PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

Good afternoon, and welcome to the PDS Biotechnology KOL event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the PDS website following the conclusion of the event. I'd now like to turn the call over to Kirk Shepard, Chief Medical Officer of PDS Biotechnology. Please go ahead, Kirk.

Thank you, Terra. Good afternoon. I'm Dr. Kirk Shepard, PDS Biotech's Chief Medical Officer, and I welcome you to the PDS Biotech Virtual KOL Meeting. Please let me show first the forward-looking statement slide. If you'll advance, please. Thank you. And now the disclaimer slide. Thank you. It's important to know that PDS Biotech is a sponsor of this round table. Each panelist is speaking at the request of PDS Biotech and information presented is consistent with FDA regulations and guidelines. Next slide. So this is the agenda for today. We look forward to presenting and discussing unmet treatment needs in head and neck cancer, the positive updated data from VERSATILE-002 Phase II clinical trial and Versamune HPV in combination with KEYTRUDA or pembrolizumab, next steps for Versamune HPV and the PDS01ADC and then the CEO summary and the panel Q&A. Next slide. So we are very fortunate and honored today to have 2 prominent leaders in head and neck cancer as participants in today's KOL event panel. First Dr. Haddad, who is the Professor of Medicine, Harvard Medical School and Dana-Farber Cancer Institute, who will discuss the unmet need in HPV-positive head and neck squamous cell carcinoma. Then we have Jared Weiss, who is a Section Chief of Thoracic Head and Neck Oncology, Professor of Medicine at the University of North Carolina, and principal investigator of the VERSATILE-002 clinical trial, who will present and discuss the trial results. Next slide. So Dr. Haddad, please begin your presentation, and we're looking forward to it. Thank you very much.

Thank you, Kirk. A pleasure to be here today. I'm really going to focus my conversation on the treatment of recurrent and metastatic head and neck cancer and also review some of the focus we've seen recently on novel agents in treating this disease. So a quick summary of where we are in 2024 and going forward. We currently have 2 checkpoint inhibitors approved for treating locally advanced metastatic head and neck cancer. Those are pembrolizumab and nivolumab, they're known as checkpoint inhibitor. They were approved based on KEYNOTE-048 study and CheckMate 141 study. The benefit from these agents appears to be limited to patients with what we call PD-L1 positive disease. We continue to look for the role of other biomarkers besides CPS and PD-L1 and how we predict responders to treatment for these agents. The response rate, unfortunately, with checkpoint inhibitors is around 20%. It can go up to 40% in patients with high CPS, but the average response rate is around 20%, which essentially is telling us that around 80% to 70% of patients who do not respond to these agents. So we continue to look for new treatment for head and neck cancer patients. For those patients who do respond, the duration of response around 20 to 30 months, we do see some occasional exceptional responders and beyond checkpoint inhibitors, we continue to offer patients chemotherapy, cetuximab to an EGFR inhibitor or clinical trials. So the approval of pembrolizumab in the United States and Europe comes from the KEYNOTE-048 study. This is a first-line recurrent metastatic head and e cancer trial. In this trial, patients were randomized to either pembrolizumab alone or pembrolizumab with chemotherapy or what is known as the extreme regimen, and that's chemotherapy with cetuximab. So it's 1-1-1 randomization. Again, these are patients with recurrent and/or metastatic head and neck cancer, who are being treated in the first-line recurrent setting. So they have not been treated for recurrent disease with chemotherapy, immunotherapy or any other intervention. This study showed a benefit of pembrolizumab over chemotherapies, cetuximab. You see here the results for the CPS 20 Group and the CPS 1 group. So these are patients with PD-L1 positive disease essentially showing that if you gave pembrolizumab for these patients, you improved overall survival. And again, this trial led to the approval of pembrolizumab in the United States. When we look at the subgroup analysis, what we see here is that if your CPS is 0, so it's less than 1, you actually do not benefit from pembrolizumab and chemotherapy continues to be the standard of care for those patients, while if you have a CPS that is 1 to 19 or higher than 19, those patients are offered currently pembrolizumab with or without chemotherapy. So the message here is that if the CPS is 0, meaning PD-L1 is 0, you do not offer immunotherapy for these patients, and that area remains an area of unmet need. In this same trial, when you look at the HPV-positive group, we actually see that they don't do as well as the overall group. The hazard ratio goes down to 0.82. With pembrolizumab plus chemotherapy, the hazard ratio actually is better at 0.65. Another trial that's looked at recurrent a static disease in that first-line setting also, that's CheckMate 651, and that study was published last year. This unfortunately did not meet the primary end point. This is a comparison between nivolumab plus ipilimumab, a CTL4 inhibitor against the extreme regimen, again, that's chemotherapy plus cetuximab, close to 1,000 patients were randomized to this study. When we look at the results for the primary endpoint of overall survival for all patients randomized, we do not see a difference in the overall survival between these 2 groups, 13.9 months versus 13.5 months. When we look specifically at that CPS high group 20 or more, we actually see those trends starting to be in favor of the nivo plus ipi was 17.6 months overall survival versus 14.6 months. But unfortunately, those differences were not statistically significant, and this study was called to be a negative study. When I look at the progression free survival, again, here we're seeing 7 months with extreme nivo/ipi 5.4 months. But with that, again, high CPS group, that duration of response is quite significant at 32.6 months. So again, showing you here that with those high CPS expressors, you do see a higher benefit from these checkpoint inhibitors. On this trial, when you look at that HPV-positive group, what's labeled here as oropharyngeal cancer, p16 positive 186 patients. We actually see that in that group, immunotherapy did not perform very well, 19.8 months versus 23.8 months. So really better outcomes for that group in this trial with the chemotherapy plus cetuximab. In my opinion, that area of HPV-positive head and neck cancer and the recurrent metastatic setting remains an area of unmet need, where we continue to look for new agents for these patients. Now beyond checkpoint inhibitors, what else is being looked at in this space? One target that has been of great interest in other solid tumors is the LAG-3. LAG-3 expression does occur on activated T cells, LAG-3 signaling limits, antigen-specific T cell responses and there is synergies seen between PD-1 and LAG-3, and that has triggered a lot of interest in looking at combinations of LAG-3 and PD-1 inhibitors. TIM-3 also is another market that promote immunosuppression. So TIM-3 expression does occur on CD4, CD8 cells, also T regs and there's also synergy noted between TIM-3 and PD-1, and that's also been a target of interest in many solid tumors, including head and neck cancer. This is one example of a trial combining a PD-1 with the LAG-3 and a TIM-3 and that trial is completed. We can wait for the result of this trial. And I show this just to give you a sense of what's out there. There are many other trials looking at combinations of LAG-3, TIM-3, PD-1 in head and neck cancer patients with recurrent metastatic disease highlighting the need to come up with new treatments for these patients beyond checkpoint inhibitors, beyond pembrolizumab and nivolumab. Another area of interest is also EGFR. As many of you know, we currently do have 1 EGFR inhibitor called cetuximab that is approved in head and neck cancer. That agent was approved 15 or 20 years ago. It's -- there's a set of new generation EGFR inhibitors. This is one of them. This is a Bicara EGFR inhibitor called BCA101. This is a trial from ASCO last year, where -- again, this is tested in patients with recurrent metastatic head and neck cancer. Combination of pembro plus BCA101. And here, what you see is that the HPV-positive group in this trial did not actually show a lot of benefit. A lot of the benefit was seen in that HPV-negative group. So for that group of patients -- for that class of drugs called EGFR, the interest actually is more in that HPV-negative group than the HPV-positive. Again, to me, this highlights the notion that we are still looking for better agents and better options for patients with HPV-positive head and neck cancer that have recurrent or metastatic disease. We recently presented this large Phase III study in the Arizona meeting 2 months ago. This is called the LEAP 10 study and this is now looking at the combination of an EGFR inhibitor with a VEGF inhibitor. So VEGF is another class of drugs that is off interest in head and neck cancer. In this trial, what we did, we randomized 500 patients to either pembrolizumab plus lenvatinib. Lenvatinib is an oral VEGF drug that is currently approved for thyroid cancer and kidney cancer and also other tumors. There were some signal of benefit in earlier studies that led to this Phase III. Again, first-line recurrent metastatic head and neck cancer patients randomized to pembrolizumab plus lenvatinib versus pembrolizumab placebo. Unfortunately, also the study did not reach its primary endpoint. These are the patients' characteristics. Close to 20% of the patients on this trial were HPV-positive. They have good performance status. They could be CPS -- the CPS or GPS is shown here. And there could be any sites, oropharynx, oral cavity, larynx, or hypopharynx. The study actually showed a higher response rate with the combination. So lenvatinib plus pembro almost doubled the response rate and the response was durable as you can see from these curves here. Also, the progression-free survival was significantly in favor of lenvatinib plus pembrolizumab, but unfortunately, for the primary endpoint, which is overall survival, there was no difference between the 2 treatment arms. And this study is a negative study not reaching its primary endpoint of improving overall survival. We currently are looking at the subgroup analysis on this trial for HPV-positive and HPV-negative, but at this stage, this study would be considered a negative study and would not lead to the use of lenvatinib in the setting for head and neck cancer patients. So looking forward of what is really expected going forward in the area of HPV-positive recurrent metastatic head and neck cancer. It is worth noting that in the ASCO meeting this year, so this is next month in Chicago, there will be out of 9 presentations in the oral session, which is the main head and neck cancer session, there will be 3 sessions focused on HBV positive recurrent metastatic disease. And it's quite interesting that actually we see 3 abstracts in 1 session focused on 1 topic, highlighting really the fact that this remains an area of unmet need where we and others are looking for new treatment options for our patients. The first one will be with a drug that is known as ISA101b. This is a randomized trial that will be presented by Dr. Evan. This is what's called the therapeutic HPV vaccine that's how it's labeled. And the second one will be a Phase I study, early study with CUE-101, which is another anti-HPV agent that combine an E7 peptide with an engineered IL-2 variant, again, this would be next month presented. And the third one is the HOOKIPA, also HPV agent, which is HB-200 immunotherapy with pembrolizumab in that first-line treatment for patients with HPV positive head and neck cancer. So these trials will be presented next month in the oral session, and we are eagerly awaiting the results of these studies. Thank you so much, and I will hand over this to Dr. Weiss now.

