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Joseph Kim:
Welcome to Clinical Research Confidential. On this show, we highlight and demystify the inner workings of this greatly misunderstood activity called clinical research. Now, why is clinical research important? Well, it’s the basis for nearly every modern remedy for sickness and a growing method to build trust and solutions meant to optimize health, but it’s not for the faint of heart. And so, on this show, you’ll hear what it really takes to succeed in the clinical research game. I’m your host, Joseph Kim, and I’ve spent over 23 years in the clinical research industry, now serving as the chief strategy officer for ProofPilot. Get ready for some adventures as we look into the underbelly of clinical research.
Joseph Kim:
Today, I’m here with Matthew Price, who has a very atypical story when it comes to clinical development and leadership in life sciences. Matthew Price is the co-founder and chief operating officer of Promontory Therapeutics. He’s with us today joining us from, where are you, Matthew?
Matthew Price:
I’m currently in Cooperstown, New York.
Joseph Kim:
Baseball hall of fame.
Matthew Price:
It’s become my remote office location during the pandemic and a place to grow our family. Our company remains headquartered in the city, New York City, and I’m there quite often.
Joseph Kim:
Great, thanks for coming on the show. It’s great to have you.
Matthew Price:
It’s a pleasure. Thank you, Joe. It’s great to be here.
Joseph Kim:
We’re going to hear all about Promontory Therapeutics, it’s very exciting science, but you have a very interesting personal story. Unlike most people that have been on this show, you don’t have a sort of, your background training in academics wasn’t really focused squarely on life science. Tell us about what you really studied and how you transformed yourself from the humanities to the sciences, and leading a company like this.
Matthew Price:
Yeah, thank you for that. It’s a nice opportunity to be able to talk about that, and I’ve begun to do that more as we’ve made our way onto the public stage as a company. So I come to biotech with a business background in terms of my training, and while at Columbia Business School, a couple of things happened. First, I discovered a passion and an intention to move into a socially driven business arena that had an IP background. So my take on what I was learning and what I was experiencing, and this was in the middle of the Great Recession, was the future is probably going to be about intellectual property-driven businesses. And I had, within myself and my sort of outlook on the world, a motivation to do good. And the other thing that happened while at Columbia Business School is I met our co-founder, my co-founder, our chief executive officer, Robert Fallon, who had been teaching there at the time, and we found ourselves discussing several different opportunities that oriented around biotech and life sciences after I’d received my MBA, and we ended up founding this company together. And what I had done before that, to your question, was originally training in history at Princeton University. I spent some time overseas in Germany following that, and I was in the music world. I was a producer, having been on stage as a performer, and what I learned in producing was, oddly or ironically, rather similar to what I do now. You have to harness other people’s talents, you have to know what product it is that you’re trying to launch and bring into the world, and you have to be multidisciplinary. You have to understand enough of each of the myriad disciplines in what you’re doing to be credible and to be effective, and you have to bring them all together. So these things all uniquely combined in my background to bring me to where I am today, but I should add that, of course, the other ingredient is I’ve now spent the better part of a decade up to my eyeballs in product development in biotech. So my generalist background is now definitely been enhanced by time in the trenches, working across all the various inputs that are needed to get to where we are as a company, which is the Phase Two stage of clinical development in oncology.
Joseph Kim:
Yeah, but I like to always remind people that we are not in the business of science, we’re in the science business. And whenever you’re in a something business, like you said, it’s multidisciplinary. It’s not just about acumen in the subject matter itself. There’s a lot of other things you need to do to motivate different disciplines to work together and reach the goal.
Matthew Price:
Very much, and as development seems to be getting more and more complex, protocols are getting more and more complex. Our own protocols have gotten more complex as we’ve evolved. We really do need, I would say, to have people with the capacity to connect dots, to understand and appreciate the through line and what the development effort is actually all about. And as we’ve done that, we’ve learned, and we’ve come to believe that small molecules have a role in immuno-oncology. This is something that may have been very counterintuitive some time ago, but we see it now as somewhat of an emerging area within oncology. And so, to perceive that, as you are in the trenches as a small company wearing many different hats and managing many different initiatives and efforts, even down to the level of detail, it’s not easy, especially as the industry has gone through such growth, and the number of approaches within oncology has just burgeoned. So to find your place within that takes, I would argue, some degree of understanding and contextualizing things that are very complex.
