Latest / BioSpace / The Radiotherapeutics Moment: How Isotopes are Changing Cancer Treatment
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- BioSpace: My name is Jennifer Smith-Parker, Director of Insights at Biospace, and you're listening to Denatured. In this episode, I'll be speaking with Dr. Phil Kandolf, CEO and co-founder of Convergent Therapeutics, and Dr. Mark Hedrick, President and CEO of Plus Therapeutics. They discuss breakthroughs like alpha-emitting isotopes, supply chain solutions, and why radiopharma is biotech's next big frontier. Mark and Phil, thank you so much for joining this episode of Denatured. If you can please introduce yourselves, that would be wonderful. So let's start off with you, Phil. Thank you, Jennifer. Really a delight to be here today. My name is Phil Cantoff. My background is one of a medical oncologist. spent most of my career in academic medicine as a physician scientist in oncology, focusing mostly on genitourinary cancers and most specifically prostate cancer. I was at the Dana-Farber for many years and then I was the chair of medicine at Memorial Sloan Kettering before we started Convergent Therapeutics in 2021. yeah, Mark? Hi Jennifer, yeah thanks for the invitation. My name is Mark Kedrick, I'm the president and CEO of Plus Therapeutics and I was an academic surgeon at UCLA, a physician scientist as well, and left about 20 years ago to start a company and now I'm the CEO of Plus Therapeutics. We developed Therapeutics, Diagnostic, and Advanced Data Analytics for Central Nervous System Cancers. Right. Well, thank you so much, both of you, for joining. So this episode focuses about the radiotherapeutic space. Phil, if you can provide 30 seconds, let's say, on the current state of prostate cancer and where the remains are met need. Sure. So prostate cancer is the most common disease diagnosed in men and most Patients are diagnosed with early prostate cancer and are curable with surgery or radiation. But there are still about 35,000 men that die of prostate cancer, either because they relapse after local therapy with surgery or radiation, or they present with advanced disease. There have been significant advances in prostate cancer over the past 20 years, extending the life of Ben with advanced prostate cancer, including hormonal therapies, chemotherapies, immunotherapies, most recently radiotherapies. The unmet need, there's unmet needs across the whole spectrum of the disease. We're now focused on patients with what we call castration resistant prostate cancer, that is patients who have gone through androgen deprivation therapy or what was commonly knows as hormonal therapy, who move on to chemotherapy. And really there are very limited options for those patients at that stage of disease. as I said, there were 35,000 men that marched through that state of disease that really need better therapies and potentially curative therapies. Thank you. And on your side, Mark, can you please talk about the brain cancer space and also maybe start off by explaining the focus of Plus Therapeutics, a subsidiary CNSI and how it fits within the company's broader strategy. Yeah, we started out as a targeted radiotherapy company specifically focused on central nervous system cancers. And as part of our clinical development, we recognize that the diagnostic options for patients, particularly with leptomeningial cancer, it also overlaps with primary brain cancers and precomal brain metastases. The diagnostics have not really kept up with the broader field. And so we developed a very high conviction that we needed to make material improvements in survival in central nervous system cancers, which have largely been flat for 50 years, particularly compared to other cancers. that we needed to integrate not only the therapeutic aspect, but also diagnostics and the data analytics. And we felt like that was the only way that we were going to be able to provide material improvements in survival to patients. then when it talks about, let's say, improving survival, I'm curious ⁓ about that. now flipping over to you, Phil, I mean, you were a longtime medical oncologist before becoming a... a biotech CEO. So what convinced you that the PSMA targeted radio antibody technology coming out of Cornell was compelling enough to build a company around? Right. So as I mentioned before, a lot of progress has been made in the context of advanced prostate cancer in past 20 years, but there's still this huge unmet need. And the data that I was seeing at Cornell using the radio antibody approach, not only targeting prostate specific membrane engine, but using an alpha emitting isotope, Actinium-225, was extremely compelling. So in the first experiment that was done, which is what I saw at that time, was a single dose, dose escalation study giving the radio antibody, which we call Convo-1 alpha, to patients with very far advanced pre-treated patients. And about 45, 50 % of patients responded to it. which is really pretty remarkable given that it was only one dose and the safety profile was pretty compelling. So that's when I got excited about it, made the switch into running this company, co-founding it and becoming the CEO. And we have since advanced the program using multiple doses of where we see the majority of patients responding, patients who have been previously treated with a PSMA directed therapy using a different