Thank you, Dr. Haddad. So my name is Jared Weiss. I'm the Head and Neck Medical Oncologist at UNC and had the privilege of being an investigator on the VERSATILE-002 study, for which I will provide you a data update. I wanted to start by just thanking PDS for giving me complete freedom to present this data as I see fit, a freedom that I will take advantage of now. At least as soon as I can advance the slide. Here we go. So as Dr. Haddad reflected, we're talking here about squamous head and neck cancer and more particularly in the context of those driven by HPV, which means mostly the base of tongue and the tonsil. These are most famous in the world for having a better prognosis when treated for cure. When you treat vocally advanced disease with chemoradiation, you're more likely to cure a patient whose cancer is driven by HPV, than one whose cancer is driven by smoking. But as these curves show, in addition to that effect, they also show that there is a real recurrence rate amongst the HPV positive patients. I have a dream of one day opening a coffee shop. Why can I not open that coffee shop yet? And it's because of a failure of uptake of vaccination. So the same vaccine that is used to prevent cervical cancer and other HPV-driven cancers is highly protective against oropharynx cancers driven by the human papillomavirus as shown in this historic data at left. Unfortunately, uptick of that vaccine was slow. It is fortunately improving, but as a consequence of this, the HPV epidemic has not yet peaked. Projections are that this epidemic will not peak until at least the late-2030s. You see here in the circle filled circles that smoking-related cancers such as larynx cancer are happily falling. But in contrast, there is a rapid projected rise in oropharynx cancer due to the ongoing consequences of the HPV epidemic. Dr. Haddad very nicely presented for you the design and results of KEYNOTE 48. I want to belabor that except to make a few points relevant to our current context. The first is that not all patients are eligible for this study when they enter the designation of incurability. This was a study for patients who had either never seen chemo or as cancer had recurred at least 6 months after their last [indiscernible]. Some patients will recur rapidly after chemoradiotherapy, whether it's given definitively meaning as the primary curative modality or as an adjuvant after surgery. And for those patients, a checkpoint inhibitor alone would be considered a standard of care. How important is this caveat? It's actually the majority of the population. In contrast to the other cancer I have great interest in lung cancer, 3/4 of lung cancer is metastatic at presentation. In contrast, when we zero in on oropharynx cancer, more than 95% of those patients, who are designated incurable disease, what we call recurrent/metastatic disease arrived there through failed attempts at cure. Dr. Haddad nicely showed this for you already. I just wanted to zero in that not all of the results of KEYNOTE-048 are applicable to our conversation. When we look at the patients who would have been co eligible, we're talking about the PD-L1 positive patients. In KEYNOTE-048, the PD-L1 positive patient had a median PFS of 3.2 months and a median survival of 12.3 months. As Dr. Haddad reflected, this was pretty agnostic by P16, -- it may well be, in fact, probably is that some of the mechanisms of response and resistance may be different between these very different biologies. But as a humble clinician, when I'm in clinic, I expect something very similar from an HPV-positive and negative patients based on the KEYNOTE-048 data. Response rates were also different even within the subgroup that we're talking about. In KEYNOTE-048 for those patients with a positive but low PD-L1. So 1 to 19, that response rate was 15%, and in the subgroup, where the PD-L1 was at least 20, it was 23%. So roughly 20% if you look at this group as a whole. Here's the design of VERSATILE-002. This was not a randomized study. This was a 2 cohort study. One cohort where those patients, who are checkpoint inhibitory and refractory and the other population, the one that I have data to share with you today are on the checkpoint inhibitor naive subjects. This was a 2-stage study, and it did go to the second stage. And that's the data available to talk about today. The demographics are shown here mostly for transparency, but what I want to highlight is that there was no excess in this study of patients with very high PD-L1s. Actually, the population that was PD-L1 high was less than half of the patients. Response rate was 33.9%, including some very deep responses. PFS is shown at top left, the median here was 6.3 months, and I leave you to reflect on the shape of the curve. But as you consider the dynamics of response and progression, the spider plot at bottom right may help you in understanding the nature of benefit from this combination therapy. What I would highlight for you is that there was durability in those patients with defined response and that there were patients coded as stable disease, who clearly drives human benefit from the therapy, and that benefit is well reflected in the PFS curve shown at top left as well as the survival curve that I will show you next. Median survival was 30 months. At what cost to toxicity, I will editorialize a bit for you and say that this is about what I expect when I give pembrolizumab alone in clinic, and there were no unexpected reactions here. The same is true of the high-grade data. So every single grade 3 to 5 event is represented here, there were no deaths. There was a single treatment-related Grade 4 event [indiscernible]. The only grade 3 or higher event to occur in more than 1 patient was fatigue. In my opinion, there's nothing surprising or new here. There has never been a head-to-head comparison of pembrolizumab versus pembrolizumab combined with the therapeutic vaccine here. This is not meant to represent a head-to-head study or comparison. However, I know that you're going to make this comparison. And so I thought I would just make the reference numbers easy for you. Here, this slide is meant to do nothing more than that. However, when looked at in context, I do think that these are very promising numbers. The purpose of a Phase II study is to justify a Phase III study or to fail to do so. In my opinion, these results do justify further study of the vaccine together with pembrolizumab. Data that I was not part of, but will briefly reflect on, looked at the combination of PDS01ADC, which is an IL-12 targeted to necrotic tumor environment in combination with Bintripuse alpha and the Versamune vaccine. And that data was also promising and nonrandomized data. PDS Biotechnology believes that these data sets are supportive of moving the triple combination as well as the double combination into randomized Phase III study to ask the question of whether there could be a significant survival improvement with these combination regimens. And I will editorialize that as a dedicated clinician and investigator, I am voting with my feet to participate in that effort. I thank you for your kind attention, and we'll turn over the microphone.