Joseph Kim:
Yeah, coming in as an outsider, you’ve probably come, have had to deal with not just challenges that people who are long in the tooth have dealt with, but because you don’t have relationships, these become exponentially harder for you, right? How do you find the right set of investigators? How do you build trust with them? You’re coming at it from a small molecule versus a large molecule. So all of these things are relatively new and hard, twice as hard as it is for someone coming in from the outside. Help us understand the big picture of how you were able to enter into this ecosystem of oncology and oncology research and what made it hard, and how did you overcome those things.
Matthew Price:
Yeah, I’d agree with you. We spent a great deal of effort building those relationships. They are now very much in place, which is a wonderful thing. And I would say, first of all, none of this would have happened without a great asset. We could be the most brilliant managers, without an asset that people are drawn to, everything that I just said wouldn’t have actionable meaning. But the opposite applies, with a great asset, it’s only great if the right people are in place to develop it. And so the company formed at the instigation of Robert Fallon and myself with the in-license of what is now known as PT-112, we licensed the whole suite of inventions by a really brilliant chemist named Racindra Bose, who at the time was working at Ohio University and later went on to be the vice chair of all research for the University of Houston. And Dr. Bose had spent the better part of his career as a chemist and as a scientist looking for solutions to really looming problems in oncology and in a very specific field of chemistry, and he solved those problems. So we were fortunate enough to interact with him through Robert’s knowledge and familiarity with the university and with him to learn about this chemistry and then to see where could the applications be. So, in a nutshell, what he knew at the time was that his invention was going to get around the problem of DNA repair resistance mechanisms, and this is a real problem in a lot of cytotoxic chemotherapies. Specifically, with the first generations of platinum chemotherapies, patients would respond, but then the DNA repair machinery would essentially block the ability of these DNA adducts being created to have any therapeutic benefit. So Bose overcame this with his invention, and as we now know it, PT-112 generates something which we call immunogenic cell death, and this is done through cancer cell-specific organelle stresses that do not rely on DNA adducts in order to be cytotoxic. And with these organelle stresses, the nature of cell death is immunogenic. So we’re now at a point where we’ve not only shown non-clinically that PT-112 is a bona fide immunogenic cell death inducer. We’re beginning to see these effects in our patients, and we hinted at that in our recent Phase Two-A data set, ESMO IO, at the end of last year in Geneva. And, of course, we’re working very hard to prove this out in human patients. So back to the origin story. Dr. Bose’s invention was truly differentiated, and as we discovered this, as we realized what we had, and as we then worked extremely hard to perfect the knowledge around PT-112 and its mechanism of action, we were, to your point, increasingly are able to build the relationships around ourselves and around the company that would allow us to be successful. I would just point to a few of the people, and this is public knowledge, that we’ve been working with for some time now. So Dan Vonhoff, who chairs our scientific advisory board, is a veteran drug developer in oncology and really one of the great minds out there in terms of understanding how a given mechanism or a given modality can be deployed and developed. He told us at one point, you guys have a tiger by the tail, and that was enough for us to know, validation was available from, let’s say, within the heart of the drug development field, and we needed to run with it, and we needed to prove this out. When we discovered and had patented the immunogenicity that I just referred to, we were able to interact with people like Chris Boshoff at Pfizer, who now, at the time, was in charge of immuno-oncology development at Pfizer and currently is in charge of clinical development. And Chris was very forthright with us and saw how immunogenic cell death could play into the emerging applications of antibodies in immuno-oncology, and we struck a collaboration with Pfizer and with Merck, Darmstadt, EMD Serono, to use our drug PT-112 in combination with their PD-L1 inhibitor. And this is the data we just reported at ESMO IO and had previously reported at both ESMO and ASCO in the past, as the study has evolved over time. So those kinds of relationships, and then in the, were instrumental to us. And then in terms of investigators, we’re currently working on our prostate cancer lead Phase Two program with Howard Scher at Memorial Sloan Kettering who really is, has been a pioneer not just in Genitourinary oncology, but in drug development, within prostate cancer and within the use of circulating tumor cell analyses, within drug development in a hunt for a way to be more effective and more quick in terms of getting drugs developed in prostate cancer. So these kinds of people have gravitated to our program through our effort, and I think relationships really are at the core of who we are as a company at this point. And a small company, to your point, needs these kinds of interactions, this kind of reinforcement, and in fact, this kind of learning from people who are preeminent in the field. And we’ve known that we need to do that as people who didn’t come as MD-PhDs with a set of known priorities. Let’s say we had to be receptive to the knowledge base that was out there, and we’ve done that, and I think people have respected that about our team. And then, just to round out the thought internally, of course, we’ve built out a team now as well. And so we have, in the meantime, folks who come with industry backgrounds and scientific backgrounds and business backgrounds that, within industry, that are deeply helpful to our effort. And to your point, team building is internal, it’s also external, and we view those two things through the same lens really in terms of how we’ve needed to manage the program and get it to the place where it is, which I would argue is at a point of proof of concept. Now we need to pivot into a launch plan in scaling up for that as a company.
