Webinar has started already, so if you guys want to go ahead.
Okay. Thank you, operator. So good morning, everyone. This is Mayank Mamtani on the Biotech research team. I'm excited to get started with our next Fireside Chat session with PDS Biotech. A pleasure to have with me here Frank Bedu-Addo, the PDS Biotech CEO. Frank, great to see you again, and thanks so much for joining us today. Maybe let's start with a quick introduction of the company, your pipeline, and maybe a summary of expected 2024 milestones, and then we can dive deeper into the two programs that we wanna talk about today.
Okay, Mayank, it's a pleasure to see you again, too. Thank you very much for the invitation to participate in the Fireside Chats, and thanks to B. Riley for having me on. PDS Biotechnology is a mid-to-late clinical stage biotech company. We're developing immunotherapies for cancer. As most of our audience know, immunotherapy harnesses the power of the immune system to treat cancer. Based upon the data that PDS has generated from multiple ongoing clinical trials, the data suggests that we have the potential to overcome some of the most critical limitations facing immunotherapy today.
So with our Versamune technology platform, we're able to recruit T- cells into the patient's lymph node, train those T- cells to recognize specific markers on the cancer that we're seeking to treat, and also arm these T -cells to allow us to generate the right type of killer T- cell in the right quantity, and also with the right killing potency, with a simple subcutaneous injection. With our IL-12 antibody- drug conjugate, which we will be talking about, later today, we're able to take a really unique approach to immunotherapy. So to date, with the immunotherapeutic approach, whether it's the checkpoint inhibitors, which are activating existing T- cells or CAR T, all the approaches today are attacking the cancer from the outside. The cancer's defenses against the immune system or against an immune response are hosted internally within the cancer.
What we are able to uniquely do with our IL-12 antibody- drug conjugate is to infiltrate the tumor and disarm the tumor's defenses against the immune system from within. So go in, disarm the tumor's defenses, and allow our T- cells to go in and more effectively kill the cancer. And with this approach, we have generated some real groundbreaking data, which we will be discussing today, but a very unique approach to immunotherapy using these platform technology approaches. PDS, based upon these approaches, has quite a deep pipeline of products. We have two of our programs which are ready to move into registrational or pivotal trials.
We also have we have seven additional ongoing phase II clinical trials addressing a broad range of indications, all the way from head and neck cancer, cervical cancer, prostate, cervical cancer, colon cancer, and prostate cancer, Kaposi sarcoma, and a number of other cancers, so a really deep pipeline. But what's also very important here is almost all these programs are being run by our partners, which allows PDS not only to be very financially efficient, but also, very importantly, to have a laser focus on which is really important for us now, which is to get our lead programs to the ultimate validation, which is the BLA and FDA approval. That's the company's focus today, is to get our lead programs to an FDA approval.
We believe that's going to be the validation of our platforms and allow us to rapidly build out these to treat multiple cancers. So based on all these programs, the other question you asked was what to expect coming up in 2024. We generated quite a bit of data in the Q4 of last year from multiple programs. So with the cervical cancer program, this is being run, as you know, by MD Anderson Cancer Center. They presented very informative information at the ASTRO Conference on ctDNA. They previously presented some data on survival and clinical benefit. We are hopeful that in 2024, we should receive additional updates on the clinical benefit and survival from these cervical cancer patients.
With the neoadjuvant trial in oral cancer, where PDS is being evaluated, PDS-0101 is being evaluated as a monotherapy, our lead program, and also in combination with KEYTRUDA as a neoadjuvant treatment. We have not had any updates from this trial yet, so we anticipate in 2024 also having an update on clinical outcomes from these ongoing studies at the Mayo Clinic. With our VERSATILE-002 program, and we expect to have additional updates sometime around the middle of the year on objective responses, PFS, and additional safety from that trial. And we have five other programs being run by the National Cancer Institute, as I mentioned, and we expect to receive updates from these trials between 2024 through 2024 and 2025.
Again, as I mentioned, these trials are primarily being run by our partners, which allows us really to focus on our ultimate goal, which is getting our lead program to an FDA approval and commercialization.
Yep. Y ou have a very busy pipeline, and I like also the focus that you have as you get into the pivotal trials that you're working on. Maybe just focusing on those two programs that really looks like where investors are most focused on, where your data has matured, the ADC that delivers IL-12, and then the cancer vaccine targeting HPV 16 specific antigens, stimulating very potent T-cell responses that you talked about.