Well, thank you, Dr. Haddad and Dr. Weiss. We will take questions at the end of the next session. So if you just remain ready for that, we could can have some questions for you at that time. Just to remind you, I'm Kirk Shepard, CMO of PDS, and I'll be talking about transforming how the immune system targets and fights cancer to promote survival. Next slide. And this, again, is our forward-looking statements. Next slide. So this is, in some ways, already been mentioned by the really concise and insightful presentations we just heard. As you can see that the cancer, head and neck cancers it's a devastating cancer, with the high prevalence and mortality, higher than some people think, head and neck cancer is actually the seventh most common cancer in the world and causes approximately 1 million deaths globally per year. In the U.S., oropharyngeal cancers or OPC are 40% of all head and neck squamous cell carcinoma cancers. And as you'll see by the left pie graph, 70% of the OPC are HPV-related. Moving to the next bar graph. The majority of the HPV-positive cancers, that is 80% to 90%, are HPV-16-positive and HPV-16 is a scary virus and that can cause a risk of developing cancer of anywhere from 15 to 200x the usual amount. Next slide. So this is also emphasizing what just spoke about by Dr. Weiss, Dr. Haddad. This slide shows the OPC incidence rate by HBV status over time. The slide shows the annual number of OPC cases on the vertical axis and the time by decades, starting with 2010 on the horizontal axis. And just for 2010 in perspective, that's 4 years after the initiation of HPV vaccination in the population in 2006. There is an estimated dramatic increase, you can see of the annual incident rates of OPC through 2040, driven by HPV-16 depicted in the curve this blue gray at the top. It's felt that the effects on the population of the HPV vaccines will not significantly occur until after 2040, where we may see some decrease. But HPV 16 will continue to drive increased head and neck cancer incidence rates for decades with the added challenge that HPV 16 inhibits immunological pathways that promote T-cell responses. Next slide. And just to look at the population that we're talking about, HPV positive head and neck squamous cell carcinoma represents a significant portion of the population. You see in total in the U.S. estimated around 53,000 and of this group that are positive for HPV-16, 18,000 and within that group, we have a group that is unresectable and metastatic that we're talking about mostly today. And as we saw on the last slide, the number of these patients will continue to increase throughout the decades. So the challenge here is that there's no approved HPV-specific cancer therapy for these patients and there is a significant unmet need. Next slide, please. So regarding treatment, why have immunotherapy failed in solid tumors like head and neck cancer, which are sometimes called cold or non-inflamed tumors. There are 2 critical limitations, and we'll present 2 platforms to address these today. One is the TME or the tumor microenvironment prevents immuno action. In other words, it's either immune desert tumor, where you have lack of T cells because T cells don't get in or get activated or it's immune excluded where you have certain suppressive cytokines and immunatory factors that prevent T cell infiltration, so the inability to access and convert the tumor to an immunogenic environment. It's the inability to weaken the cancers protection or its own defense. The second is an inadequate T cell response. The inability to generate the right type and quantity of effective tumor infiltrating and tumor killing T cells. It's a suboptimal attack on the cancer. Next slide. So let's look at PDS's 2 agents that are included in the triple therapy. The mechanism attacks a tumor from both the inside and outside of the tumor with unique combined mechanisms. First, PDS01ADC detected here in the figure and the green #1 is on the inside attack of the tumor. I think many of you are familiar with IV or subcu IL-12 treatment from the past. IL-12 is a pro-inflammatory cytokine produced mainly by dendritic cells and acts mainly upon natural killer T cells and CD8-positive T cells, but was limited in the past by its severe systemic toxicity. PDS01ADC is an immunocytokine fusion protein composed of 2 molecules of IL-12 fused to each of a heavy change of the human IgG1 with an antibody that targets exposed necrotic DNA. PDS01ADC binds to the necrotic DNA, which we find inside of the tumor and the IL-12 remains bound to the tumor and does not release into the systemic circulation. The PDS01ADC infiltrates weakens the tumor's protection from the immune system and actually stimulate T cells in the TME to promote expansion and prolong effective killing. Second agent, Versamune, the outside attack on the tumor, is depicted by the purple #2. Versamune is a proprietary lipid nanoparticle and T cell activating platform coded with a positive charge facilitating the uptake by dendritic cells, a unique and overexpress image of a cancer, and in this case, that's what HPV-16 is manufactured and mixed with the Versamune nanoparticles to create a subcutaneous injection of a proprietary formulation, of Versamune and a tumor-specific formulation. Once in the dendritic cell, the tumor-associated antigen is processed to facilitate pathways in the lymph nodes and induces the right type and quantity of potent killer T cells and target and infiltrate the tumor. Next slide. Besides the agent's mechanism of action, we also have compelling clinical survival data to support the triple combination pivotal study. There are 2 studies, let's say below the first-line R/M. First, there's the multicenter, multinational VERSATILE-002 study of Versamune-HPV and pembro in first line, which was just presented by Dr. Weiss showing a 30-month median survival, demonstrating the power of Versamune in T-cell action when added to pembrolizumab. Second, there is the NCI triple study of Versamune HPV, an immune checkpoint inhibitor and PDS01ADC in first line in advanced HPV-positive cancers showing a 42-month median survival, demonstrating the power of PDS01ADC and IL-12 in converting the tumor to an immunogenic environment. And these were both in first line, but the NCI produced data also the triple combination in a more difficult population of second-line resistant patients. And as a stress test, -- it showed a 5-fold increase in survival with a median survival of 19 to 20 months, added data that increases our confidence in the triple combination in first-line relapsing metastatic HNSCC pivotal study, which is outlined in the light green box in the right corner. Next slide. And this slide, the strong survival benefit of Versamune-HPV and PDS01ADC is shown compared to the pembrolizumab, the approved standard of care for first-line relapsing metastatic head and neck cancer. In the first bar, you see down at the right in the KEYNOTE-048 study, pembrolizumab-treated patients had a 12.3 month median survival. The next bar in dark one, in the LEAP-010 study, pembrolizumab-treated patients had a 17.9 month median survival. The next blue bar in the VERSATILE-002 today's subject, patients treated with Versamune-HPV and pembro showed a 30-month median survival. As you can see increasing this median survivals from the past by about a year, showing again the effect of adding Versamune-HPV to pembrolizumab. And finally, with the dark blue bar, the NCI triple combination study that was a median survival of 42 months when reached adding PDS01ADC to Versamune and pembrolizumab, reflecting the effect of the PDS01ADC on survival. Next slide. Supporting the clinical data, was also interviews in consultation with individuals in the academic and community oncologists. First was the consultation with KOLs at the recent head and neck conference and then an independent survey of [ 20 ] oncologists to vet the triple combination data and program by experts. The survey showed a strong preference to use the triple combination in first line versus second line. And you can see there, the high rating it had from the physicians and some strong statements came out of this. The preference as first-line treatment, you can see down below in the first statement, they comment it would allow patients to buy past chemotherapy and to use a potentially stronger therapy upfront as many oncologists feel, including myself as an oncologist, you want to put your heaviest guns upfront because after that, when they become recurrent or relapse, we have more of a problem with them responding. Next slide. So all we've heard about the mechanism of action, data, expert opinions from KOLs, how do we get to registration. Well, here is a diagram of the pivotal study design. For VERSATILE-003, which was a study design for Versamune and pembro versus pembrolizumab that's in the bottom 2 arms. We have already had alignment. We've have alignment with the FDA for that study. But based on the strong survival data with the addition of PDS01ADC to form the triple combination, a third arm of the triple combination will be added. The median overall survival primary endpoint and the study size will be designed for potential success in both treatment arms versus the control of pembrolizumab. And so the data and the surveys built on robust data from VERSATILE-002 and from the triple combination [ and for ] in the following 3-arm pivotal Phase III study design. All right. Thank you very much for your attention, and I would like now to introduce our CEO, Frank?

