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Phillip Koo: Hi, this is Phillip Koo and welcome to UroToday. Today we have with us Dr. Neal Shore, who's the medical director at the Carolina Research Institute in Myrtle Beach, South Carolina. He's the lead principal investigator for the COBRA trial, which just presented their phase I/II data recently over the past couple months. Before we get into the data from the COBRA trial, Neal, can you tell us a little bit about Clarity, who I think might be new to many of our viewers?

Neal Shore: Yeah. They're an Australian-based company and they came to us, myself and many of the investigators on this study, using a Copper-64 moiety, and what particularly drew my attention to this wildly exciting area of PSMA PET, which is bringing nuclear medicine front and center and people like you and your colleagues to really help us better understand and identify disease with greater accuracy so we can have impact on clinical utility. PSMA PET has been really quite revolutionary. We've got multiple different radiopharmaceutical tracers that we use, and what was interesting to me was when they said, "Well, we have this copper that we're using, Copper-64." It has a very, very long half-life, and then I think we'll get into it, but it has a bivalent structure, so it has two spots where the copper adjoins to the tumor as opposed to one. So maybe a concept of greater stickiness. I thought that was very intriguing and it has a very long half-life, so there's some interesting throughput or clinic implementation things that I think we'll want to discuss.

Phillip Koo: I think it's interesting, Clarity, when I first learned about them in sort of learning about these technologies and whatnot, it really sounded appealing. I love the way, how you talk about that increased stickiness and how we'll see that translate into the clinic. They have their trial, the COBRA trial, which is looking at patients with biochemical recurrence. Can you sort of present to us some of the data points that were shared at a recent meeting?

Neal Shore: Yeah, thank you so much. At AUA we had presentations and we have more coming forward, but maybe I can put up some slides and kind of go through them concisely and folks can have access to them afterwards when we finish our presentation.

Phillip Koo: That sounds wonderful.

Neal Shore: Well, yeah, thanks very much, Phil. By the way, I never want to miss an opportunity to thank you for all you've done as a nuclear medicine radiologist in educating urologists and medical oncologists and radiation oncologists as to why in the US, and so many of your colleagues have done this internationally. Nuclear medicine is really a very hot and sexy field these days, prostate, where new things are coming out in kidney as well. My colleagues on this trial, 50-patient trial, you could see them listed here, my good friends in colleagues from Urology San Antonio, Tower Urology in Los Angeles, New Mexico Cancer Center, and our center in Myrtle Beach.

So why do we do this? We looked at the BCR, the high-risk patients, that's what the COBRA is and I'll explain exactly what the COBRA schema was. But when we have BCR patients who fail radiation or prostatectomy or both, we know, especially if they have rapid doubling times, they're going to develop metastatic progression or radiographic progression. And then, ultimately, it sets off a whole cascade of therapies. We've made advances, but we want to treat the right patient at the right time, as it's often said. And PSMA not to be confused with PSA, distinctly different antigen because it has extracellular and intracellular domains, the PSMA PET agents have been really remarkably helpful, much better than conventional imaging, CT scan, technetium bone scan.

And so, what you see here, and you see the schema here on the side, is you have this SAR-bisPSMA with a copper moiety and it is bivalent. That's really a key thing. You can see the bivalent nature as the radioisotope is joined by this very unique SAR chelator. It holds the isotope. That's in the sort of the upper left portion of the diagram. And then you see where there are two tumor-specific receptors to specifically these binding motifs. So to really connect the chelator ultimately, which holds the copper, but ultimately brings it into where the PSMA is, theoretically you can get this greater stickiness as we talked to or talked about and potentially pick up smaller lesions and get greater detection. That's sort of what attracted me. As we had mentioned earlier, the half-life for the bisPSMA copper, it's very long. It's about slightly less than 13 hours, whereas 18F and gallium are less than 2 hours. So that gives you some potential flexibility and deliverability of product and scheduling. There's been some early work suggesting this higher uptake, so I thought that was particularly interesting.

Here's the COBRA study design. We looked at patients, obviously, who had prostate cancer, they had BCR, PSAs that were greater than 0.2, and we looked at these patients really primarily in the prostatectomy domain. We also had patients who had to have a PSA greater than or equal to 2 from nadir with radiation or even with cryotherapy. They all got baseline conventional imaging. They had negative or equivocal findings. And so they got injected on, here we say day 0, but really it's same day, they got an injection. And then the next day, same day, next day. Here the same day as day 0, next day is day 1. And then they got their injection and then they were imaged 1 to 4 hours on the same day post injection, and then 24 hours later.

Of course, we were looking at safety and tolerability, it's a phase II study, but as well as the detection rate or what we call the correct detection rate or it's spelled out here on the bottom, it's important and it can get a little confusing, but the rate of the proportion of true positive participants out of all scan participants. We talk about this standard of truth, and essentially that's basically seeing either confirmation subsequently on subsequent scans up to 180 days, we followed these patients out to 6 months with repeat imaging. So a standard of truth confirmation would be confirmation on a conventional imaging of something that we saw on day 1 or day 2 or here we're calling it day 0, day 1, same day, next day, or a change in PSA if there was a therapeutic use of application, or ideally getting tissue, which is always the hardest thing, harvesting through either with interventional radiologists or a surgeon to go in and get the tissue.

Just briefly, the demographics. Older population, not as old as an mCRPC population. Good performance status, 50 patients all pretty much ECOG 0s, 75% prostatectomy, 15% radiation, combination of about 4%, and a few cryopatients. As you'd expect, these patients, a lot of them were grade group 4 and higher and some were grade group 3s. The PSAs are down here and there's a range. Pretty tight, though. We didn't have real large range. These were patients who had pretty low PSAs. Important to keep that in mind when you look at some of the field of how many of these studies have been done.

