Fred Saad: Well, thanks, Oliver. It's a nice challenge, near to the end of the career. That's good.
Oliver Sartor: Well, today we're going to be talking about an interesting new asset from Bayer, a PSMA-targeted actinium molecule that a lot of people didn't know much about. Some people call it trillium, you may refer to it by a different name. But Fred, you presented at ASCO GU and I thought made quite a splash with the presentation. So, I wonder if you might take us through some of the highlights, please.
Fred Saad: Sure, it's my pleasure, Oliver, and we were very happy to see that ASCO GU accepted this as an oral for a phase-one study, but I was also very impressed with the results we've gotten so far. So, let me just share some of the results very quickly and then we can talk about them. Okay. So Oliver, so what I presented at ASCO GU is really the first-in-human study of actinium-225 in mCRPC, the phase-one PAnTHA study. So basically, it's a new compound, actinium-based, with a Macropa chelator for stabilization and efficient labeling of the actinium compound. And really, I don't have to explain to you or the audience how excited we are having radioligand therapy for prostate cancer, both the alpha-emitter radium-223 that you led a lot of the work, and more recently lutetium, which is a beta particle. And really, I think we've all been looking for an alpha-emitting agent, given its high toxicity in terms of the cancer effect, but the lower adverse events of adjacent tissue. And so, the PAnTHA study is really an mCRPC study where there's PSMA-positive disease. All patients had at least one prior ARPI and at least one prior taxane. So really, a VISION-type study looking at dose escalation. We went up to four doses, 75, 100, 125, and 150 kilobecquerels per kilogram to see efficacy, but also toxicity of this new compound. And it's really four cycles given at six week intervals. And what we saw was there was really no dose-limiting toxicity.
We were able to go up to 150. In about 12 to 13 patients in each arm, we started with three and then we had a backfill. And in terms of adverse events, which is obviously the main objective of a phase-one study, we saw, as we expected, about 85% of patients having xerostomia, but the vast majority were Grade 1, some Grade 2, but no Grade 3 or 4 xerostomia. And then other adverse events that were more in the grade one area of fatigue, nausea during treatment. But overall, no dose-limiting toxicity, no patients had to discontinue or very few had to discontinue, and very few had to have a dose modification before the 150 dose. But I think what got us very excited was the PSA response, which was obviously one of the main objectives of this phase-one study, where we saw overall 62% of patients getting a 50% PSA decrease, 40% getting a 90% decrease. But looking at the 125 dose, where I think we're hitting the soft spot with 83% of patients getting a PSA-50 response, and two thirds getting a 90% response. And overall measurable response was 71% at the 125 dose. And you see radiographic response in about half the patients had had measurable disease, you see quite impressive results for these heavily-pretreated patients. What was also nice was that across all the SUVmeans, we saw responses. Obviously the higher the SUVmean, the more responses.
And SUVs above 10, which is not that high, 93% of patients had a PSA response if they had an SUV above 10. And we had exploratory analysis in terms of ctDNA fraction, where we saw reductions at basically every dose, but at the 125 dose, we had a ctDNA clearance in 36%, and a decline of 89% of the ctDNA fraction at that dose, and ctDNA and PSA response correlated really quite well, and we're still exploring some of that analysis. I'm just showing you here a couple of cases that exemplify what we were able to see at the 125 dose. As of two cycles in this patient who started with a very heavily burdened disease, and after two cycles, it went from about 2,800 tumor volume down to 471. So, it's 83% reduction in volume, as you see by the imaging. And the PSA plummeted to basically undetectable compared to the baseline. And another patient, again, where we have significant reductions in imaging and in tumor volume. And again, PSA that declines to almost undetectable levels in these heavily-pretreated patients. So, these are the exciting results that we've seen. I have to temper my enthusiasm, still phase one, but I think we're going in the right direction. So basically, about 62% of all patients had a PSA response, 93% for those with high PSMA expression. And we're going to go forward with the 125 dose, because of the response rates of 71%, PSA response rates of 83%.
And now we're going into a dose expansion part of the study, where we're looking at the post-chemotherapy setting, similar to what we just analyzed in the phase one, but also in patients that haven't yet been exposed to chemotherapy, and we have an arm of the post-lutetium patients. And all of this is going to inform the phase-three study that we hope to be able to start very soon. So, thanks for listening and happy to discuss.
Oliver Sartor: Yeah. Fred, it's very impressive data. And that PSA-90 is particularly impressive. That's highly unusual. These are taxane-pretreated, ARPI-pretreated, and probably a lot of them had more than one ARPI. Very impressive results. So a couple of questions. With the actinium, the xerostomia has been potentially rate-limiting with some of the other molecules, 617 I&T type molecules. Now I wonder if you might be able to comment a little more on the xerostomia. Yes, Grade 1 in the majority, some Grade 2s, no Grade 3s, but Grade 2 is a wide spectrum. And I don't know if your personal experience or with the experience of other investigators, were any of the doses held or reduced because of xerostomia? Was it dose-limiting in any way, or did you just keep dosing and everything was okay?