Thank you. Thank you very much, Kirk. And I would like to thank everyone for their attendance today. I would also like to sincerely thank Dr. Jared Weiss and Dr. Robert Haddad for taking the time to share their experience and thoughts on our VERSATILE-002 trial in the state of head and neck cancer treatment today. We are especially grateful to Dr. Weiss for being the lead investigator on our VERSATILE-002, which has been a very successful trial, meeting its primary endpoint and fulfilling the very high expectations that we had when we initiated this important study. We are also very grateful to Dr. Haddad, who is one of the leading experts in head and neck cancer and who shared his insights into current treatment approaches and novel approaches in development. We very much appreciate your time and insights regarding the standard of therapy and the unmet needs that remain in the treatment of the current and metastatic head and neck cancer. Now today, I am more optimistic than ever about the potential for PDS Biotech to provide a significant advancement in the treatment of recurrent and metastatic head and neck cancer, leading to significantly increased survival. This deadly disease continues to be a real and growing challenge with significant increases as we have seen in the incidences of HPV-16 positive disease. It is well established that once head and neck cancer becomes recurrent or metastatic, these patients have a short survival of about 1 year. PDS Biotech based on the data presented by our panelists today, has a real and meaningful opportunity to completely change the prognosis of the disease with our triple combination. The VERSATILE-002 survival results generated in the multisite, multi-country trial provide a powerful demonstration of our dual combinations potential to significantly improve patient survival. The data from the triple combination in both first and second line, recurrent and/or metastatic HPV positive cancer patients provide an exciting indicator of the complementary power of PDS01ADC to even further enhance patient survival. So how do we go from here to successful registration of the product. So in light of the results of VERSATILE-002 and the impressive results of the National Cancer Institute triple combination study, we conducted market research with head and neck cancer oncologists and the payers. As a result of the insights gained from this market research, we are prioritizing the triple combination as a first-line treatment in recurrent and/or metastatic HPV-16 positive head and neck cancer. As a result of this, we have added the triple combination arm to the VERSATILE-003 design, which was previously accepted by the FDA as a registrational study design. The statistical endpoints are based on the survival data for the double combination, which we believe puts us in a strong position for success with the triple combination. We continue full steam ahead as we complete the steps necessary to get our pivotal trial up and running this year. Also, we look forward to the opportunity to provide an update on the other 2 ongoing Versamune HPV trials this year. We are hopeful that MD Anderson will provide a clinical update on the trial of Versamune HPV and chemoradiotherapy in locally advanced cervical cancer later this year. The previous updates have been extremely encouraging. We are also hopeful that we will get an update from Mayo Clinic on the Neoadjuvant trial of Versamune HPV with or without KEYTRUDA in early-stage oral cancer. Now as we mentioned at our last earnings call, we have the capital to take us into the fourth quarter of 2025 and we ended the first quarter of this year with a healthy cash balance of more than $66 million. Based on all the information we have today, we are considering various options to finance development of our lead program, including potential partnerships. Now since we have provided a comprehensive business update today, rather than having a live earnings call, the updated financials will be provided in a press release on the 15th of May 2024. Once again, I thank Dr. Weiss and Haddad for their valuable insights. I would also like to thank all in attendance today for your time as we look forward to an exciting 2024. Thank you very much, and we will open up the floor for the panel discussion as well as Q&A at this time. Thank you very much.

