Ken Herrmann: So, very up-to-date topic, right? The betas are the ones, the established ones. All the products we currently use the most, PLUVICTO and LUTATHERA. Both of them use obviously lutetium-177, which is a beta emitter. The beta emitters in general, you give a higher activity. They have a longer path length, and overall, they actually create only single strand breaks.
In contrast, when we talk about alpha and why we are so excited about alpha meters is we give less radioactivity. They have a less path lengths, have a higher energy, and very often create double-strand breaks. When we unlock the area of alphas, there are currently two which are the most advanced, the third one which is following. The one I think everyone has heard about is actinium, actinium-225. The half-life is around 10 days, has a very, very high energy. And again, is the one which probably is the easiest approachable for now.
The second one, which gained a little bit of more attention in the last one or two years is Lead-212. Lead-212 has a short half-life. We talk about less than a day. It's more frequently a generator product, and we have also much less clinical experience so far, however, still quite exciting.
And the third one is Astatine-211, which is a cyclotron product that we talk again about a half-life, which is relatively short, and we even have less experience. Overall, I think it's pretty clear that as much as we love the betas, we are impatiently waiting for the first alpha in prostate cancer outside of radium-223 to be approved.
Phillip Koo: That's great. So Phil, oftentimes when I think about this, it's almost like picking your favorite flavor of ice cream, and everyone has their own opinion, and you listen to a lecture on a certain isotope or whatnot, you get an average of, "Oh, that's the next one that's going to hit it." So, clearly there are a lot of misconceptions out there. From a clinical perspective, Phil, break it down for us in terms of what are some of the misconceptions out there and where do we need to head to clarify some of these?
Philip Kantoff: Right. I just want to echo Ken's excitement about the fact that we're moving into the alpha era, if you will, in radiopharmaceuticals. Although, as Ken pointed out, radium-223 has been around for at least a decade now, but it targets not the cancer cell, but the microenvironment. So, in the case of the main alphas that are being used right now in experimental stages, actinium, the main misconceptions that I've come across when I started five years ago in this field, prior to this I was practicing medical oncology and doing research, and I've become more of a radiopharmaceutical person over the past few years, was the fact that there was a limited supply of actinium, and it was mostly derived from radioactive waste. And there was a lot of concern about the ability to gain enough actinium to do clinical trials for commercialization, ultimately.
I think that's largely been resolved. We've been using the thorium cow methodology of actinium for the past few years, but now what's come along because of great interest in actinium is accelerated derived, different forms of accelerator derived, carrier-free, so without any contamination actinium-225. And companies like NorthStar, as an example, but there are other companies that are making ample supply of actinium, commercial grade actinium. So, the concern that Neil and I shared years ago about, will there be enough actinium to do the things that we want to do, I think has largely been resolved. The other concern regarding actinium were the daughters. So, when actinium decays, it decays into bismuth and francium, and there was concern about the damage that these daughters would do to the kidneys and other organs. And at least the dosimetry experiments that we've seen, Neil and I and others, is that they are not, first of all, not present for a very long period of time, and they're not of any significance. And clinically it's been our experience that they have not caused any end organ damage.
Those are the misconceptions around actinium-225. And with regard to lead-212, the main concern has been the short half-life, as Ken pointed out, the 10-hour half-life. And the concern there has been the ability to distribute the lead coupled to the small-molecule ligands. And I think the companies that are involved in lead are figuring it out. Either it's going to be centralized and transported, or decentralized and produced locally at different sites, or even at the sites where the lead asset is being given. So, I think these things are all being worked out. The concerns, I think are diminishing as we move forward. A lot of people are working in this field right now, so I think the problems will be solved.
Phillip Koo: I think that's a great reminder, Hal. I think we've always recognized there have been supply chain logistical challenges with radiopharmaceuticals. It's a new area, but it's amazing. And I think that's the beauty of just the way capital markets work and whatnot. There's solutions that can be created. And I agree, there was a lot of buzz about the shortage of actinium, but clearly that's not an issue today. And it's exciting, because I think this is a great potential option for patients in the future.
So Neil, let's turn it over to you, and talk us through a little bit about how you deliver the isotopes to the right target, and in this case, PSMA. We've heard a lot about small molecules. We're hearing stuff about antibodies. So, talk us about the delivery mechanisms and how you approach the delivery mechanisms and the isotopes, because we know that pairing, they sort of need to fit together. And oftentimes it's very personalized.
Neil Bander: Yeah, it's an important question. Ultimately, at the end of the day the efficacy is a function of how much energy you deliver to the target cell. And that in turn is a function of how many receptors are expressed on the cell surface, and how long the exposure is to the binding agent, whether you're talking about small-molecule ligand or an antibody. We can't control the number of receptors on the surface of the cell, but we do have some control over how much of the binding agent we provide and how long it's available to bind. So, in the case of small-molecule ligands, they have a relatively short half-life. That's fine for imaging, but it really truncates the amount of the binding agent you can get into the tumor cell. If you have a half-life of only ... Circulating half-life of only, let's say, three or four hours, there's a limit to how much you can get into the tumor cell.
