Charles J. Ryan: Hello from ESMO 2022 in Paris. I'm joined by Dr. Neil Fleshner, who has two roles. He's a Professor of Urology at Princess Margaret and the University of Toronto in Canada, but he's also the Co-Founder and Chief Medical Officer of POINT Biopharma, which has a really interesting trial underway called the SPLASH study. This is a phase III study, and unlike a lot of phase III studies, they've been offered the opportunity to present some preliminary data. Welcome, Neil. Good to see you.

Neil Fleshner: Nice to see you as well.

Charles J. Ryan: Great situation, I think, here for us to get a peak at some early results from this phase III trial. Tell us about SPLASH and why you're presenting data early.

Neil Fleshner: SPLASH is a large phase III program, really looking at the lutetium-based therapy. In our case, we use the PNT2002 molecule, and we're looking at it in the pre-chemo space. So men who are failing the ARPIs, the androgen receptor pathway inhibitors. Traditionally, as you know, usually chemo would be the next treatment, but we know so many men never get chemotherapy, that we have tried to position this product in that particular space.

Now, because we leveraged academic data for our phase III program, the FDA wanted us to do a run-in, essentially a mini phase II, mostly for dosimetry purposes, to validate dose, and also to get some sneak peek, if you will, around efficacy and safety. And that's what we're able to report here. So it is quite unique in that we have a little bit of preliminary data. Of course, once the phase III randomization actual phase completes and it is rolling now, that'll be it. Obviously data locked from that portion of the program.

Charles J. Ryan: Sure. We'll talk a little bit about the efficacy date in a moment. I wonder if you could educate us a little bit on this issue of dosimetry and why it was important for the FDA to want to validate dosimetry and what do you actually mean by that? Is it looking at safety or is it looking at the actual dose that's delivered? I think there's some lack of clarity on that.

Neil Fleshner: Dosimetry is sort of the science by which when you inject a radioactive molecule, you can use, in this case spec scanning, to see particularly critical organs of interest. For example, in the case of PSMA, we know the salivary glands pick it up, we know the kidneys pick it up, we know the lacrimal glands pick it up. So I think the FDA wanted some contemporary North American, if you will, data, just to validate the prior findings with our molecule, even though our molecule has been used extensively, it's also known as the PSMA I&T, it has been used extensively as what we call home brew. So it was being made in the basements of hospitals in Australia and parts of Europe.

The initial I&T molecule is actually fairly unstable, and what POINT did from our IP point of view is we built a ring around taking a molecule that's sort of got a half-life of hours, and we turned it into a half-life of about a week. By doing this, we can now have a commercializable product.

Charles J. Ryan: Okay.

Neil Fleshner: So the FDA, I think rightly, said, "Okay, well, you kind of changed it a little tiny bit, so let's see some up-to-date, modern North American dosimetry."

Charles J. Ryan: But unlike in past examples or with other therapies, they might say, "Do that phase two and come back to us," They said, "Go ahead with your phase III and just report on some interim."

Neil Fleshner: Yeah.

Charles J. Ryan: Okay.

Neil Fleshner: We did have a DSM who obviously looked at the efficacy as well as the dosimetry. There were some thresholds that we had to fulfill and we got the may proceed pretty much as we were going. So it was fairly seamless to move into the randomization phase of the entire program.

Charles J. Ryan: Great. So what you're reporting here at ESMO is some outcome data on a mixture of patients in the chemotherapy-naive state, as well as the chemotherapy-exposed state, all of them have had AR pathway inhibitors. Tell us about what you found.

Neil Fleshner: Just to clarify, patients, about 20%, did get prior chemo, but only in the hormone-sensitive space. So nobody could have died in the castration resistance space.

Charles J. Ryan: Okay.

Neil Fleshner: What we saw, we were quite pleased. Our median progression-free survival is 11.5 months. As you know, that compares to historic controls in the 3 to 5 month range. Obviously this is a single arm, there's no true control, but we're really excited that we've de-risked our protocol with such an impressive rPFS. What's really interesting if you think about it, about what we're doing, we're taking men on drugs, and the ARPIs do have side effects, and we're actually de-escalating therapy. We're taking that drug away, they're getting four injections over a 32-week period as an outpatient, and half of them still have non-progressive disease at roughly a year. That's pretty impressive, in my view, movement in the prostate cancer field and in men's health.

Charles J. Ryan: So certainly encouraging for continuing the accrual to the phase III

Neil Fleshner: No question. Of course, we need to complete the phase III.