Thank you, Frank. So just to open up the panel discussion, and we will have general Q&A later on also. I would especially like to take the presence of Dr. Weiss and Dr. Haddad for some specific questions. And from the audience, too, please feel free to ask them because these are the 2 world's experts on head and neck cancer. Maybe first for Robert. Could you comment on HPV 16 tumor treatment. It's the experience of some clinicians that HPV-positive 16 head and neck cancer have a good response upfront, they're curable but they don't see patients later on, it seems as though they relapse and have very difficult once they have metastatic disease as far as their outcomes. And it's perhaps HPV-16 related to this as far as their difficulty in being treated?

Yes, Kirk, thanks for the question. So I think what I would say is -- when I talk to my patients, the reasons people get head and neck cancer there are 3 reasons or 3 main reasons why patients get head and neck cancer. They either are heavy smokers, they're heavy drinkers or they have HPV. Those are the main reasons why patients get head and neck cancer, specifically oropharyngeal cancer. In terms of prognosis for that patient, who has a new diagnosis of oropharyngeal cancer. Yes, it is true that HPV-positive patients. have a better outcome, better survival compared to the HPV non-related head and neck cancer. Those who are smokers and/or heavy drinkers. But what we are talking about today are not that group of patients who have an initial diagnosis of head and neck cancer, but rather those patients, who have recurrent head and neck cancer. And for those groups of patients, there are really no specific HPV directed therapies available to them at this stage. And what we end up doing is we end up treating those patients in a similar fashion to how we treat patients with non-HPV head and neck cancer, which is immunotherapy. And as I showed you in my slides and Dr. Weiss has showed there seems to be less of an effect of immunotherapy in those patients compared to the HPV negative group. And when you look at the data I presented from Bicara with EGFR with the HPV positive and negative, it seems that EGFR inhibitors as a class also works better than that HPV negative group. So we have to differentiate when we talk about prognosis, the initial diagnosis and the recurrent astatic setting -- and there's really a clear difference in those. And with recurrent disease, those are patients who are not curable and are in need of new therapies. And it does seem that immunotherapy for that group is not as a single agent is not as effective as chemotherapy or more is desired in terms of response and survival there.

Dr. Weiss, thank you very much for your discussion on VERSATILE-002. As the prominent investigator in that study, what are your thoughts now going on to a triple therapy that we've talked about today in first line of HPV-positive 16 head and neck cancer?

Thank you for the question. I think when I look at the non-randomized Phase II results that I just presented as well as the triple combination results presented at ASCO 2022. I'm excited by what I'm seeing in both sites. They both substantially raised the hypothesis that we can add to pembrolizumab to improve on those outcomes. When I look at pembrolizumab -- when I first looked at pembrolizumab, it was so exciting relative to what we had before, right? It was a totally new mechanism of action. The clinical profile was very exciting. It gave what patients were asking for, some chance at cure or at least durable control where that probability was close to 0 before. And while there are immune-related adverse events, I would say that it's not hard to look at KEYNOTE-048 or any clinical practice and say that it's less toxic than the extreme triplet. Almost everything is less toxic than the extreme triplet. But now, gosh, a decade later, I think we have to reflect that, that glass is still half empty, if not more than half empty. And I'm talking here about 2 glasses. The first is that while it is exciting to show that we cure a high percentage, right, 85%, 90% of HPV-positive disease that 10% to 15% that are not cured are very real. Dr. Haddad, myself, other oncologists see these patients every day in clinic, and we're seeing more and more of them. There's a human tendency to round large numbers to 100 to round small numbers to 0, but that 10%, 15%, they're real and they are growing because of that HPV epidemic. And so these patients reach this designation of incurability at greater numbers. And while the exciting part of pembro is that when it works, sometimes it really works, the glass is more than half empty, if you look at the proportion of patients that benefit, right? If you look at the PFS curve of some of the earlier studies that were single agent, they're a cliff on the left side. right? The majority of patients progressing at their first assessment. And even if we look at these more moderate results in the highly selected group, right, the PDS highest group of at least 20, that response rate was 23%. And -- that is a minority of patients. And so there's substantial room for improvement here. And when I look at the results of both of those 2 reference studies, they're really excited. They strongly raised this hypothesis and I strongly believe that it merits study in a Phase III study. And I'm excited to offer that to my patients who I care very much about.

