Oliver Sartor: Sure. So let's back up just a little bit, Neeraj, and thank you for having me. One of the things that's interesting is that lutetium is not the only isotope. People have been talking about the alphas and betas for a long time and the alphas are typically things like actinium. That's the one that everybody knows about. And on the beta side, it's been lutetium, maybe terbium, a little bit of copper. So it turns out that people have been thinking about alternative alphas for a long time. And it turns out that lead-212 is an interesting isotope. A single alpha, not the four alphas of the actinium. So this is from a little company in Norway, interestingly put together and founded by Roy Larsen and Øyvind Bruland, who also put together Algeta many years ago that brought radium-223 to the world. So this little Oslo-based biotech is focusing on lead-212 with the PSMA-targeted therapy and their first shot on goal is with the ARTISAN trial.
And so they're going to be using the lead-212 in a phase one study to begin to explore the activity of the lead-212 in advanced prostate cancer patients. So that's the basics of the ARTISAN. Of course, I can give you much more detail, but it's a lead-212 PSMA-targeted CRPC phase one trial. At ESMO, there was another lead-212 trial in prostate that caught a bit of attention. That was from AdvanCell. And we're not here to talk about the AdvanCell trial, but I'll simply say that lead-212 became validated as an isotope through the work of AdvanCell group. And now, the ARTBIO group is going to provide a competitive stance. They need to produce, they need to work hard, they need to work fast, because the truth is this field is moving incredibly rapidly.
Neeraj Agarwal: So for our colleagues and out there in the community and even in academics, how it is different, you alluded to that for a second, but could you please elaborate on the difference between the typical actinium and this novel molecule?
Oliver Sartor: Yeah. So the actinium molecule, actinium-225 is the one that we're typically going to be talking about, has a half-life of about 10 days, meaning that it will take about 10 days to have that first decay. Once the decay happens, an alpha will be ejected from the parent isotopic nucleus. And by the way, you can't chelate these things in. When that alpha goes out, the mother, if you will, and the alpha are going to go equally in opposite directions, so you cannot chelate, because the force of that recoil is so strong. The actinium then undergoes a series of additional isotopic decays with a total of four alphas. Now, only one of those is truly targeted, but the half-life of the other alphas is relatively short except for bismuth, which can wander for about 45 minutes and that's been a little bit of a concern.
The lead-212 is not 10 days. It's 10 hours. 10.6 hours to be precise. So completely different in terms of the half-life. In addition, the lead-212 has a single alpha, not the cascade of alphas that you get with the actinium. So you have to inject your compound, bind, hopefully get excretion rapidly and 10.6 hours later, 50% of the energy will be delivered. And if you double that, which in essence, will be 21.2 hours later, 75% of the energy. So with actinium, 50% of the energy is delivered over 10 days. Here, 50% of the energy is delivered over 10.6 hours. There's a belief by some that the relatively rapid dose rate is going to be more advantageous, that a shorter lived isotope will be able to deliver the energy in a shorter period of time, meaning more effects on the cell.
One of the things that's interesting about lead, a couple of things that are interesting, you can get pretty creative on some of the dose and schedule. With the actinium, you're probably talking about six weeks, eight weeks between doses, because of that long half-life. Here, you might be dosing again within a week. Here, you might be dosing three times in three weeks. There's different ways to play this short-acting isotope. We're going to learn more about it. The other thing that's advantageous, I think, on the lead front is in the microenvironment, which is filled with a variety of immune cells, potentially T-regs, as well as those cells that are going to be pro-immunogenic. The continuing isotopic delivery over 7 and 10 days or longer can really alter the microenvironment and it may or may not do so in a favorable manner. We don't fully know. With the lead-212 of the 10.6 hours, we feel like the isotope is going to be delivered and then there's going to be the recovery and the immune cell, the influx are not going to be damaged by the isotope that comes in.
Neeraj Agarwal: That's very interesting.
Oliver Sartor: Yeah.
Neeraj Agarwal: What are implications on the side effects then? So we assume that rapid assault on the prostate cancer and the disappearance of the isotope or those alpha particles may allow marrow recovery to be much faster.