isotope, lutetium-177. So one of the big advantages here is the difference in isotopes, and we can talk about that some more and all the different isotopes that can be used and the different combinations that can be used, but the alpha therapy is much more powerful, potent than using a beta. And using an antibody approach we felt was advantageous over using a small molecule approach. So we have advanced that technology with multiple doses in patients with far advanced disease, even patients who have been previously treated with a small molecule using lutetium, which is the beta. So, you know, very excited about it moving forward. Yeah, that's fascinating to see. potential here. So on that account, Mark, you've said that radiation is still the most effective way to kill brain cancer cells, but historically we haven't been able to deliver enough of it to tumors safely. how does your approach change that equation? the radiation's been historically delivered pretty much everywhere. I mean, prior to the resurgence in target radiotherapeutics, but by external beam radiation. And to overcome the complications of offsite toxicity, Radiation oncologists who are the ones responsible for organizing the therapy for patients will use something called fractionation, where they'll give a specified maximum amount of dose over multiple days, give little bits on top of little bits to try to get an improvement in survival. And it is the biggest, provides the biggest incremental improvement in survival to glioblastoma, for example. But what we do that's different is we take that Essentially that dose that one can give over many doses in fractionated way with external beam radiation, give 10 times that amount all in one dose. And the delivery technology combined with the formulation of our lead drug is called Rayobac, delivers essentially all of that decay to the tumor. And we get essentially no systemic toxicities, no bone marrow toxicities that are common with too much radiation and too much chemo. So it's really a combination of the radioisotope, the formulation, the delivery technology that allows you to really ramp up the amount of radiation. And we've shown that that actually seems to improve survival in phase one and phase two so far in GBM. Now, Phil, we've talked before about some of the challenges with radioisotopes. And I'm just curious, we talk more about actinium. So supply there has been a challenge. So what are some of the critical supply chain issues that Convergent has been able to address? to ensure it has enough supply for late stage studies or commercialization. Right. Thanks for that question because when I started back in 2021, people had significant doubts about the ability to produce enough Actinium-225 to do our clinical trials. But basically the field which was evolving into these in the alpha direction, was it going to be enough for doing phase two studies, doing more advanced studies and ultimately commercializing it. So initially the supply was from the Department of Energy, at least our supply, and they were producing it using this thorium cow methodology. Other companies were using the thorium derived actinium from radioactive waste derived from the Ukraine or from Russia. so people had legitimate doubts about the ability. to produce ample amounts of actinium back in 2021. But what's happened as has been the case with other isotopes is that there are, of course there's interest in it. There are companies that have emerged that have been able to produce massive amounts of actinium-225 using accelerator generated methodology, using radium as a source rather than the thorium source. So. At this point in time, there are companies that are ready to produce commercial grade and commercial quantity Actinium-225. So that really is, you know, it started before we got started in the field, probably over a 10 year period of time, but we're now at the point where there's an ample amount of Actinium-225 to supply, not only us, but other companies that are interested in using it. Marc, let me ask you a similar, kind of similar question along those lines where where radiotherapeutics, as I mentioned, they come with practical challenges like short isotope half-lives, manufacturing logistics, and regulatory complexity. So where do you see is the biggest bottleneck the industry still has to solve? Is the manufacturing aspect in your end or some other areas? I mean, I think generally deferred fill probably, I think an issue still is logistics, getting the drug to the patient on time, depending on what the particular physics of the radioisotope is. probably one of the bigger issues, if not the biggest issue. And I concur with Phil. I've seen the same thing. Over the last decade, the number of service providers, contract manufacturers, radiation service providers, has sort of expanded dramatically. And it's made it a lot more feasible to not only be creative with the therapeutic and the radioisotope, but improve the logistics. So for us, probably the biggest limitation is the radiation service provider component because rhenium-186 is made in a reactor, a tank reactor. There's not one of those on every street corner. I mean, the key for us really is to have a primary and a backup provider of those services. Everything else is relatively straightforward. the drug has a long half-life, so it's about a 90-hour half-life. We have some wiggle room in terms