Gary Ulaner: Thank you very much for having me, Dr. Sartor.
Oliver Sartor: One of the things that caught my eye, Gary, and I actually called you and we spoke about this a little bit, was the copper 61 imaging you were doing. And I'm a prostate guy, so I noticed the prostate data. And it was quite striking to me. You seem to be seeing lesions, albeit not histologically confirmed, but see things that certainly look like lesions with your copper 61 that we were not seeing with a conventional PSMA PET imaging. I wonder if you could start out a little bit by talking about copper 61 and then maybe move on to the molecule that you're using to bind the copper 61 and PSMA to. And then we'll get into some of the sensitivity specificity things. Okay?
Gary Ulaner: Sure, that sounds great. So I think a lot of people are under the impression that all positron-emitting radioisotopes are the same when they're performing PET imaging, and that is not true. Each positron-emitting radioisotope has their own physical properties, which can affect the way the sensitivity and specificity and the way PET scanning is performed. Now traditionally we think of PET scanning for targeting PSMA or PSMA-targeted PET as using fluorine 18 or gallium 68. Those are the two most commonly used radiotracers. There are new agents, newer agents that are being evaluated like copper 64, and what you've alluded to is an agent called copper 61.
I think I have a slide that may help us be able to compare some of the strengths and weaknesses of the different radioisotopes. So I have that here. And if we look, some of the most important things when comparing radioisotopes are the half-life, the positron yield and the positron energy, each of which is very important towards the ultimate production of a PET image. Fluorine 18 and gallium 68 have relatively short half-lives. Fluorine 18 less than two hours, gallium about one hour. Where copper 61, the agent that we're talking about today, the half-life is about three and a half hours.
Advantages for that, number one is that fewer number of production sites around the country would be able to distribute the agent throughout the entire continental United States or Europe say. And secondly, the longer half-life allows you to image patients at a later time. So for example, we've become used to imaging bone scans at about three hours because we know we get the best images on bone scans at three hours. Well, copper 61 images appear to be better at four hours or six hours than they are at one hour, which is traditionally when we image fluorine 18 and gallium 68 agents.
The other is, very briefly, positron yield means for every 100 molecules or atoms of the radioisotope, how many positrons do you get? The higher the positron yield the better, because the more positrons you get, the more signal you get. Thus the higher the signal-to-noise and the better the image is. Fluorine 18 is the gold standard there with a positron yield of 96%. Positron energy also can affect how the resolution and thus the sensitivity specificity of PET images. And a lot of people might think, well the higher the energy the better. That's actually the absolute reverse. When we look at energy of an agent, the higher the energy, positron energy, the farther the positron travels from its site before it annihilates and creates two photons. And it's the photons that are detected on a PET camera, not actually the positron.
So I like to think of a bullseye. And if I have the cancer cell in the middle of the bullseye, what you want is for that positron to travel as short as distance as possible before it annihilates so you stay at the bullseye, you stay at the cancer cell. The longer the positron travels, the farther you get away from the bullseye and the more blurring you get of the image, the lower the resolution of the image. So for fluorine 18 again, fluorine 18 being the gold standard here, low positron energy of fluorine 18, 0.6 MEV, means the positron travels a very short distance and stays real close to the bullseye. With gallium 68, the positron energy is about 1.9, more than three times higher. Those positrons travel farther and thus the resolution of gallium 68 images are lower than fluorine 18. You can see copper 61 is somewhere in between, not as good as fluorine 18, but still better than gallium 68.
So fluorine 18 has the best positron yield and positron energy of any of the agents that we use for positron imaging to date. But copper 61 has this advantage of a longer half-life. And as we'll see, that longer half-life allows a better bio-distribution of the molecule in the body. Longer uptake, if I go there, longer uptake of copper 61 between one hour to two hours to four hours results in higher SUV values of the lesions, the malignancy detected on the scans, as well as lower backgrounds, like liver backgrounds and bone backgrounds. And that combination of higher SUVs of lesions and lower SUVs of background structures really helps improve the signal-to-background ratio and allows us to detect more lesions on scans.