Maybe just talk high level, the distinguishing features of the two platforms and, you know, how sort of you're seeing this kind of, in your mind, being positioned relative to each other, taking advantage of also the clinical data that you've generated, I believe, in one case more specific to head and neck cancer in earlier line, and then, maybe, in the second case, in refractory late-line patients and without being as specific, predefined to a particular tumor type.
Right. I think that's a really important question, Mayank. So looking at those two platforms, I'll start first with the Versamune, with the Versamune platform. So with the Versamune platform, what we're doing, what we are able to do uniquely here is to take a marker specific to a cancer, combine it with the Versamune technology, give a simple subcutaneous injection. As I mentioned, the ability to really generate the right type of killer T-cell, and very importantly, in the right quantity and also with the right killing potency, is quite, quite important. So today, this, this goal is being sought to be achieved using multiple approaches. You know, with live vectors, people are utilizing DNA vectors, RNA technology, for example, CAR T is trying to accomplish the same thing.
What we are doing is really allowing our immune system, activating the critical immunological pathways that allow the immune system really to maximize its potential to get the right type of T-cell that's needed to actually attack and kill the cancer cells with a simple subcutaneous injection. The goal, really getting it into the patient's lymphatic system or lymph nodes, right? So that's very critical. But again, this is a platform, so it allows us to pick, for example, with PDS-0101, HPV16 as the tumor marker that we're training the T-cells to recognize. With PDS-0102, it's the TARP protein that's expressed in prostate cancer and breast cancer. We allow the T-cells to recognize that marker, and with PDS-0103, it's the MUC1. So again, a very versatile platform that allows us to address a broad range of cancers and generate these really powerful T-cells.
Now, in terms of high level, what we've seen today with this technology, really, the cervical cancer data that was generated by the MD Anderson is very important because it does one very important thing. What they've done differently from what many of other trials are doing is, their goal was to really characterize and confirm that not only are we generating the right type of killer T-cells, but that these killer T-cells are actually infiltrating into the patient's tumors, right? Because, again, today, as you are very much aware, a lot of our peers are characterizing the T-cells in the circulating blood. And a T-cell that's in the circulating blood is really of no use or benefit to a cancer patient. These T-cells have to infiltrate the patient's tumors to be able to actually kill the patient's cancer.
So that was really important information for them to really demonstrate that we're generating very efficient accumulation of these killer T-cells, specifically in the patient's tumors. But the other very important thing they also showed last quarter was not only these are actually biologically active killer T-cells, they showed a very significant decline in circulating tumor DNA. So when they combined our PDS-0101 with standard of care, they showed that at five weeks, there was a 92% decline average in circulating tumor DNA in these patients. Some patients had a 100% decline. With the standard of care at five weeks, the decline is only about 52%. So a really dramatic enhancement in elimination of the patient's tumors when PDS-0101 is added and generates these anti-tumor T-cells. So that was very important. And then switching over to our head and neck cancer trial.
So with VERSATILE-002, we had two arms. So you may recall that we had the first arm focused on head and neck cancer, the patients who would traditionally be going on to checkpoint inhibitor therapy. So these were referred to as the checkpoint-naive patients. And then the second arm was the patients who would have failed all treatment options, including checkpoint inhibitors. So these are the patients who are really at the end of the line, who are typically going into hospice. So in terms of how we look at that data, so to put it in perspective, these patients with head and neck cancer will typically go on to KEYTRUDA as a monotherapy, or they would go on to KEYTRUDA plus chemotherapy, right? The published results in terms of survival for these two are approximately 30%.
So 29% two-year survival with KEYTRUDA, and 31% two-year survival with KEYTRUDA plus chemo, which means that if you go on either one of these two, you have a 30% chance of living for two years or more. A nother way to look at it is 30% of patients will live two years or longer. Now, when we add PDS-0101 on top of KEYTRUDA, that goes from a 29% two-year survival to a 74% two-year survival. That, to the best of our knowledge, is the longest survival that we have seen in this patient population in head and neck cancer. Again, very important and strong demonstration of the power of the right type of T-cell in extending patients' life.
I think in terms of how investors look at, should look at this, I think if you listen to, I will tell you what our key opinion leaders in head and neck cancer think. From their perspective, there are two critical elements that they're looking for in a head and neck cancer therapy: survival and safety, right? Survival, I've just gone over the data, very extensive improvement in survival in these patients. But what is also very surprising to many people and of significant interest to the KOLs was the safety. So this, with the safety, for example, if you look at KEYTRUDA, what's been published is that 17% of these patients will have grade three or higher adverse events, which we would consider serious adverse events.