Well, thank you very much. Thank you very much for both of you for answering those questions. I would like to sit here and ask you more questions, but I know Frank, my CEO would be very angry if I used up all the time. So I'm going to look forward to working with you more in the future. But I do want to open that up to other people who may have questions for you as far as the panel. This is a real opportunity to have 2 experts like this on the line. So anybody, please, I don't have a vision into the Q&A, feels that they have a clinical question, something about studies if you like to ask this is your opportunity.

Great. Thanks, Kirk. So we will begin our Q&A session with the audience. Our first question comes from Joe Pantginis at H.C. Wainwright.

Thanks for the details and especially congratulations on the data update today. That's very promising. So I was hoping to ask a two-pronged questions for doctors Weiss and Haddad. First, I was hoping to get a bit of perspective on the actual head and neck cancer indication. You obviously have the data from KEYNOTE-048 and [ LEAP ] that you presented. And I guess that I was asked the question this way. What are the ranges of survival in 048 and [ LEAP ]. Would you expect patients to even reach the 30 to 40 month survival range that the VERSATILE study has seen?

So I think we have to be very careful about cross-trial comparison. I hate to be a broken record on that, but it's a really, really, really important caveat. One thing that I think you're alluding to is that survival on the same regimen tends to improve over time, right? So it was once an experimental arm when it becomes the control arm of a study a decade later, usually survival improves. Because we've had advances in detection, we have advances in supportive care, we have advances in subsequent therapies, which trial patients, by definition, are more likely to have access to. And so that caveat is not just an annoying academic at an investor conference. It's very, very real. That said, I don't think there's any way to torture these numbers to not be exciting or to not justify Phase III study. Dr. Haddad.

Yes. No. I mean, again, it's hard to give really predictions, but the way we look at new combinations is we look at the numbers of overall survival and response rate. And we tried to put those into perspective knowing what we know about what existing therapies we have currently that we are using in our clinics. And we try to make an educated really decision about whether those numbers are clinically meaningful. And it's not about just the p-value and the response rate, but it is clinically meaningful for the patient. So we have a lot of experience right now with checkpoint inhibitors, nivolumab and pembrolizumab. So we know what to expect with these agents. And those numbers that Jared and I have showed in terms of response rate and overall survival, it comes down to around really all of those trials you look at, you're going to be in that ballpark of 20% response rate and maybe 12 to 18 months overall survival. And as Jared said, things every time we do a Phase III trial, you see that the data from trials we presented this year are better than trials that we presented 5 years ago and 10 years ago. And there's a lot of reasons for that, and that takes a lot of time to go over, but supportive care is better, they added better second-line therapies and third-line therapies, et cetera. But ultimately, those are the numbers we want to improve that 20% and that 12 to 18 months overall survival. And then we start really talking about hazard ratio and where we want those numbers to be, again, to be clinically meaningful for the patient. So that's how we go about really making decisions about taking a combination or a drug from a Phase II to a Phase III. And what you saw here with the combination, the triplet in our field of head and neck oncology, those are exciting numbers to see for those patients who have really been looking for new options for a long time. Head and neck cancer treatment is really lagging behind other solid tumors. And it's a great area of unmet need, but if you look at the past 20 or 30 years, we haven't had any really advances outside of the checkpoint inhibitors for our patients.

That's very encouraging. And I guess the second part of my question is more pragmatic. Obviously, the 002 study is an open-label study. And as you as physicians, the investment community obviously looks with increased risks or risk perceptions for open-label studies. So -- but you as physicians to decide to move into pivotal or be part of a pivotal study, I should say, what are the factors that you consider here? Obviously, the data that were updated today, but what other potential factors can contribute to your confidence potentially in the upcoming randomized study and your decision process?

I mean, one part will be the toxicity of the combination. So we spent a lot of time looking at the Phase II and Phase I data to really make a decision whether the combination or the drug, if it's one single drug the toxicity is manageable. We look at whether the patients exist. There are a lot of trials that do not complete accrual because it's hard to find the patients and the trial are so restrictive in terms of inclusion and exclusion. So we spent a lot of time really working with these trials and trying to make the inclusion exclusion criteria as realistic as possible to the real world. Because you can design the best trial in the world, but if you make it so exclusive that you're just not going to find the patient, it makes no sense. So we look at toxicity, we look at inclusion, exclusion, feasibility. And an effort like a Phase III trial requires a lot of patients and requires a lot of sites. So that's a key component of doing a Phase III. I mean these trials take a lot of effort to put together.

I very much agree. I would highlight and bold the comment about looking at efficacy in the context of added toxicity. That's extremely important. The other thing that I would add is we look at competing trials, right? We have a lot of trials available to us. And in addition to all those markers of, is this one promising in order to participate it also has to be promising relative to the other opportunities available for our patients.

Very helpful. And then if you can just bear with me, I appreciate it. Just a quick question for the company. Your upcoming July meeting with the FDA, is that just to get final agreement to add the triple arm or are there outstanding questions that still need to be addressed?

Frank, do you want to take that question?