of, if the patient is late to clinic or so forth to recalibrate it. The supply chain really sets up nicely in part because of the long half-life, but the number of providers and expertise available to a small company like us is substantial and huge, huge benefit. Yeah, that makes a lot of sense. I'm curious with the kind of the overall broader area of radiotherapies. ⁓ With the major resurgence of interest we've seen in the space, particularly in oncology, what changed in the past few years that has suddenly made radiopharma such a focal point for biotech and for big pharma? guess I'll start, Mark. So in the oncology space, probably around 15 years ago, there were a couple of drugs that were produced, Bexar and Zevlin, which were used. The target was CD19 and used in lymphomas. they demonstrated efficacy, but there was a lot of resistance to using them so they were not a commercial success. And I think people sort of shied away from the whole approach for a while. Then in the context of prostate cancer, where I think the biggest advances have been made in this area, Radium-223 just the isotope itself was administered to patients with advanced prostate cancer. And it did show maybe 10, 15 years ago, modest survival advantage in patients with advanced prostate cancer. Once again, not a huge commercial success, but it was a proof of principle that you could use a isotope and prolonged survival. I think the, and that enabled the widespread use of radioisotopes, not only in academic centers, but also in community centers. So in order to administer Radium-223, you had to ⁓ acquire a alpha license to supply it. So a lot of community hospitals, in addition to academic centers, have the capabilities now of administering radioisotopes, not only for diagnostic purposes, but for therapeutic purposes. But I think the biggest advance in the solid tumor area so far, Mark, I don't know if you agree or disagree, but was The advancing of Pluvicto in the field of prostate cancer ⁓ was developed, actually the early development was with ⁓ a company called Endocite using a small molecule, lutetium, in men with advanced prostate cancer. They demonstrated a survival advantage, which was great. They solved a lot of the problems with regard to distribution, being able to conduct a large phase three study. ⁓ a pretty huge commercial success. So a lot of the roadblocks were overcome and there's been a massive interest in radiopharmaceuticals as a result of the success of Pluvikta. I don't know how Mark feels about it, but what I've seen that's been a huge opening for the field. I completely agree. I won 31, so to prove the concept and then Pluvikta proved that. commercial viability. that those, those two things I think have created, created the interest. And it's, you know, I think we're just at the beginning. Don't you think? mean, I think there's almost any, any oncologic disease has a potential radiotherapeutic component of their treatment. Yeah. to emphasize that Mark is saying, I forgot about the fact that, you know, thyroid cancer was cured maybe 70 years ago using I-131 very effectively. So that was sort of the proof of concept at that point in time. And I just took that for granted, but Mark pointed it out. But in terms of the potential, I think it's enormous to Mark's point because there are many targets on the surface of cancer cells that are being addressed with antibody drug conjugates, T cell engagers, et cetera. A lot of those targets have not yet been explored in the context of radiopharmaceuticals, only a few of them, but the potential for using different carriers, including small molecules, peptides, modified antibodies, antibodies, the different isotopes, short acting, long acting, just enormous potential for treating many solid tumors, liquid tumors. But right now it's, it's, it's in this infancy, I think, in terms of which isotopes to use against which targets, which carrier mechanisms will be the most effective. And in addition to that, you're also dealing with antibody drug conjugates and T cell engagers and other targeted. So I think the potential for this whole targeted approach toward surface targets and potentially intracellular targets conceivably is enormous. And I think we'll make a huge advance in cancer in the next I would say 10 to 20 years. Yeah, Mark, I love to hear you because you're nodding a lot. I love to hear your perspective. I agree. no, can say it nearly that well. you know, it is, I'm going to maybe highlight really a very, very profound point that Phil made. that is the, unlike the small molecule or a more simple therapy, this, these therapeutics have many levers one can pull. In fact, there's a variety of radioisotopes, variety of formulations, a variety of linkers, a ⁓ variety of ways to deliver it. And working out the dosing oftentimes can be an important part of the overall equation. So it's really, it's profound opportunity in the sense that there's so many different variables that one can bring to bear to optimize the treatment. makes it sort of complex to figure out and optimize those, but the power there and the versatility is enormous. Thank you so much, Marc, and thank you so much, for joining this podcast. This has been a fascinating discussion of the potential for radiotherapeutics, radiopharmaceuticals out there. So thank you so much for your input. 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