Conversely, in the case of an antibody, let's take an antibody like CONV01 or J591, as it was previously called, that has a half-life of 10 to 20 times the half-life of a ligand. And so, while that antibody is present, PSMA is continuously pumping in that antibody and its associated payload. So, you can deliver a much greater amount of isotope to the tumor cell. It's also not just an issue of uptake, it's an issue of resonance time. How long does that agent stay within the target cell? In the PSMA we showed many years ago is internalized by an endocytic pathway, the classic endocytic pathway.
In the case of a small-molecule ligand, when that gets internalized into an endosome and the pH drops to 5.5 or six, what we see happens is that the ligand dissociates from PSMA, and when that endosome recycles back to the cell surface, it releases the ligand back into the extracellular fluid. Again, a critical difference in the case of the antibody is that when the antibody binds PSMA and gets internalized, it does not get released. It does not dissociate from PSMA at the pH you see in an endosome, and it does not get released into the extracellular fluid. In fact, it gets redirected to a lysosome. So, the intracellular retention time of an antibody and its payload is substantially longer for an antibody.
Now, I would be remiss if I didn't add the fact that in the case of a small-molecule ligand, after it gets externalized it can rebind to an open receptor, but because of reasons of stoichiometry, that really only has a benefit in cases where you have a high level of PSMA expression. And that likely explains why the greatest benefit you see from a ligand lutetium is in the top quartile of tumors with respect to expression of PSMA.
I think another important consideration, and probably what explains to a significant degree the great interest in ligands is the issues of tissue penetration. Ligands are very small. PLUVICTO has a molecular weight of 1,400. It penetrates tissues very readily, with the possible exception of the blood-brain barrier. It penetrates the vascular tissue, and it penetrates in tumor and normal tissue very readily. That's an advantage, but it's also a disadvantage, because what happens is, it also readily penetrates the glomerulus and gets excreted. In fact, 25% of the injected dose gets excreted on the first pass through the kidney, never even gets a chance to see tumor. It's also a negative in that it easily targets normal tissues which express PSMA, and we know about the issue of salivary and lacrimal gland targeting.
In the case of the antibody, it's about 100 times greater mass than the ligand. It does not penetrate normal vessels very well, which explains in part why it has a much longer circulating time, but that disadvantage, or arguable disadvantage, is offset by the fact that the antibody stays in the circulation much longer, so it has a chance to compensate for its slower penetration into tissues. And that the fact that it penetrates normal vasculature more slowly, it is balanced by the fact that it does penetrate leaky abnormal tumor vessels very well. So, you actually get preferential distribution into the tumor vascular bed more so than a normal vascular bed. And it explains why we don't see any uptake on PET scans of the antibody in the salivary glands or lacrimal glands. It also explains why in our biodistribution and dosimetry studies we see very low doses to the kidney and can detect no dose being delivered to the salivary glands.
There's probably one more point I would make, and that is that proponents of the small-molecule ligands argue that the longer circulating time of the antibody is actually a negative because of the marrow exposure, and that's true. The marrow exposure is greater with an antibody, and myelotoxicity is what determines the dose-limiting toxicity. But the reason we can develop a significant therapeutic index is because of some of the factors I talked about earlier, that is the long retention in the tumor and tumor exposure is substantially greater than what you see in the bone marrow where you have no binding and a much shorter resonance time. So, when all of this is put together, from my perspective, I think antibodies offer a much more specific, tumor-specific delivery than small-molecule ligands and a more efficient mechanism to deliver radiation to the tumor.
Philip Kantoff: I agree with everything Neil said, but it's not a one-size-fits-all kind of situation. And in the case of the antibody, lutetium is really not a great partner in my mind. For the reasons that Neil described, the path length for lutetium is much longer. With the circulating time of the antibody it causes more toxicity than with an alpha. Similarly, lead-212 is not a good partner for an antibody as well, because it half-lives out before the antibody can actually do its thing in the cancer cell. But we do feel that the best way to deliver actinium, which has a long half-life, as you said, Ken, 10 days, the best way to deliver actinium to a PSMA target is with an antibody, for all the reasons that Neil described.
Ken Herrmann: I think what is really important, what you all mentioned is, of course, absolutely correct, but the big thing is the verdict in the clinic is still out. And there are a couple of reasons, for example, yes, the bone marrow is one of the challenges for the antibody. The salivary glands obviously is one of the challenges when we talk about PSMA-617 or PSMA-I&T when it's connected to actinium. And of course, it all also depends a little bit at what line of treatment we are going to talk about. Because when we talk about late lines, then it's not as important as, for example, when we talk about early lines, the quality of life. It's quality of life is always important, but obviously the earlier we go, the more important it is. So overall, I think it's exciting times, because we have a couple of compounds, including the lab program, including the actinium-J591 program or CONV01 program, also the conventional actinium-617 I&T. I'm really, really curious to see how they perform in the clinic, because this is in the end, I think the hard endpoint.
Phillip Koo: Ken, I think you're absolutely right. And what we're seeing now is there probably isn't a one-size-fits-all solution where the same isotope and delivery mechanisms will be used in every part of the disease continuum. So Ken, from your perspective, what do we need to think about for earlier stage treatments with radiopharmaceuticals? How do we optimize that balance between target, getting enough dose to the lesions and minimizing adverse events?