When you add chemotherapy on top of that, that goes from 17% to 72% of patients having severe adverse events. If you look at PDS-0101 added onto KEYTRUDA, we are only seeing 13% of patients having grade 3 adverse events, no grade 4s, and no grade 5s, so very well-tolerated. And actually, one of our investigators actually was compelled to write a story about one of his patients who was on the therapy, who saw really dramatic shrinkage of the tumors without any of the typical side effects you would expect from a cancer therapy, other than some soreness at the injection site and some fatigue. That was it. So very well-tolerated, really unique compared to what you see happening in cancer therapy today. But the other arm I mentioned is the checkpoint refractory arm, right?
So over the last couple of earnings calls, one of the key things I've mentioned is that we are waiting for the data from the refractory arm with the double PDS-0101 and KEYTRUDA to really help us understand exactly how these technologies are working, and to be able to design our triple combination, which I'll get to next. So with these patients, as I mentioned, once they fail checkpoint inhibitors, they really have no, very few alternatives, no FDA-approved therapies available. If they don't take any other therapy after this, which, it's reported about 50% don't, their one-year survival is only 17%. Their other option is to go on what we call salvage chemotherapy. Once they go on to salvage chemotherapy, their one-year survival rate is 30%.
When we look at PDS-0101 plus KEYTRUDA, we see the 12-month survival rate goes to 56%, almost 60%, and these are patients, the vast majority of whom have failed and progressed on KEYTRUDA. So that's, again, a very strong demonstration of the potential of PDS and the T-cells, really to extend patient survival. However, what we see in this particular population of patients who are checkpoint-resistant, is that we did not see any confirmed objective responses, meaning that the tumor shrinkage was not as significant as in the checkpoint-naïve population. And that was very important because what it means is that the T-cells are entering the patient's tumors, but not very effective in fighting against the cancer's defenses, so probably getting exhausted. So T-cell exhaustion is one of the limitations of the T-cell approach.
So now let's switch to the third trial, where we now have our IL-12 antibody drug conjugate. As I explained earlier, with the IL-12 antibody drug conjugate, what we're able to do is to actually infiltrate the tumor and disarm the tumor's defenses from within, right? So now looking at doublet, but plus our IL-12, if you look at these checkpoint-resistant patients, with the high-dose IL-12, we now go from a 0% objective response rate to a 63% objective response rate, right? So now a real dramatic improvement because we're able to disarm the tumor's defenses and allow the T- cells to go in. But what the IL-12 is also doing in the tumor, it's also a very powerful T- cell activator, so it provides the fuel for the T- cells to continue to fight and kill the cancer.
If we look at the survival of these patients, right, typically, their survival is about three to four months. That's what's been published. With this combination, including IL-12, we're showing approximately a 20-month median overall survival, so a really dramatic improvement. Now, what's also important here is, even though we are able to now treat these highly resistant tumors, this has also shown really groundbreaking results in the checkpoint-naïve patient population, right? So if we go back to the population where KEYTRUDA and KEYTRUDA plus chemotherapy have shown two-year survival of 29% and 31% respectively, what we really wanted to understand, and the data that we got in the Q4 of last year told us about this combination, was we originally had two-year data. What we wanted to understand was the durability. How long-lasting are these anti-tumor responses?
In many immunotherapies, you get a sharp drop-off in survival from one year to two years. Probably an even sharper drop-off from two years to three years. The two-year survival was really impressive, 75% two-year survival. What we wanted to understand was, would there be any drop-off going from year two to year three? What we found out was that every patient who was alive at two years remained alive at three years. The three-year survival rate is 75%. If we look at the objective response rates, goes from 19% with KEYTRUDA to 75% confirmed objective response rates using the IL-12 in this population.
That's why I really describe this as real groundbreaking data that we've seen in some of the most difficult-to-treat cancers, by taking this unique approach of being able to generate the right type of T- cell, infiltrate the tumor with the IL-12, disarm it, and allow the T- cells to go in and perform their function a lot more effectively. This is also a platform that we are applying to a broad range of cancers beyond just head and neck cancer or HPV-positive cancers. It allows us now to take PDS-0102 or PDS-0103, and really apply, apply the same approach to treating some of these difficult-to-treat cancers.
Yeah, that's very profound. And maybe just a couple of quick rapid-fire kind of questions, like the tolerability profile.
Yes.