Fred Saad: Well, basically in the vast majority, we just kept dosing and everything was okay. When we looked at the analysis, we only had a couple of patients that had to dose-reduce, and only a couple of patients that had to stop at the higher doses. So very, very few patients at each of the dose levels, basically one patient had to reduce or stop, but the vast majority of the 50 patients we put on were able to continue. And we had no Grade 3 or 4 xerostomias. And what was nice is that some of these grade twos reverted back to grade one or completely disappeared. So, it was during treatment mainly that we saw this, but much less than what we expected in terms of severity, compared to historical actinium compounds.
Oliver Sartor: Well, that's really nice. And one of the other rate-limiting steps has been thrombocytopenia, particularly with the antibodies and hematopoietic. But I didn't even see thrombocytopenia at Grade 3 or 4, which to me was quite surprising. There was no thrombocytopenia at grade three, four?
Fred Saad: No, there was really nothing to really talk about. And we did have a couple of thrombocytopenias in patients that came in. I mean, these are obviously patients that had at least one taxane, but several had had two taxanes before coming in. So yeah, we were really happy with the thrombocytopenias. We did see some lymphopenias that were transitory, but nothing that made us stop treatment. And so overall, no dose-limiting toxicity of the whole 50 patients that came into the study.
Oliver Sartor: Yeah, outstanding. The other question is about the number of cycles. If you go look at the WARMTH study, for instance, where actinium is mainly 617 or I&T was given to patients, that were actually a fairly small number of cycles, two to three cycles, and then stop. I wonder, how many cycles have been administered here? And with repetitive cycling, did you find any limitations you may not have seen with one or two?
Fred Saad: Right. Yeah, and this is something obviously that we're going to continue to explore. Overall, the objective was for four cycles, and the median number of cycles in the 50 patients was actually four, and it's about a little bit more than 80% that actually got four. So in that sense, it was fine, but obviously, and you know this better than anyone, I think we're going to have to adapt to the reality of patients and what setting they're going to get it, how much tumor volume they have. Because as I showed you in one of the examples, basically after two cycles, there was very little, if anything, left behind to treat. So, I think we're going to have to take this adaptive model of treating patients as they go on and what's nice...
Oliver Sartor: Yeah, very well taken. But the fact is, you are able to get in four cycles on median and I think it's absolutely outstanding. And you didn't even get any DLTs at the higher dose, you actually dropped back a bit to the 125 instead of the 150 to carry forward in the larger exploratory trials. So again, I think that's outstanding. One more question, Fred, because there has been some concern with the SSTR2s and others about the possibility of renal toxicity. Now, you don't see that in an early fashion, it's more of a late finding. Was there any hint of renal toxicity, rising creatinines that might have been attributable to the drug? We all know that prostate cancer patients may have some rise from your renal obstruction, etc. But any renal safety cautionary issues you might've run across?
Fred Saad: Well, this is a big part of the study that we're spending a lot of effort looking at the renal toxicity, how much we're able to give, and so this is being measured. So we had a couple of patients with creatinine rises now, whether it is due to drug or like you say, other causes, but we're clearly exploring that. And we had one that had to discontinue because of renal issues. We're still figuring it out, getting as much knowledge, and we're constantly measuring all of this throughout the study because obviously you, I, and the FDA want to make sure also that in terms of renal issues, we're under control, because we are trying to give as much as possible.
Oliver Sartor: Terrific. No, and these patients are desperately ill. The VISION trial, the control arm was less than one year, it's only 11.3 months in the control arm. And even with the PSMA 617 lutetium, it's only 15.3 months. And when you go to the PSMA4 setting, which is the taxane-naive, it still was only about 24 months. So these patients desperately need our help. Fred, we're going to need to wrap it up here in just a moment, but any final words or thoughts you'd like to share with our listeners? And by the way, terrific presentation. Thank you.
Fred Saad: Thanks, Oliver. Well, look, I think this is one among many different RLTs or drugs in general. So I think this is a really exciting time and we're really, I think, making headway in how we bring these earlier in the disease setting safely is what we really need to do. Right? We don't want to reserve these treatments always post-chemotherapy, because a lot of patients would prefer getting this and avoiding chemotherapy altogether.
Oliver Sartor: Well, it's an exciting new time to be able to have new modalities, multiple new modalities coming into the field. We didn't talk about T-cell engagers, but they're provocative, the new isotopes, not only actinium, but some lead data that's provocative. We're moving pretty quickly right now and to make a whole new treatment paradigm for those with advanced prostate cancer. You're contributing and I appreciate all your contributions in the past and present and future. So thank you, Fred. Really appreciate what you're doing.
Fred Saad: Thanks. Always fun working with you. Take care, Oliver.