Ken Herrmann: So, the earlier we go, I think the more quality of life plays a role. And for example, salivary glands where really the patient notices significantly, and if this changes it really changes the way he perceives daily life. I think this is really important. It's more important than, for example, when we at later stages when there is really more or less a do or die situation.
The second thing is in early lines we most likely will talk about combination therapy. It's not very likely that it's going to be a monotherapy. And there, again, it's also very important that when we talk about the toxicity profiles that they're complementary. Overall, and this is again for me, when I think about what is the sweet spot of, for example, non-salivary gland toxic agents, I think it's in the early lines. Because there we really, really want to make sure that the patient benefits and doesn't have a negative impact on the quality of life.
Phillip Koo: So Phil, Ken brought up combination therapies. As a medical oncologist, what are your thoughts on combination therapies and where do you see some of the biggest potentials to create a synergy with radiopharmaceuticals?
Philip Kantoff: Yeah. So, one of the obvious combinations which has already been played out has been the combination of an androgen pathway signaling inhibitor like an enzalutamide or the like with a PSMA-targeted agent, because when you reduce androgen, you increase the expression of PSMA. So, we've seen that in one study combining PLUVICTO with enzalutamide, very exciting data there. So, combining androgen deprivation therapy of some sort along with PSMA-directed therapy is one thing. In our hands, I'm very impressed with the combination of our agent CONV01-?, which is the radioantibody coupled to actinium, along with a checkpoint inhibitor. Prostate cancer, as you know, is largely a cold tumor, with the exception of patients who have a high mutational burden, in which case checkpoint inhibitors are helpful in that setting. We've been impressed with the durability of responses to the combination of giving an alpha in the form of the radioantibody with pembro. We've seen very durable responses with that combination that have played out. This is work done by Scott Tagawa.
The other combination, which we're very excited about is based on Neil's work, and Neil can probably expand on this better than I can, but the concept that the antibody that Neil discovered, J591 or CONVO1, binds to a different region in the PSMA molecule than the small molecule does, which binds to the active site, allows you to give both at the same time. And what Neil showed in vitro was that when you use the antibody, it increases, to Neil's point before, the uptake and retention of the small molecule, because it allows the small molecule to be trafficked from the endosome into the lysosome where it resides in the cancer cell for a long period of time.
So, an experiment was done, early experiment was done with very low doses of CONV01-? in combination with PSMA-I&T lutetium. And once again, the response rates were very high and the durability of the responses were really pretty profound, and the toxicity was minimal. So, it is the synergy between the small molecule and the antibody using an alpha and a beta, which have complementary types of radiation, or for that matter, you can use an alpha and an alpha together, but that experiment has not yet been done yet. So, I'm very excited about those three combinations. So, combinations with androgen deprivation therapy of some sort, combinations with checkpoint inhibitors, and using the alpha, as we call it, the alpha-beta or small-molecule antibody combinations.
Phillip Koo: Great. So, we could talk for another hour, but I think we have to bring this to a close. Maybe we'll go around and really quickly, one thing you're excited about when it comes to alpha particles, and one area of concern that you might have that needs to be addressed. Neil, I'll start with you, Ken, and then I'll end with Phil.
Neil Bander: Well, what I'm excited about is the future in the sense that we will really get to explore the potential of an antibody alpha when we get into earlier stage patients with small volumes of disease where the alpha is particularly effective, as well as the antibody. And I think when we start treating patients with small volumes of disease with the antibody alpha, we'll be curing some patients that otherwise would be destined to die.
Ken Herrmann: So, the thing I'm most excited about is that we have so many different options coming up. So, it's not one program and it's hit-and-miss. We have many different programs, and I'm pretty sure one of them will really make it. So, the thing I'm most concerned about obviously is that because we have so many programs, obviously not all will be winners, that our field is resilient enough to also accept certain failure. So, sometimes you have the feeling that if there's one bad message, everyone else jumps out of it. Again, this is what I'm most concerned about. Overall, long-term, I'm super, super excited about alphas.
Philip Kantoff: Yeah, I agree with everybody, and I think there are going to be opportunities for different alphas to be used in different settings, and not only in prostate cancer, but other diseases as well. But to Neil's point, I do see a day when we use alphas in low-volume disease, possibly in combination with other agents where we can actually cure people who otherwise would not have been cured. Alphas are probably best in low-volume disease, better than betas. So, I think the future is bright for radiopharmaceutical therapy.
Phillip Koo: That's wonderful. I love to hear the word cure with a lot of these drugs that we're testing. And if we could achieve that, it's a huge success obviously for so many patients out there. So, appreciate all your perspectives, and there'll be hits and misses, but overall there are going to be a lot of hits, and I think we'll all be better for it, especially all those with prostate cancer. So, thank you all for sharing your insights. Really appreciate it. And we'll get together again soon.
Philip Kantoff: Thank you, Phil.
Neil Bander: Thank you.
Ken Herrmann: Thank you.