Sure, I will be happy to do so. So as Kirk mentioned, we have already had alignment with the FDA on the VERSATILE-003 trial, which was the 2-arm trial. Based upon all the market research we've done in discussions with oncologists, we've made a decision to add on the triple combination trial to that. One of the key reasons here for that triple combination or the 3-arm trial is -- as many of you may already know, we're going to have to look at contribution of agents with a triple combination. So even if we were not seeking approval for the doublet arm, we would have to run the doublet arm to really understand those contribution of agents. So first of all, you have KEYTRUDA. You have KEYTRUDA plus PDS0101 to really understand the contribution of PDS0101 or Versamune-HPV. And then we have the third one, which then includes the PDS01ADC, again to show the contribution of PDS01ADC. And so that's the reason for the [ 12121 ] design. This is the key component of our discussions with the FDA and to get feedback from they are being comfort with the FDA and adding that arm on to the design with the FDA had already agreed would be a suitable pivotal trial design or registrational trial design.

Our next question comes from Wayne Wu at Cantor Fitzgerald.

So maybe just 2 questions from us. First is how far are you in your preparations for the pivotal study? And then -- did anything surprise you about the latest readout from the VERSATILE-002 study?

Well, Frank, I can go first on that. We expect to start the trial this year in 2024. Regarding surprises. I -- I mean, I was very enthusiastic that the data stood where it was and it was mentioned by Dr. Haddad and Dr. Weiss, too, that I'm looking at the AEs, here we're adding on an agent to pembrolizumab, and I think one of them said that it was like giving the one drug alone. So to me, it's like the perfect combination to include it to a triple. But I can't say that anything surprised me.

Yes, Kirk, to add to that. I mean since when we started this trial, I mentioned that we had some really high expectations. And when we started the trial, as Dr. Weiss mentioned, the response rates are about 1 in 5 response rate. We were very hopeful that if we could get this from 1 in 5 to 1 in 3, that would be very significant. We were also very hopeful based upon the memory T cells that we have seen in both our preclinical as well as our early human studies that if we could get the survival beyond 20 months that, that would be really good for us. right? And so we've been very highly encouraged. I wouldn't say there's anything really surprising because this is really what we expected based upon the earlier studies that we had done leading up to this VERSATILE-002 study. We're extremely encouraged with the survival we've seen today, extremely encouraging. And this is really what we were hoping that our product would be able to achieve to really start to demonstrate the differentiation in being able to generate the right type of T cells, the memory T cell responses that can be more durable and give the patients greater survival -- that's what we appear to be seeing today and also very exciting to now see the additional impact of being able to deliver a safer IL-12 into the tumor microenvironment to make these T cells potentially even more effective within the tumor microenvironment. So very encouraging today.

Our next question comes from Mayank Mamtani at B. Riley.

Thank you. Very helpful session, and let me add my congrats to the update also maybe just a couple of data clarifying questions for Dr. Weiss. How many responders still remain on the study. I'm not sure if I saw the swimmer plot. And any chance you have the median DOR -- and then on the OS curve, is there a censoring rate that you've calculated, obviously, like the confidence interval, lower bound where it is, but just to get comfortable with these curves in a single arm, some of these metrics are important. So if you could address that, Dr. Weiss, that would be great.

So the maturity measures of the curves are provided both in tick marks and in number at risk below to provide granular transparency to you as to the extent of maturity of the data. I have not memorized how many are still on treatment. And so I hope one of my PDS colleagues might be able to help here.

Kirk, do you want to take that? Or should I take that?

Yes, go ahead, Frank.

Yes. I think we have 10 or 11 patients who are still being treated on the trial. And we -- if you -- Mayank if you look at those patients, all the dots you see on those curves, as Dr. Weiss mentioned, those are all patients who have been confirmed to be alive. Each of the survived patients is sensored to confirm that those patients are still alive. And as of today, we only have 2 patients who have been lost to follow-up. So these are -- this is quite mature data that's been presented as Dr. Weiss said.

That's fantastic. And maybe for Dr. Haddad, is there any relevant biomarker work ongoing in the HPV positive side of things. I think you referenced 3 presentations coming up at ASCO, things that we could get comfortable with even stable disease patients responding to immunotherapy from a survival standpoint, would love to hear your thoughts on that.

Just like everybody on this call, I'm looking forward to see what will be presented at the ASCO meeting because obviously, we haven't seen the data yet. I think you're asking a question about the biomarker, it can be biomarkers like things like 2 mutational burdens or CPS. And I think you're asking about something else, which is what we would make us comfortable with whether the patient is responding or not. So ultimately, from the perspective of treating patients, taking care of patients, what we are looking for is really halting the tumor progression. And that could be in various forms, could be in the form of a complete response or a partial response, but also sometimes in what we call stable disease, where the tumor is not growing anymore. And we've seen that with some of the checkpoint inhibitors where the effect really tends to be on overall survival, but not necessarily on the response rate on shrinking the tumor. So those can be actually powerful, variable. Even though for registration purposes, we often are asking ourselves and asking companies to focus on overall survival because that remains really the gold standard? Are we improving survival. So we can look at a lot of parameters of stabilization of the disease. We can look at fancy biomarkers and gene signatures. All of those are important and really help us understand what's going on at the tumor side and also at the patient side. But ultimately, we want to see overall survival improvement. And that's what we saw with unfortunately lead time and lead time, which is a recent example from 2 months ago, it was actually -- the data was really, really good. It was a doubling of the response rate. There was a doubling of the progression-free survival, but we did not hit the overall survival endpoint, which was the primary endpoint. So ultimately, we want overall survivor. We want to see better outcomes in terms of OS for our patients. That's what we are focused on.

Yes. Very helpful. And then for the company, Kirk or Frank, in terms of some dose optimization work that remains as part of your Phase III development. Could you maybe talk to what sort of objectives you'd look to accomplish before you can get to that randomized portion? And if today, you are able to provide in terms of time lines when that interim analysis could be planned in that because you do have that Phase III protocol worked on for several months. You just have to slot in additional arm for the triplet. So I was just curious if you have any updated thoughts on the Phase III data analysis, when -- or at what number of patients you'd be looking to present that.