Maybe just mechanistically, why is it different, or so remarkably improved, say, versus, you know, versus KEYTRUDA chemo combination, like you said? And what was the triplet tolerability? Maybe comment on that also. And then, very interested to hear, how should we think about the update that you're looking to put out, I think Q2 or middle of next year. Will that have both doublet and triplet dataset? and I understand we'll get to your phase III design in a minute because, you know, we should talk about that too. But, what, you know, will we get incremental there, be it around ORR, be it around, you know, durability? Where should we focus on? If you could address maybe those two, three questions quickly.
Sure. I jotted down some notes, so if I leave any of those out, please remind me.
Sure.
Starting with the IL-12 and how it is different and why we're seeing such differentiating data. IL-12 has been studied for quite a while. It hasn't really been successful in clinical trials. There have been two key problems with IL-12: toxicity, lack of safety, because it's a highly inflammatory cytokine, and also, lack of efficacy, potency. Now, one of the key reasons for that is that recombinant IL-12 that has been delivered is delivered into the patient's blood, right? One of the key things I mentioned is that the most relevant T- cells to the patient are actually infiltrating the patient's tumors and not hanging around in the patient's blood. Activating an irrelevant T- cell type doesn't really do much for the patient. That's one problem. The second problem is IL-12 has a very short residence time in humans, right?
And so a lot more has to be dosed and a lot more frequently than is typically safe for the individual, right? Because it's eliminating the body so quickly, a lot more has to be put into the patient to actually get any potential therapeutic benefit. Also creates a lot of toxicity, but also, again, as I mentioned, it's the IL-12 is not really going where it is supposed to be, which is into the patient's tumors. What's different about our approach and what's unique, and this, if you recall, this is a product we acquired about a year ago because we saw the potential in this product to really revolutionize how we treat cancer. This IL-12, we have two molecules of IL-12 conjugated to an antibody that we call NHS76.
This antibody binds specifically to expose DNA from dying, dying cells, which you find in the tumors, right? So by binding this IL-12 to the antibody, what the antibody is doing is taking it into the patient's tumors. What we've also done, which is slightly different from what antibody drug conjugates do today, is antibody drug conjugates allow a dissociation of the drug once it gets into the patient's tumor. In this case, we have fused the IL-12 to the antibody, so the IL-12 cannot dissociate from the antibody, right? By doing this, we avoid two problems. We avoid an inflammatory IL-12 going back into the patient's blood and causing toxicity, and also, we avoid a really short residence time in the patient.
By keeping it onto the antibody, what happens is this antibody goes and binds to the exposed DNA in the tumors, and it holds IL-12 in the tumor. Y ou have a sustained residence of the IL-12 in the patient's tumor. B y having that sustained residence in the patient's tumor, it gives it the time to really alter the internal constitution of the tumor and disarm the tumor's defenses. But what it also does is it now stays in there. When the T- cells come into the tumor, it provides that fuel for the tumors to really expand and perform their function. B y doing this, we also eliminate and significantly reduce the toxicity because we don't have free IL-12 circulating in the patient's blood. But at the same time, the IL-12 is now located in the tumors rather than the circulating blood.
With this approach, today we have data from 250 patients with our IL-12, so this is not a small population of patients. We've a large number of patients, and we have not seen any of the toxicities associated with the recombinant IL-12s. Very well tolerated, very few grade fours, predominantly grade twos and some grade three toxicity, so really well tolerated. And so this is really different from what you see, what has been done in the past, where a recombinant IL-12 has been administered to patients.
Yeah.
This is a very different, very different approach, which really is focused on getting it into the patient's tumors and holding it in the patient's tumor, so it can get its job done.
Right. And maybe just the medical update, and maybe if you could connect that with the phase 3 study progress. It looks like you got some guidance from the FDA and recently, and you're getting close to first patient dosing. Maybe if you could talk about the design for that and how maybe an interim analysis you may look to build in, obviously, you know, design for a full overall survival endpoint. Talk maybe about doublet, and then maybe, we'll if you have time, we can also get to the triplet.
Sure. So with the doublet, that is the PDS-0101 in KEYTRUDA, PDS-0101 in KEYTRUDA combination. And so, yes, you are correct. We did get some very useful feedback from the FDA in terms of what they wanted to see in the design, that design has the control arm being KEYTRUDA, so it will be PDS-0101 in KEYTRUDA, with KEYTRUDA as the control. The FDA requested specifically that the output be the primary endpoint be overall survival. The FDA made it very clear, just like the key opinion leaders have done, right? So the FDA and the key opinion leaders are on the same page. Neither one of them really care about objective response rates or PFS. What they're focused on is survival and safety. The FDA's position was objective response rates and PFS haven't translated to survival.