This is a summary slide showing the number of lesions detected comparing Pylarify in a phase one trial of eight patients to the copper 61 PSMA molecule. And the copper 61 PSMA I&T, as we can see as we go from scanning at one hour to two hours to four hours, more lesions are able to be detected. And this seems to be a result of, again, the higher SUVs of the lesion compared to the lower SUVs of the background. I'll show just one more slide, an example of this phenomenon, in which is a 61-year-old gentleman with biochemical recurrence, with a pretty low biochemical recurrence, 0.4 nanograms per ml. The standard of care, Pylarify or 18 FDCF-PYL PET CT performed, detected three osseous lesions, which are strongly suspicious for osseous metastases. Again, as you mentioned, no histology on this phase one trial, which is for optimal imaging parameters and safety. Histology will be performed in the subsequent phase phase two.
When we look at the copper 61 PSMA images, we can see that over time, from one-hour imaging to two-hour imaging, we start seeing more lesions, and the lesions we see become more apparent. And by four hours we see the most number of osseous lesions apparent because the lesional SUVs are increasing, while background SUVs are decreasing. And I really think this copper 61, this ability to image later when the PSMA molecule is more highly bound to PSMA on the cancer cells is allowing us to detect more lesions, and thus may turn out to be a more sensitive PSMA-targeted PET imaging agent.
Oliver Sartor: Interesting, Gary. And it looks to me like you've got more sensitivity. I mean, just seeing more of these lesions. I'm looking at the Pylarify scan and I'm looking as hard as I can and I don't really see those upper thoracic lesions that are pretty evident on the copper scan. I mean, you don't have to be a great genius to see them. And even the ones that are present on the Pylarify, kind of jump out at you, have a higher SUV to me. The bottom panel that you have is quite interesting because you see the accumulation. Yes, at one hour you clearly see the lesion, but it's more crisp and that background is diminished a little bit later. Now somebody, including me, would ask, okay, copper 61 is good. What about copper 64? I mean, you've shown some improvements. And how would you think about copper 64 versus copper 61 in the imaging game?
Gary Ulaner: That's great. Well, obviously the agents are produced differently, so there's going to be some differences in ability to supply. Copper 64, back on our chart of these different physical properties, has the advantage of about a 13 hour half-life. So a single copper 64 production site, say in St. Louis, essentially could deliver agent to the entire continental United States. That would be a big advantage. And copper 64's half-life would allow you to image not only at four hours, but you can probably image next day. So you definitely have the advantage of longer ability to image it at long times, just like with copper 61.
One of the difficulties that we might see with copper 64 is its positron yield. The positron yield of copper 64 is only 18%. So when compared to fluorine 18, you're getting about one-fifth the number of positrons in an equivalent dose of the radiotracer. So you may get less signal, and that lower signal could hamper sensitivity. There are ongoing clinical trials of copper 64 PSMA-targeted imaging agents, and we will have to see the aggregate data as to whether the half-life improves the imaging more than the reduced positron yield hampers the imaging.
Oliver Sartor: Got it. Very, very helpful. Now, when we're thinking about copper, we also have to think about what it is bound to, the ligand. I didn't hear much about the ligand and wonder if you might enlighten us. Is this dissimilar than say PSMA-11 or DCF-PYL, pretty similar, same sort of binding? There you go.
Gary Ulaner: They're very similar. So we know that Pylarify is DCF-PYL and Illuccix or similars are the PSMA-11. The copper 61 PSMA agent that we used in this phase one trial was PSMA-I&T. Obviously there are differences between DCF-PYL, PSMA-11 and PSMA-I&T. But the chemical properties of these three PSMA ligands are more similar than the properties. And the physical properties of the three radioisotopes are more different. So I believe that the radioisotope component, fluorine 18, gallium 68 or copper 61, is playing a larger role in the differences in the sensitivity and specificity of the images than the chemistry of the PSMA ligands, the DCF-PYL, the PSMA-11 and the PSMA-I&T.
Oliver Sartor: Got it. Now, Gary, I have to think ahead a little bit because when I see these type of images with a PET emitter I think immediately of a beta emitter, like copper 67. And that may be a little more forward-thinking and I don't want to get into any proprietary issues, but certainly you could imagine taking this with copper 67 ahead as a therapeutic. Is that a reasonable thing to say?
