which basically reflects triggering of innate immunity that individuals over the last 20 years have all been working very diligently and actively to pursue as far as accomplishing when you're trying to generate an adaptive immune response. And people have used CPG, they use toll-like receptor 7 and 9 in different TLRs to try and get this innate triggering. But I think the fact that we specifically see triggering of Type 1 interferons is what is absolutely unequivocally differentiating about Versamune. And importantly, this is really related to the simple enantiomeric specificity of Versamune. You do not see this with other enantiomers of our [ data ]. Getting to your second question about translational documentation that, indeed, we are seeing triggering of this tumor-specific T-cell immunity and that the T-cells are tracking to tumors. It's something that we've been wanting to document. And we're very encouraged that we're going to be able to actually get that information from a window of opportunity trial that was launched and opened in March 2022 by our colleagues at the Mayo Clinic in Rochester, Minnesota. Specifically, this trial is going to look at the delivery of neoadjuvant PDS0101, either 3 doses of monotherapy or 3 doses in combination in patients with HPV-positive oropharyngeal carcinoma before they proceed to definitive curative surgery with trans-robotic oral surgery and resection. So this is actually going to allow us to look at delivering PDS0101 in patients who have very pristine immune systems, who have not been irradiated, whose immune systems have not been assaulted by chemotherapy. And it will allow us to specifically ask, do we see induction of these HPV16-specific T-cells; do these T-cells track to the tumor; are the T-cells that are tracking to the tumor, are they associated with pathologic response; and how does that compare to studies that have been already done with pembrolizumab monotherapy in this population in the neoadjuvant setting. As everyone has probably aware, there is tremendous buzz and enthusiasm about the neoadjuvant delivery of patients, a checkpoint inhibitor to patients with rectal cancer that was reported on Sunday. It's a small subset of patients with DNA mismatch repair, but there was 100% progression of tumors and literally elimination of the need for chemo radiation or even further surgery in this small population of 12 patients. So I think that is highlighting the potential and the desire that everyone has had in the immuno-oncology space and in the therapeutic space to really look at our interventions earlier in disease. And that's where we're really going to get at those translational questions, Joe.

Our next questions come from the line of Robert LeBoyer with NOBLE Capital Markets.

I had a question in the triple therapy refractory group. And in the group who was stratified by the patients who've got the high dose and the low dose, with the low dose coming in with only 1 out of 14 patients showing the overall response. And I know Dr. Bedu-Addo went through some of the mechanisms early in the call, but could you just explain a little bit about how you had a difference of 63% versus 7% in the two because I had heard some speculation and some questions about which of the 3 drugs in the combination was actually achieving the response and question whether the checkpoint inhibitor with M9241 should be tested without PDS0101 and questioning the actual contributions of each drug to the response.

Robert, thanks a lot. That's actually a question that many people have been asking and seeking to really understand what's happening there. So one of the key things to note is that with all these agents in drug, even with monotherapies, a certain minimal amount is actually required to trigger the right mechanisms, right? So you always want to understand how much of each component is necessary to achieve their optimal clinical benefit, right? So if you look at the first, the slide I showed earlier, where you look at the high dose and low dose, you are correct. With the high dose, we had a 63% objective response rate and a 7% objective response rate. Now remember, this is -- this does not mean tumor shrinkage. It's just higher than 30% shrinkage, right? So that's the arbitrary number that pertains to the objective response, right? So it's 29% response rate with that patient -- far worse than a patient who had a 31% response rate, 31% tumor shrinkage, for example. Who knows? I don't think so, right? But if you look at overall tumor shrinkage, it's about 45% when you look at both high and low dose. So a number of patients actually had stable disease and started to see tumor shrinkage. They just have not reached a 30% objective response rate. But what's very important here in terms of how the components interact with each other, if you now look at the patients who are HPV16 positive, right? So these are the patients whose tumors are expressed the right target for PDS0101, right? PDS0101 is training and priming killer T-cells and helper T-cells to recognize specifically HPV16, right? So when you actually enroll patients, the 7 patients who are enrolled who are HPV16 negative, their tumors did not express the right marker for the T-cells to recognize and kill their tumors. Now when those patients were dosed with the triple combination with a high dose M9241, right, so now they're getting the high dose NHS-IL12, despite the fact that they got the high dose NHS-IL 12, not a single one of those patients had any tumor regression. Now that is very important because what that suggests is that even if you get the high dose NHS-IL12 and even if we reduce the immune checkpoints, you reduce the tumor hiding using MDCs, unless you can generate that powerful killer T-cell response to go in and kill those exposed cancers, you may not see good therapeutic benefit or you may not see good tumor shrinkage, right? And so that's very important and clearly demonstrates the potential role of PDS0101 in generating those powerful killer T-cell responses. So the role of Versamune is twofold here. First of all, Versamune is interacting with NHS-IL12 to overcome certain immunosuppressive mechanisms, right, to expose those cancers and make them much more visible to the immune system. Secondly, what Versamune is doing, as Lauren explained, is now presenting those tumor-specific antigens into the correct pathways and generating a powerful T-cell attack against those now exposed tumors, right? And so both are critical for you to see the optimal clinical responses. Now what's also very important is that the low dose, even though the effect with the low dose wasn't as potent, we can see here that in terms of survival, even the low dose patients saw significantly enhanced survival, right? So the 77% survival at 12 months was no difference between the high dose NHS-IL12 and the low dose NHS-IL12 groups, suggesting that it is very likely that the tumor regression of tumor shrinkage was happening at a slightly lower or slower rate than we were seeing for the high dose NHS-IL12, right? So these studies really demonstrated that each of these components is critical to observe in that synergy, right? So with Versamune and NHS-IL12, we need both of them to induce that inhibition of immune suppression plus the Versamune produces those. With bintra, it's already been demonstrated and published that bintra is a key in overcoming or exposing the tumors that hide using the new checkpoints, right? So it performs its function as a bispecific checkpoint inhibitor. And therefore, as Lauren explained, looking at single, dual and triple combinations the triple combination was definitely shown to have the optimal or the most significant anti-tumor benefit. Robert, I hope that answered your question.

And Frank, we have time for one more question.

There are no further questions at this time. I'd like to turn the call back over to management for any closing comments.

Well, thank you very much again to all for joining us on today's call. We remain encouraged by the data presented at ASCO in the VERSATILE-002 trial, seen the enhanced clinical responses as well as seeing no treatment-related Grade 3 or Grade 4 toxicities. We believe it's very significant, even though the data is quite early. In the triple combination for the first time in the clinical setting, seeing what we have seen in terms of the potential to more broadly overcome immune suppression and really provide clinical benefit to patients who are refractory to checkpoint inhibitors in very late-stage cancer patients. We see all this data as being highly encouraging to the company, and we look forward to progressing all 4 Phase II clinical trials to the clinic and also being able to provide updates as we go along. Thank you very much again for attending and for all your questions. Thanks, and have a great day.

Thank you. This does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.