Oliver Sartor: Absolutely. We think marrow recovery would be much faster. One of the beautiful things in all the pharmaceutical trials is these are traceable isotopes. You know where they go and to some extent you're going to know about the toxicity very quickly. In a 10.6 hour isotope, you don't have to wait three and four and five weeks to be able to see the toxicity. Typically, you see it fast, but then you get more fast recovery. The nice thing about the lead is the short circulatory time leads to little in the way of marrow tox, at least in the preliminary data that we have so far. The actinium with the longer lived antibodies in particular are prone to circulate within the marrow and lead to a longer marrow suppression. So I think the tox profile is going to be different. I think the effects of the microenvironment are going to be different.
It's also interesting to be able to drug an isotope at about 10.6 hours. You don't need to have huge retention. If you want to retain an actinium, you have to make it stick on that tumor for 10 days in order to get 50% of the delivery of that initial alpha. Here, it's 10 hours. So the ligands that you can use can be relatively wrap it on, wrap it off, but if you're retaining for the 10 and 20 hours, retain for 20 hours, you deliver 75% of the isotopic energy. That's interesting. So back to the trial for a second. This little company out of Oslo with its roots, if you will, in the radium-223 going all the way back to Roy Larsen and Øyvind Bruland who put-
Neeraj Agarwal: Which you led and presented 10 years ago.
Oliver Sartor: Well, with Chris Parker. Chris Parker was the overall PI. I was co-PI on that trial. It was the first alpha to be approved in medicine and a little bit of a shocker. I think nobody knew what was happening and I-
Neeraj Agarwal: Absolutely. I still remember.
Oliver Sartor: Yeah.
Neeraj Agarwal: Right. Yeah.
Oliver Sartor: What is radium-223? Where did this come from?
Neeraj Agarwal: Yeah. One of the most well-tolerated drugs in prostate cancer. Yeah.
Oliver Sartor: Incredibly well-tolerated. The other thing I should really mention about alphas, and I'm sorry I didn't mention it earlier, they have a really short path length. So the typical beta like lutetium is going to be going out a millimeter, maybe two millimeters, which doesn't sound like a lot, but it's a fair amount of tissue to be radiated that is necessarily near the tumor, but not necessarily the tumor itself. With the leads and the alphas, we're typically talking about microns, so typically 40 to 80 microns, not millimeters. So it's a completely different scale.
This is microdosimetry, if you will. You don't radiate tissues beyond the area of deposition unless they happen to be depositing and staying there for reasons we don't understand. But the beautiful part of that is we can trace this with a isotope. We can do SPECT on the lead-212 and follow the isotope in the body to know where it's going.
Neeraj Agarwal: Fantastic. So much to learn about this aspect of radioligand therapy. Assuming everything goes well, ARTISAN trial shows safety and efficacy like we expect, how do you see this new radioligand therapy being positioned in the prostate cancer space?
Oliver Sartor: It's a great question, because the space is evolving so rapidly. And we just had the PSMAddition trial presented at ESMO, which is the upfront hormone-sensitive, but perhaps isotopes might even lead off in the treatment of hormone-sensitive disease. Very different than the VISION trial, which is really at the end of the patient's life cycle. So how to develop the drug is going to be complex depending on the changing landscape. And I'm not sure that I'd make a commitment now to say do this, do that, because we need to get the data to show the efficacy, to look at the toxicity, maybe to think about combinations. By the way, interesting combinations with PARP inhibitors also presented at ESMO, interesting potential immunotherapy interactions with the lead-212 that may be distinct from that of the longer lived isotopes like lutetium, actinium. There's a lot to think about, so as we begin to build up the experience with lead-212 and the context of the ARTISAN trial, we know the landscape is changing and we'll have to adapt to that landscape.
Neeraj Agarwal: And we want to encourage the community out there to think about this trial. ARTISAN trial available on clinicaltrials.gov. And hope you accrue fast and so that it can go to phase two and phase three trials.
Oliver Sartor: Absolutely.
Neeraj Agarwal: And we have the drug available in the clinic.
Oliver Sartor: Yeah. Neeraj, we need to learn and we need to learn with these new isotopes and these new therapies. And within the expanding field of knowledge that is prostate cancer, the patients are really the beneficiaries. The patients are the ones who benefit when we know more and have more tools in our tool chest. We hope that we have more tools and then use them wisely in combination, in sequence to be able to help the patient. That's why we're here.
Neeraj Agarwal: I love the way how you always think about patients and end with the focus on patients.
Oliver Sartor: Thank you.
Neeraj Agarwal: Thank you very much, Dr. Oliver Sartor, talking about his wisdom and future of radioligand therapy. Thank you very much.
Oliver Sartor: Thank you, Neeraj.