What they really want to see is extension in patient survival. ... which is exactly what we are really showing dramatically with our results to date. And so that's how that trial has been designed. We have built in an interim data readout, which will allow us to have discussions. Our goal really with the interim data readout is to allow us that opportunity to have discussions with the FDA, pending what the data looks like at that point, pertaining to any potential accelerated approvals, for example. Right, and so we've already submitted that, the final design to the FDA and received the FDA's green light to go ahead and initiate that trial. This trial specifically is in checkpoint-naïve patients. So these would be the patients who have not yet been treated with checkpoint inhibitors and who would traditionally be going on to checkpoint inhibitor therapy.
Right, so that is what we call the doublet, VERSATILE-003. The triplet that will contain PDS-0101 and a checkpoint inhibitor, very similar to the doublet, but have the IL-12 antibody drug conjugate added to that combination. Where we see the opportunity really is in checkpoint-resistant patients initially. We're looking at what is the most rapid path to commercialization with these patients? One of the things we also realize is today, checkpoint inhibitors have become mainstream, right? A vast number of patients are being treated with checkpoint inhibitors. However, the response rates in these patients are very low, so we are generating a larger and larger number of checkpoint-resistant patients. It's actually projected that the market for in checkpoint-resistant cancer by 2033 will be over $100 billion. There is no clear product or combination that's poised or set to dominate this market.
What we have shown with our technology is that we have the potential to dominate that checkpoint-resistant market. What we're doing within this approach is really to go into checkpoint-resistant patients. So we have had initial discussions with the FDA in terms of defining and outlining what the regulatory strategy and pathway would be for this trial and this design. One of the key things we wanted to find out from the FDA was, as you know, in the current triple combination, the data we just discussed, the checkpoint inhibitor was an investigational checkpoint inhibitor owned by Merck KGaA, bintrafusp alfa. Right, what we wanted to do - that would make it three investigational agents.
What we wanted to do was to replace that with an FDA-approved checkpoint inhibitor that will leave us with two investigational agents and simplify that registrational pathway, which the FDA agreed that we could replace that with an FDA-approved checkpoint inhibitor. The other thing we really wanted to understand was, these patients have a really short survival. Can we go into this trial as a single-arm trial and get to the approval that way, or would the FDA want to see a control arm in the study? The FDA strongly recommended that we have a control arm. And so in these patients, as there's no FDA-approved product, we will allow the investigators to use what we call an investigator's choice chemotherapy, because that's really the only alternative patients have at this time
And so that's the approach we will be taking for this trial. We've taken the FDA's input. We're designing that trial. We'll get the final, just like we did with the VERSATILE-003, get the FDA's final blessing before we initiate the trial. But very similarly, over here, what we're doing is, again, building in an interim data readout, 'cause what we'd again want to do is, if the data looks anywhere close to what we've generated to date, have the opportunity to discuss with the FDA potential accelerated approvals, right? And so really giving us that opportunity and to really get these to the finish line as quickly as possible. W e are very optimistic about both trials and looking forward- to getting to, to an FDA approval.
I guess maybe just to wrap up, how about your balance sheet, obviously, you know, there's a lot for you to execute on, and capital in this environment is an important consideration. How are you thinking of non-dilutive sources? You've obviously been very lean in how you've done things in the past, but obviously now it's prime time executing on later-stage trials, or as a company-sponsored study. So maybe just talk about that and how you're also thinking of milestones from these two later-stage studies that will overlay some of those capital considerations.
Absolutely. You're right, we're heading towards prime time now. And as we reported at the end of last quarter , we had approximately $54 million in cash. As you mentioned, we've had a very low burn rate. We've been burning at the rate of $67 million per quarter. However, once we start either one of these trials or both, the burn rate is going to go up significantly. W hat we're doing is we've been extremely strategic in how we determine how we move forward and when, right? We're looking at a number of options available to PDS. We will have to make a decision in the near future, but we're looking at multiple options strategically in terms of what we believe is going to be best for the company and the company's shareholders to move these forward.
Again, as I mentioned before, we're looking at a number of options, including potential partnering, commercialization partnerships, all of those on the board. W e will make a decision in the near future as how we best do this strategically to move these programs forward. But that's our key focus today, is really getting these programs to go into t hose registrational trials.
Makes sense. I think with that, we'll wrap up. Thanks again, Frank, for being part of our conference, and I appreciate the folks in the audience tuning in. We'll get started with our next fireside chat momentarily.
Thank you very much. It's been a pleasure. Thanks a lot.