Joseph Kim:
Yeah, very exciting. And I think what I love about this whole story is when the science is exciting, people will come out and be generous with their minds and their work, and it looks like the science is quite exciting. Let’s talk about PT-112 in a little bit more detail with regard to what did you see in, say, mouse models and other pre-clinical studies that may be translated differently, whatever you can say is fine, of course, that translated differently into humans. Are there any adjustments that you needed to make in terms of expectations, thinking about other biomarkers, manufacturing, what changed?
Matthew Price:
It’s a big question. I would take this by saying, let me put it this way. Preclinical efficacy models have traditionally not incorporated immunocompetence. So the traditional models, which we started out with, would tell us nothing about these immunogenic effects that we now know the drug causes. And interestingly, the drug was effective in those models that were immune-compromised mice, particularly in GI and in lung cancer models. Now as the field evolved, those models became less relevant. So let me describe to you where we got particularly excited. So first off, in our publication in the journal Oncoimmunology, this was done with Lorenzo Galluzzi, who really is one of the world’s leaders and one of the early pioneers in immunogenic cell death research. We knew we needed to move into immune-competent models, and Lorenzo helped us to pioneer how to showcase these effects of PT-112 within a really stringent validation system that he has pioneered from a methodology perspective, and we did that. In fact, I would say the most fascinating model we’ve run was his vaccine model, where you actually don’t treat the animals, you kill the cancer cells in vitro, and you basically package those dead cells into a vaccine, because if the way in which you’re killing the cells is responsible for damp release, in other words, it creates damage signals or dangerous signals that are recognized by the immune system. When you put that as a vaccine into a mouse, the mouse will basically have those dangerous signals and those immune signals available to it, such that when you reinject live cancer cells, no tumor will form. And we showed that we could do this with PT-112, and we showed that we could do it at a rate of success that was really much higher than anything expected, and in fact, than anything published. So we think we have the best-in-class immunogenic cell death inducer based on that validation and other things like it. We also saw t-cell infiltration in the mouse tumors, even with our monotherapy. So when we treated immune-competent mice, we could see that PT-112 alone, or in combination with immune checkpoint inhibitors, was responsible for driving changes that were favorable, meaning more immunogenic in the harvested mouse tumors that were analyzed ex-vivo. These efforts in our, let’s say, validation, were really extremely helpful to us. The same goes for multiple myeloma, where we use the wonderful model at the Mayo Clinic, which is a genetically engineered Orthotopic Immunocompetent model, really the best of all worlds, and saw that PT-112 was, from what we learned, the third most potent drug ever used in that model. So these were great successes in terms of non-clinical validation and excitement for us in the company. But your question goes to translating. So what are the challenges? What changed? Of course, the minute you’re looking for something in a disease-bearing human population, everything is different, and I don’t think anyone can claim to understand the totality of why that is different. You work by trying to get a handle on the various factors involved, be it the population and the nature of the disease, be it the nature of prior treatments that a given patient has had, and eventually to your question about biomarkers, our current prostate cancer protocol does involve markers for circulating tumor cell reductions and for changes in t-cell populations in the patients. And so by those means, we can try to get a handle on what we’d like to think is a form of proof of mechanism in the human setting, and we will be, that data is all emerging, I can’t really speak to it, but we will be presenting it in time and moving forward with our plans to advance through Phase Two. I’m sure you have some follow-ups on this, and I’m happy to dig in …
Joseph Kim:
This is, love is understanding that the models, models are never translatable, that’s where they’re models. But if you can improve the model, you get a little bit closer to what you hope to expect to see in humans, for sure.
