Phillip Koo: Hello, welcome to UroToday. We're very excited to have with us today Dr. Jeremie Calais, who's the Director of Clinical Research at the Ahmanson Translational Research Center at UCLA. We're very fortunate to have him with us today to celebrate the FDA approval of gallium 68 PSMA-11. So first off, I just wanted to congratulate you, and thank you for all the work you and your team have put towards making this day a reality.

Jeremie Calais: Yes, thank you for having me. Thank you for that. It is indeed great news. I will definitely not take the credit for that. This is really a team effort, leading by Johannes Czernin, Thomas Hope, Xiaowei Zou, and our German colleagues. And it's clearly a team effort, and it was mostly coordinated by our regulatory affairs experts and also the chemistry people. So it's really a great team effort. And even more, we joined two institutions working together.

Phillip Koo: So the question that I think has been asked numerous times to me personally, and by patients and other providers, is when will this be available for their patients at UCLA or UCSF?

Jeremie Calais: Yes. So the date of approval was December 1st. So from December 1st, it is not a research procedure anymore, it is approved by the FDA for use in the US. Now, the next step is to make it standard of care, and the standard is more defined by reimbursement in Medicare and the guidelines as well, the clinical guidelines. So the next step is really to get reimbursement codes from Medicare. This will take another paperwork administrative adventure of several months, I guess. And it could start only from the date of FDA approval. So now we start a new administrative journey and we hope that in the next month, during the year, we get a clear workflow with full Medicare reimbursements set up with CPT codes that able to be reimbursed. But as of now, Medicare has not set up the codes yet. It's not set up yet.

Phillip Koo: Great, thank you. So there are two indications for PSMA-11, at initial diagnosis or initial staging and biochemical recurrence. Yesterday, we talked to Dr. Hope more about the initial staging piece. This biochemical recurrent piece, can you talk about the trial that led to this part of the label?

Jeremie Calais: True, there were two trials, one initial staging, one biochemical recurrence. The biochemical recurrence one was again a joint trial between UCLA and UCSF. We pooled the dataset that led to a cohort of more than 600 patients, 635 patients, that all had recurrence after initial definitive treatment, either surgery or radiation therapy. And they were followed over time. And our German colleague, Dr. Fendler, set up in the protocol very strict criteria to define the followup of the lesions, because what really requires the FDA is to have validation of the findings.

When the PSMA PET literature was exploding, it was all about detection rate, which is in fact positivity rate. Very sensitive. You have high positivity even at low PSA value. So, of course, it's exciting, it's promising, people were all excited about that, but when you go to see the FDA, what they want you to do is of course show that you have a more sensitive test than what is already available, but they want to be sure that what you show in the test is what you're looking for. Here, prostate cancer lesions. So they really ask us to get some validation method of the positive findings.

And so we had different criteria, PSA decreased after focal therapy on the positive lesion without any hormonal treatment. Other imaging findings with other modalities, such as MRI, or coding, or whatever procedure. Other imaging modalities that confirm your finding on your PSMA PET. Or of course the main one, the gold standard is the pathology on the biopsy. And we follow this 600 patient cohort, and in more than 200, we were able to get a validation of the lesion. And the main strength was more than 85% of specificity, which means when you see something, it is very, very likely a prostate cancer lesion. And so for the biochemical recurrence population, that's what you're looking for. You want to test that it's sensitive and that you can rely on it. Of course, there is no 100% of sensitivity, no 100% of specificity, that doesn't exist, but you can be pretty sure that what you see is probably some prostate cancer and that you can try to adapt your treatment management based on the location of this metastasis that you have discovered, or the local recurrence if it's the case.

Phillip Koo: So this isn't the first time we've had a radiopharmaceutical approved in that biochemical recurrence space, but you've shown through some of your other studies that clearly gallium 68 PSMA-11 is the best tool that we have. So what advice do you have for the physicians managing patients with biochemical recurrence? Should every single patient get one of these tests?