Sure. So my good question there with -- I think that's important. So -- the reason for the dose optimization first. If you may recall, the NCI did their study at 2 doses at a 16.8 microgram per mg dose, which we consider the optimal dose, we saw really good responses with that dose level and they looked at a significantly lower dose, which was the 8-microgram per kilogram dose. With that dose, we saw much lower responses, even though the survival was very similar, the response rates were significantly lower at the 8-microgram per kg dose. What the NCI has published is a dose optimization study where they have shown really good responses about a 12-microgram per kilogram dose. So it's imperative that we take a look also at that 12-microgram per kilogram dose to find out whether we're getting the same level of responses as the highest dose. And that's really the purpose of our dose optimization. We know at the 8-microgram per kilogram dose, they didn't see good responses, and that is in agreement with what they've published showing the much better responses 12 and above. right? So it's important for us to do that to establish that either we see better responses at 16.8% or we see very similar responses at the 12-microgram dose. We set approximately 40 patients because typically, the FDA wants to see about 20 patients per arm in these dose optimization studies. So that will also provide us a really good opportunity for some data readouts and present data at that time. right before moving into the randomized controlled study with the dose that we select coming out of that dose optimization study. In terms of the timing, we first of all want to just have that discussion with the FDA, make sure that they are comfortable, we are comfortable, we're in alignment. As you mentioned, we have already started a lot of work with site activation and so forth because of our experience with preparing for the VERSATILE-002, so a lot of those activities are already underway. Our goal is to get these studies moving as quickly and efficiently as possible. And so we will provide further updates once we've been able to have those discussions with the FDA and get alignment on the exact trial design that we're moving forward. Kirk, anything you want to add to that?

No, covered it. Thanks.

Our next question comes from Jim Molloy at AGP.

Thank you for putting on the KOL event, very helpful. And then maybe for the docs. Could you talk a little bit about on the combo? And obviously, you're adding in additional compounds, keeping a close eye on talks. I think you guys mentioned that earlier. It's looked good so far. But what are you guys going to be looking for in particular going forward? And what sort of signals you were keeping a close eye on.

So I think the answer to that is, honestly, a little bit generic, the same things we would look for in any study, which is to say safety and efficacy. The safety profile has been characterized and is sufficient to justify Phase III study, but all Phase III studies are monitored for safety as they go. And typically, there'll be a DSMC that will be looking in a blinded fashion as the study goes to ensure that we are appropriately protecting patients. As far as what we as investigators will see as far as what PDS will see, as far as what you will see as analysts not much as the study goes on, and that's consistent with standard study designs and disclosure time points. I'm sorry if that didn't answer the right question, feel free to push further.

All right. Maybe on the enrollment then, can you -- you guys did mention the enrollment environment always challenging in oncology studies. Anything in particular you're looking for or keep an eye out here, again, just sort of standard enrollment issues.

So randomized Phase III studies are always harder to enroll to than studies where the patient knows for sure what they're going to get. How hard is that? It depends a lot on is there an arm that the patients could be scared up, right? So when studies like KEYNOTE-048 were going on, there were some patients that declined to enter that study because they didn't want to get the extreme regimen. The control arm was what people were afraid of. There's no such concern here, right? The control arm is the current standard of care, which does not have cytotoxic therapy. And the question is, can you add something to that or 2 things to that? And I think that this study culturally hits an area where both patients and treating oncologists have a thirst, where we see an unmet need that it's not good enough. We like cytotoxic free regimens. We like the potential for a tail to the curve, but we're not getting there as often as we would like. We're getting there a minority of the time. And so I think it for very good reasons, hits the cultural thirst of the time. And I don't foresee challenging discussions with patients, except to the extent that it is a randomization and that's always a little bit harder than a nonrandomized study. Dr. Haddad, what's your perspective on accrual to this one?

Yes. I mean we had mentioned the competing trials in the United States and worldwide for head and neck cancer patients. So for us, just like any academic center, we -- this is a big part of how we assess combinations. It's not only whether they're exciting and they're interesting, but also what else we have open for our patients and can we accrue to those trials. So I would say that this is a specific targeting HPV positive patients, which is an area of unmet need. What I showed you that's going to be presented in ASCO, those are early studies, so they're not into the Phase III arena. So this is now going into registration. So there is more, there could be more exciting venues to pursue here with this combination because it's registration -- they're not early, they pass this toxicity, safety threshold, even though that will continue to be assessed. But to me, when I'm looking at trials, a big part of what I look at after I get excited about a concept is can we accrue to the trial? So what's competing with this trial currently. And this is a moving target, a moving field. What's available today in May of 2024, might be completed by September of 2024, and then there are other trials coming on board. So the competing landscape of trials, and that's across all solid tumors. It's 1 area we pay close attention to.

Yes. Did I hear Dr. Robert Haddad, correctly. You're saying, there'll now be a dose optimization trial first, and then the Phase III triple perhaps starting sometime next year?

We haven't given guidance on the time lines yet, but you are correct. The dose optimization will come first because we want to determine the best dose to move forward with that triple combination, right? We don't -- we have not evaluated 12 in the triple combination yet the 12-microgram dose has been shown to be active as a single agent in the single-agent trial. So that's critical for us to do to make sure that -- we are not giving the patients too much drug then or more drug that they actually need to get the response that we're seeking, and that will be done with the dose optimization study. And then that selected dose will then move into the randomized part of the study.

I've been asked to take one more online question, and then I think we wrap.

Okay. Actually, Yes. If you can hear me, Dr. Shepard. This is an excellent exchange on the question-and-answer most of the online convections that were submitted have been addressed. Just one for you. What attracted you to PDS. If you could answer that question.

So we're going to end on a personal note. So I've been an oncologists for a long time. And I've seen many promising therapies. And what attracts me PDS first of all, I always wanted to go to a biotech, I've been mostly large-to-medium sized. I was attracted by the team. Certainly, the data. The data turn my head right away because as Dr. Weiss and Dr. Haddad knows we see promising data sometimes, particularly in response rates. And when I saw the survival rates, to me, let's face it the patient is dead or alive. To me, that was really convincing that something is going on here. So that included with the pipeline. I hope that's enough, but that's what attracted me to PDS have been very happy here. Thank you for the question, Tom. All right. So anyway, thank you very much to all the participants, especially to Dr. Weiss and Dr. Haddad. Again, it was tremendous answer, great exchange, is exactly what we're looking for and also to the staff. So have a good afternoon. Thank you very much.