Matthew Price:
The logic was if we can show this immunogenicity with PT-112 in models, where might it be best applied in humans? So to my earlier point, with colorectal cancer model in the non-clinical setting is very different from treating prostate cancer patients in the clinic. How did we make that leap? There were empirical observations which we presented early on where we saw Phase One prostate cancer patients doing extremely well on our monotherapy Phase One study. And then, we extended the logic that prostate cancer is a disease setting where immunotherapy has had a lot of challenges and is neither truly broadly approved, or broadly adopted, and the disease is known as immune cold. And so the logic was, let’s follow the data and let’s look for a creative application of the program. And so that’s really why we’re at the point of scaling our Phase Two study in the metastatic prostate cancer setting, because the observations we’ve made and the hypothesis we’ve generated, they make sense.
Joseph Kim:
So now, let’s transition to the human world. As you alluded to, humans are very different. There’s the totality of the complexity there, no one really understands, particularly around behaviors. People want to do things, but sometimes they forget, or it’s hard to do. And this is both from the researcher and the patient when they’re participating in research together. Conducting cancer research is not easy to do. This isn’t vaccine research, which is you jab them, and you come back in six months and take some blood, and certainly, it’s hard for the patient. So what learnings can you relay to us about the difficulties of designing and running cancer trials from both the patient and researcher perspective? And have you had to make any adjustments?
Matthew Price:
Yeah, it’s a great question, and I think it’s something that is most likely lost on the average observer of the industry. I have both gone through the effort of designing and running these trials, I’ve also accompanied a family member who passed away of a lung cancer through the process from the other side, you know, and trying to get that family member onto a clinical trial. And so I think it is a very, it’s a delicate topic because from the industry perspective, we want more patients to want to do clinical trials. And at the same time, it is a major commitment, and it’s a leap of faith for a patient in many cases, not in all cases, but in many cases, and particularly with an early-stage program. And I think what’s important is that the investigators are the ones who are really making those decisions, and they are doing so in the context of the patient-physician dialogue, right? So confidential to us and confidential to anyone, right? That dialogue is the place where things should be done right for a given patient. And it’s important that sponsors are not part of that dialogue, and yet we have to know that it’s there because we need to look to understand where the unmet need is. Go after addressing the unmet need with the knowledge that there are probably alternatives to our trial, to our program, and to solving this conundrum, really, which is what patients should be on a given protocol and how can we offer something that’s appealing? We have solved that really almost exclusively by informing the investigators about what we know about our drug. And I would say that point is one of the biggest challenges in clinical research because a sponsor, on a multi-site trial, the sponsor is the one who knows the totality of what’s going on across the different clinical sites. And it’s very difficult to inform and keep the investigators who have busy lives, busy practices, a lot of demands on their time, you know, about what we’re seeing, and yet it’s essential that they’re informed about what we’re seeing such that they can go into that patient-physician dialogue with the right approach. So that has been our, let’s say, philosophy, and it has worked in the sense that I just described it. I would say, though, to your question, what is changed? The pandemic changed everything. And what shocked everybody about the pandemic, I think, was that a cancer patient might decide to stay home rather than seek treatment or even seek a clinical trial when they need it. So the ramifications of this early on in the pandemic were really acute, you had a lot of, you had lockdowns, shutdowns, patients not coming out, and so enrollment was definitely impacted. But to your point about behavior, because the ripple effects of that have been extraordinary. Sites have really struggled, clinical sites have struggled with keeping staff, and that has impacted the way in which sponsors like us can enroll a trial. A lot of money came into the industry because of the success of the COVID therapeutics and vaccines, and was looking for opportunities that meant that company formation accelerated. That meant that clinical trials numbers increased, and let’s say competition for enrollment on those trials became more of an issue than it was, particularly if there’s no staff available to run that. So there was nearly a perfect storm in our experience of continuing to enroll these trials, and it wasn’t a momentary storm, it was like a rolling storm that took on different shape and form and moved around the country, moved around the world. It has been a real struggle, I have to say honestly. But back to your point about relationships, sticking with the investigators, listening to the data, and just keeping at it has been, I think, the ingredient that has helped us through that.