Jeremie Calais: Yes. So that was a good question before when patients had to pay to cover the cost of research procedures. Of course, if the PSA is too low and you know that the positivity rate of the scan is directly correlated to the PSA level, and you know that the PSA's around 0.2 or 0.3, the sensitivity will still be pretty low. The detection rate is about 20 to 30% only. And here you say do you want to spend that money? We're not sure we see something. It's very difficult. Now, today, if the PSMA gets reimbursed and fully available for all, I would say I don't see a major contraindication to do the scan.

Why not? You try to do it. If you're able to locate the disease, that's good. You'll have a single lesion to show or you see something. And if the scan is negative, well at least you know that the disease is still very small and you're not able to see it, and you tried. And I don't see any contraindication to do it. So I would say yes, any patient with a suspected recurrence should do a scan to at least know if you have a negative scan, or that has specific treatment implications, or some lesion at a specific location that can maybe be amenable to focal radiation therapy, for example, or other treatments.

Phillip Koo: Yeah. And I agree with you as well. I think there's value in obviously a positive test that tells you where the disease might be. But as you mentioned, I think there's value in a negative test as well. And that was a dilemma that we faced oftentimes is if the PSA level is too low, is it even worth getting a fluciclovine or something else? But I think from what you've shown and the data that you've presented, I think any patient who's labeled biochemically recurrent, it probably makes sense to get one of these, if it's available. I guess that question is availability. So what are some of your predictions with regards to availability? And if you try and go right now, it's limited to UCSF and UCLA, but what do you think the timeline is going to look like?

Jeremie Calais: You have several players in the PSMA PET landscape. Just to try to summarize that, FDA looks at this PET tracer as a drug, and UCLA and UCSF are considered the manufacturers of the tracer. So the FDA's granted for this manufacturing process at UCLA and at UCSF. It doesn't mean it cannot be done anywhere else, it just means because of the one-hour half-life of gallium, you cannot distribute it anywhere else. So it has to be done so far until now just at UCLA and UCSF. We waived the exclusivity of the NDA, and so basically any other site that has the capability to manufacture the gallium 68 labeling and the clinical synthesis of gallium 68 PSMA-11 the same way it was done in the NDA of UCLA and UCSF can file an ANDA, abbreviated NDA, to the FDA to be able to do the same as well.

So you have local sites that can do the same that we did, which would be quicker for us. For them, I mean. And so they could provide gallium 68 PSMA-11 like that. Then you will have other PSMA PET tracers that are on their way from industry vendors. They have submitted their NDA as well, and the F-18 compounds labeled, I think it will be a key moment because it will enable central production and widespread distribution to even remote places with the F-18 capability. So I think the next step would be to have F-18 labeled PSMA compounds approved by the FDA, and then it would be very widely available. But as long as it's gallium, you need local sites to file their manufacturing production approved by the FDA.

Phillip Koo: Yeah. And we know some of those F-18 labeled ones are going through the process right now. So hopefully, maybe in the next year or so, we'll see the approval of one of those. Getting the FDA approval for this obviously is monumental. How do you think this is going to impact research and clinical trial research moving forward? And where do you think our attention should be now that we have FDA approval for this in the United States?

Jeremie Calais: Yes. We had many meetings with the FDA people and they were very helpful, so we really want to thank them again. They wanted to help academia to bring this new promising tracer to reality here in the US. And they were helpful. And as academic researchers, we really learn how to fit in the frame what the agency was looking for, understanding their needs to be able to apply successfully for this application. And there were some prior applications like that, DOTATATE, DOTATOC, C-11 choline, some local sites already went on their own to the FDA, but the more we do that, I think the FDA is really willing to consider other new applications for other new promising tracers, even from small sites. And I think the more people are doing that, it should really help the research and academia to try again, and show that it is possible. And it is possible to do it if you listen to the FDA that at the end is very likely to help sites to apply for new tracers.

Phillip Koo: Yeah, I agree. I think the journey and the story that this collaborative team had is inspiring, and hopefully, it inspires more clinical research teams throughout the country and throughout the world to work together, number one, and to go down this road, which is not easy. So I think you've taught us all a lot of lessons. So thank you very much, Dr. Calais, for joining us and for spending some time with us.

Jeremie Calais: Yeah. It was a pleasure. And until next time.

Phillip Koo: Thank you.