Charles J. Ryan: Yeah, of course. Tell us about where that is now in the process and where geographically you are.

Neil Fleshner: We are open in Europe, we are open in UK, Canada, and U.S.. We have numerous sites and we have guided that we will complete accrual by the end of this calendar year, 2022. So we're really excited about that and hope to have top-line data to present around the middle of next year in 2023.

Charles J. Ryan: Very accelerated and very encouraging, exciting. For patients out there and clinicians out there listening, and still 2022, it could be for patients who have been exposed to chemotherapy in the castration-sensitive state or the chemotherapy or the castration-resistant state, you're just not seeing those yet?

Neil Fleshner: No. That is not allowed.

Charles J. Ryan: Okay.

Neil Fleshner: The whole idea is to insinuate this compound upstream from chemo in the CRPC space.

Charles J. Ryan: Understood. Okay. Very good. But study is still accruing and they might want to look for a site locally near them that might have an opportunity for them.

Neil Fleshner: Absolutely. And we are open throughout, particularly in North America, there's going to be a site next to virtually everybody, certainly in the bottom 48.

Charles J. Ryan: Okay. And the trial is called SPLASH.

Neil Fleshner: Correct.

Charles J. Ryan: It's a great name for a trial by the way.

Neil Fleshner: Well, it's an acronym. It's the study of prostate lutetium after secondary hormones.

Charles J. Ryan: Very good. Well, even better. It's a great acronym. With regards to the lead-in study, you are looking at overall response rate as your primary endpoint for this lead-in. Tell us how that reflects your design of the SPLASH trial overall and your feeling on the significance of these outcomes today.

Neil Fleshner: We're reporting on a host of outcomes. The rPFS, as I mentioned, at 11.5 months for a median. We also are reporting our ORR and the subset of patients with soft tissue disease evaluable, and we achieved a 60% ORR, which is generally considered to be quite high in this disease. We also reported on our PSA 50, we achieved similar to VISION, we were 42%, they're 46%. We were happy with that in the sense that, of course, this is not androgen-receptor-targeting therapy, and if you look historically, [inaudible], radium, cabazitaxel, this is even better in terms of the PSA 50, not to mention, we were mandated to stop the ARPI, which, as you know, takes the break off of PSA reduction somewhat.

We're also reporting on some AEs associated with therapy. We're really excited because we do have a different dosing schedule to Pluvicto. What we found was quite amazing, it was we had 2 patients, 2 of 27, had grade 3 anemia and 0 cases of thrombocytopenia or leukopenia grade 3. So we really feel that for the SPLASH patient, a well man who's just starting to fail ARPIs that this is sort of the right Goldilocks, if you will, balance between efficacy and toxicity, for men who are not that close to death. Now, obviously, we're going to have to await the final trial to see how the control group does, et cetera.

Charles J. Ryan: It's four treatments over 32 weeks.

Neil Fleshner: Correct.

Charles J. Ryan: The toxicity, the safety markers that you see are not necessarily day of infusion types of events there.

Neil Fleshner: Right. I think it's akin to sometimes chemotherapy, where neutropenia happens weeks later. Our lower dose, we think, perhaps, that extra 2 weeks between allows a little bit better marrow recovery before you give the next cycle, et cetera. So we're really quite happy that we think we have threaded the needle here between, as we all want to do, balance efficacy and toxicity.

Charles J. Ryan: Just briefly a couple words on the endpoint of the SPLASH study that this is leads into.

Neil Fleshner: The final SPLASH ultimate randomization phase, the primary endpoint is rPFS, and we have secondary endpoints, including OS and ORR. We recognize survival may be difficult to get, because we do have it built in crossover. And we did that for a couple of reasons. A lot of men want this therapy for moral and ethical reasons, but we also did it because we felt it was going to help with data integrity and trial fidelity, because there's such a big movement to treat men as they start failing before they radiographically progress. So by holding out the carrot of having the lutetium therapy around the corner, we think it's going to be easier to tell men and their clinicians, "Just hang on, wait till the independent radiological review is done, and then we can offer you this therapy."

Charles J. Ryan: Yeah, I think that's a great idea. If you reflect back on almost all of the phase III studies using rPFS as a primary endpoint or co-primary endpoint in the pre-chemotherapy space, they almost all have crossover.

Neil Fleshner: Yeah, and again, many of them still show an OS benefit because...

Charles J. Ryan: You powered it that way to.

Neil Fleshner: Yeah, exactly.

Charles J. Ryan: Great. Well, thank you so much.

Neil Fleshner: Great to see you. Thanks for having me today.