Joseph Kim:
Yeah, the one thing that stuck out that I hear a lot of people say during the pandemic, even post-pandemic, is this staff turnover. And when it comes to research, this isn’t just clinical care, it’s very specific clinical care that is the protocol, and to train somebody up on that is not easy, particularly for a complicated study. How hard has it been to make sure that when staff turnover does happen, that they’re quickly trained or that they’re not making errors just because they’re new?
Matthew Price:
And it’s a real thing, to your point about human behavior, I mean, all of us who are humans in clinical research are human. So there’s no way around these issues other than transparency and persistence, really. To generate the data that come out of a clinical trial requires enormous human input, and it may read as numbers on a page at the end of the day, but it is really a very different challenge to generate that data. Yeah, we’ve had to manage during the pandemic, retraining people remotely. The, most of the major research centers wouldn’t allow on-site visits because of the pandemic, so we’ve only recently been more back out physically in front of people. Remote training and regular meetings, not just investigator meetings, working-level meetings with coordinators, data managers, etc., have become essential, and you have to have a good CRO to rely on to be able to do that, and those organizations have turnover, too. So I’m not going to gild the lily, as the saying goes, it is a messy effort and a constant effort to ensure that these things are done properly, they’re in compliance, but most importantly, people know why we’re doing what we’re doing, and it takes a lot of effort, no question.
Joseph Kim:
Yeah, thank you for that. Last question. What’s the next big milestone you’re looking forward to?
Matthew Price:
Great question. So we have three Phase Two programs right now. One of them was just presented at ESMO-IO that was our lung cancer combination with PD-L1 inhibition. We would like to build upon that, so we’re in discussions to create the next stage of development. We have the clinical leadership ready for that, and we’re looking for the right combination approach and partner. So those kinds of discussions are ongoing. This year, we’ll also be very important for the enrollment on our prostate cancer Phase Two, which will be a significant proof of concept effort and also a dose optimization effort under FDA’s Optimus, Project Optimus, where sponsors are being encouraged to do dose optimization prior to launching a pivotal study. That’s a very important regulatory initiative. So the Phase Two in prostate cancer will hopefully satisfy that. That’s a, that is a very important milestone for us. And the third Phase Two is actually sponsored by the National Cancer Institute. So that’s our program in Thymoma, that is a rare disease program in contrast to the prostate and the lung cancer programs. Thymoma has no FDA-approved drug, actually, and that’s the reason, coupled with data we generated in Phase One and published, that’s the reason that NCI is involved with us and generously running our Phase Two there. So all three of these programs will have milestones coming up, as I’ve described. Enrollment and data milestones, and then, in the lung cancer case, hopefully launching the next stage of development. And then, of course, to do all that, we have to be properly capitalized in a constrained environment. We’re a small biotech that has managed to fund our way into Mid-Phase Two development. It’s now time to scale that funding through whatever combination of venture capital or private equity sources, or industry sources, and those discussions are ongoing as well.
Joseph Kim:
Very exciting, Matthew. The science is exciting. I love the story, and I love how people have been coming out of the woodwork and been so generous from all angles, investigators and pharma, to help you be successful and impact real patient lives when it comes to a wide variety of cancers. Thank you so much for joining us today. It’s been a pleasure talking with you and learning more about Promontory. Have a great day.
Matthew Price:
Thanks so much, Joe. I really appreciate the opportunity.
Joseph Kim:
Thank you for tuning in to Research Confidential. We hope you enjoyed today’s episode. For more information about us, show notes, transcripts, and resources, please visit ProofPilot.com. If you’d like to debunk a clinical research myth, share some war stories, or maybe just show our audience what kind of heroics it takes to pull off gold-standard research, send us your thoughts, episode ideas, and more to Help@ProofPilot.com. This show is presented by ProofPilot and is powered by Outcomes Rocket.
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| hosted by Joseph Kim