And so we looked at the identification of pelvic lesions by the SAR-bisPSMA scan, had to have equivocal entry scan, and they could have used the DCFPyL as well as other conventional imaging. Here's just kind of an interesting example, and what you can see here at the lower portion especially, which correlates with the CT imaging above, one can see, you start to see the differences from the day 0 to day 1 and how it really kind of pops visually. What was interesting is, why bother to get scans? You get scans, you get blood work always to see if it's going to change your clinical paradigm. And in our study, 48% of patients ended up having a change in their clinical paradigm based upon the SAR-bisPSMA imaging. So if you get more lesions and you can identify more, obviously that's going to give you some conclusions. This is pretty compelling. This is just an image.

Again, small studies, 50 patients, but when you look at day 1 or the same day and then the next day we called it day 0, it's sort of a non-American language use of day 0, day 1. I think we'll move forward and call it day 1, day 2 or same day, next day. But don't want people to be confused by that. A really important thing here is that 50% of patients had a lesion identified by the SAR-bisPSMA on day 0 and up to 80% on day 1. We only had one adverse event of any significance. It was a grade 2 worsening. And we see this across PSMA pet. It's an extremely well tolerated imaging device.

Another few nice examples here. I think the key here, and again, these anecdotal cases, but what we saw here, particularly if you look at the PET imaging on the far left and then you basically go from the first day of imaging to the second day, day 0 to day 1, you can see how you could have potentially missed that if you didn't have that extended time to look at. Now, you wouldn't do a next day with the existing PSMA PET-approved agents because their half-lives are so short. The half-life for this specific bisPSMA copper is a little slightly less than 13 hours. And then you can see, again, the ability to pick up some very small lesions in the middle panel, as well as in the panel on the far right. So again, it's our early phase II study. We were very excited to see small lesions being picked up, more lesions being picked up on the second day.

This is another way of looking at it, looking at the different SUVs, the mean and the max. Oh, and of note, we had three independent readers, centrally read. We also had local readers, but we were reporting on the central independent readers. You can see the differences on the same day, next day, the day 0, the day 1, respectively, in terms of SUV and the tumor to background ratio, which is really important as well. You see a really nice consistency amongst the readers and how it increases by the second day.

I think we'll talk about in a minute, Phil. Well, how do we contextualize that? And is it practical to have patients come back the next day after being injected? What we concluded, we're going to go to a phase III study that's already ongoing in a pre-prostatectomy, a cohort phase III, much like other PSMA pet devices have done. One AE of any significance. Increase in obtaining positive findings up to 80% by the second day, and that we're equivocal or negative on standard of care imaging. Picking up lesions as small as 2 millimeter. And so, there is this now really very interesting concept. It's kind of new. Most of the times we inject, we image same day. That's it. So I think it'll take some opportunity and education to figure out how do we work that throughput. And I'm excited about that because we're always trying to figure out greater efficiencies, not only for the patients, but certainly for our clinics. And like I said, there's a phase III trial that's underway. So thank you for letting me present this and look forward to further discussion.

Phillip Koo: Neal, this is wonderful. And it's interesting. We had that increased stickiness, we have a more stable chelator, and we have this longer half-life, which allows for this next-day imaging that is showing signs of improved and better performance. Neal, you've been at the leading edge of research when it comes to PSMA imaging and PSMA therapeutics, and also given the wealth of clinical experience that you have in this space, what are your thoughts on this idea of injecting the patient and not necessarily imaging in the first day, but having them come back? How do you think that'll be received in the clinic?

Neal Shore: Yeah, I think it's really kind of novel and interesting because you can make the assumption, and what we're having a challenge with right now, because we are very fortunate. We have access to both DCFPyL and to gallium, and I'm really happy to have that access. But there are some supply chain issues and scheduling, depending upon when you can get the tracer available and when you can optimize the use of your camera, your PET camera. So theoretically with this, if it were to get approved, you could inject a whole bunch of patients on day 1, we call it day 0, I like day 1 better or same day, and then bring them all back, crack a dawn the next morning and just run them through one after another after another. I think there'll be a lot of advantage of that, not only that, but also in the clean rooms and just getting patients through in a very, very efficient process. Now, it could be a problem for somebody who lives really far away needs to get home, but I think for most folks this could actually offer some real advantage.

Phillip Koo: Great. Clarity, this technology is very exciting. This introduction of a copper compound, I think, really opens up a lot of new possibilities. You talked a little about a pre-prostatectomy trial or pre-definitive therapy trial. You have the BCR trial that's going to open up a phase III. What's next for Clarity? I believe they also have a therapeutic in the pipeline as well.

Neal Shore: They do. If you think about it, if you've got this unique chelator and this bivalent approach, and if you could arguably then bring a payload in with greater efficiency, that's pretty exciting. And so they are working on that and they have several early phase studies doing a lot of great work on this in Australia, and I'm sure that it'll ultimately go global with their phase III studies.

Phillip Koo: Well, thank you very much Neal. Thank you for this presentation. Also, thank you for being such a wonderful partner for nuclear medicine and I think a lot of this doesn't happen without these partnerships with urologists and medical oncologists out there. So it truly is multidisciplinary and it is privileged to work with you so closely.

Neal Shore: Thanks, Phil, really appreciate it. Great to have an opportunity to talk about this. It's an exciting area for all of our colleagues.