Gary Ulaner: I believe people are thinking exactly as you are, that this could be used as a true theranostic pair with copper 61 within the chelator to the PSMA-I&T as an imaging agent and copper 67 as a chemically identical therapy agent.
Oliver Sartor: The so-called perfect pair. There we go. Gary, I have to ask what is next on the imaging side. These are beautiful images. I would like to have them in my clinic say tomorrow. Do you think that might happen or do you think there could be a little lag before the clinical trials actually take place that'll lead to regulatory approval? I think you see what I'm driving at.
Gary Ulaner: Yeah, I get it. It won't be tomorrow. Hopefully it will be reasonably fast. I go to an analogy, Posluma, the PSMA-RH7.3, from first clinical trials to FDA approval was less than 18 months. Incredibly rapid. This copper 61 PSMA-I&T will be moving into phase two this year, in 2025. I believe that phase two trial can be completed early in 2026 and move to phase three trials in 2026. So depending upon how rapidly a larger phase three trial can accrue, I think data can be accumulated that can move towards regulatory approval by the end of 2026 or into 2027.
Oliver Sartor: That's terrific. That's good to hear. I mean, it looks like good imaging to me. It really does. And when we begin to think about this broad field of theranostics, it's so amazing to me, just big picture, that we go back a decade and we could never find these lesions that we knew were present. The PSA was rising, CAT scan, bone scan, MRI, nothing, nothing, nothing. And now we see so many of these patients, it's truly changed our practice. We're using SPRT, we're using conformal radiation in all sorts of new ways, we're understanding metastatic disease, where we previously thought it was non-metastatic disease, completely changing our treatment paradigm. And quite frankly, Gary, we're better doctors today because of these type of tools. And when we get a little more sensitive, I think we'll be yet again a little better doctor to be able to take advantage of this beautiful sensitivity.
Gary Ulaner: I agree with you entirely, Oliver. PSMA-targeted imaging is the new standard of care for detection of disease in patients with a high-risk newly-diagnosed prostate cancer and within patients with biochemical recurrence. I sometimes hear people say, "Let's talk about standard of care or the conventional imaging and then we'll look at the PET." And I think people need to realize right now that the PSMA-targeted PET imaging is the conventional imaging, is the standard of care. That is the imaging that is, until someone comes up with a better target, going to be what we rely upon for the best imaging for patients with prostate cancer.
Oliver Sartor: I agree with you. I mean, the standard imaging for me is PSMA PET. The conventional imaging, there are certain advantages in my opinion, which may not be perfect by the way. In terms of subtle changes like capsular invasion, the MRI gives very beautiful resolution in and around the capsule. I can have the Pi-RADS lesion scoring system. But you know what? The ability to contribute important knowledge using PSMA PET for intraprostatic lesions is also coming. So I'm telling you, I like the MRI for certain features in and around the prostate, but yet I like what I'm seeing on the molecular imaging as well.
So the whole brave new world that we're living in, and it's evolving so fast, you're absolutely right, conventional imaging now is PSMA PET. But I think there's going to be an evolution toward a more optimal future when we able to use these better PET scans. And this looks like it might be a better one. And give even more meticulous and careful thought to the treatment planning and our treatment decisions for patient benefit. Gary, anything else? We're about to wrap up. Anything else you'd like to say before we wrap up?
Gary Ulaner: Just a great thanks. The copper 61 technology, one of the reasons why copper 61 hasn't been used in the past was because of the difficulty in its production. The team at Nuclidium in Switzerland has developed the technology for being able to produce copper 61 at quantities and purity that will now allow it to be used for PET targeted, to be added to PET radiotracers. So that team at Nuclidium really deserves a great deal of thanks. And now that copper 61 has been shown valuable for PSMA-targeted PET, it's likely that it will move into radiotracers that are used to target other molecules such as SSTR-2 and FAP.
Oliver Sartor: Absolutely. It won't stop at PSMA. I can see that. Gary Ulaner, thank you so much for being on UroToday. Thank you for sharing your insights and your important work. I appreciate what you do to help push the field forward. And with that, thank you and enjoy. I hope our audience will enjoy the presentation today.
Gary Ulaner: Thank you so much for having me, Oliver. It was a pleasure to be here.