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Sam Chang: Hi, I'm Sam Chang. I'm a urologist in Nashville, Tennessee, and we are quite fortunate to have one of the rising stars in urologic oncology, Dr. Sunil Patel. Dr. Patel is an Assistant Professor at the Brady Institute at Johns Hopkins University, in the Department of Urology there, and I've known him since he was a resident, actually out in San Diego. He has really started quite a few trials at Johns Hopkins, and he's going to talk about one that looks at a novel agent for patients with BCG-unresponsive disease. This was presented at the AUA 2024, so thanks for spending some time with us, and we look forward to your presentation.

Sunil Patel: Thank you very much, Dr. Chang, for that kind introduction.

I'm going to be discussing a very interesting study. It's called the Orion Bladder Cancer Study. It's a phase 3 single-arm study. Again, a little interesting, the nuance there, but to evaluate the efficacy and safety of paclitaxel-hyaluronic acid conjugate administered intravesically to patients with BCG-unresponsive CIS of the bladder, with or without Ta or T1 papillary disease, and this study is supported by Fidia Pharmaceuticals. I do not have any financial disclosures to mention.

This study, along with a lot of other trials in this space, are really focusing on the non-muscle invasive bladder cancer space, and we're seeing this more and more commonly, especially, and we just saw recently at the AUA, which is really a fascinating and exciting time to be a part of the bladder cancer space. Bladder cancer is the most common solid malignancy in men. It's about 82,000 new cases diagnosed last year. The standard of care for the vast majority of non-muscle invasive bladder cancer has been transurethral resection of bladder tumor followed by instillation of BCG, and BCG has been around for many years and we've had very good success with it, and there are a solid number of patients that actually have a good response to it.

However, we do have roughly around 40% of patients who experience a tumor recurrence, and we're really left with what to do with those patients. Historically we would offer them an upfront cystectomy, and many patients are either medically unfit to undergo a cystectomy or they wish not to undergo a cystectomy, but cystectomy is also associated with significant morbidity and mortality, so really we needed to come up with new drugs, and that's really been a fascinating aspect of this study, but also this space in bladder cancer.

So this study, ONCOFID, is really using a proprietary new drug. It's a conjugation of paclitaxel and hyaluronic acid, and this drug specifically targets CD44, which is overexpressed in bladder cancer cells. Hyaluronic acid has been shown in prior studies, and it may help the anti-cancer medications, specifically this one, paclitaxel, to be more effective, specifically in drug delivery, and ONCOFID-P-B, which is the drug's name, is given intravesically, similar to a lot of other drugs in this space. The phase 1 study and the early drug results of this study with this drug were quite promising. At the end of the intensive phase, which was 12 consecutive intravesical treatments, 15 out of the 20 patients enrolled achieved a CR, and then patients were still having a complete response or CR after three, six, nine, and 12 months of a maintenance phase, and respectively, there were 65, 60, 45, and 40%, respectively, at three, six, nine, and 12 months.

Only seven patients, five mild, and two moderate, had drug-related adverse events that were reported, and no drug-related serious adverse events and no drug-related withdrawals have been reported, so no grade four or five as well.

This study specifically is following up on that as well. ONCOFID is administered to patients, again, with CIS, with or without papillary Ta or T1 disease and unresponsive or intolerant to BCG and/or unwilling or unfit to undergo a cystectomy. So 600 milligrams of this drug is administered by intravesical instillation for 12 consecutive weeks, again, the intensive phase, followed in patients with a complete response, which is deemed by cystoscopy and biopsy, followed by a maintenance phase, which is 12 monthly instillations, and this trial will also include a subgroup analysis of 30 patients that will have papillary disease, so Ta and T1.

The interesting thing and the great thing about this study is it's an international study, so we're going to have a good heterogeneous population. Again, this study is based out of Italy, with about 35 planned activation sites across France, Italy, Poland, Spain, and the U.S.

The current status of this trial, as you can see, we have patients enrolled in all of the countries. Italy is leading the group and the U.S. has about three patients, and a couple currently in the last few weeks have actually just been started in the screening process, and there are about four patients in the subgroup analysis as well.

So really the take-home, which we're seeing a lot in this space, is we're really trying to provide a safe alternative to cystectomy in patients with BCG-unresponsive CIS with or without papillary disease, really offering another alternative, another solution, and potentially another way to save patients' bladders, especially in this difficult disease space.

Sam Chang: Sunil, that was a great presentation. Let me ask you a couple of questions, as this area or disease state gets much more attention with lots of different alternative treatments, either alternative medications, alternative delivery treatments, chemotherapy versus immunotherapy, those types of things. So does this fit, you think, more in the chemotherapy space in terms of the paclitaxel? Is it a combination, both cytotoxic and immunotherapeutic? Tell me a little bit about the mechanism of action.

Sunil Patel: Yeah, so great question. I would look into this and specifically think that this is more of a cytotoxic drug, given the paclitaxel, but however, very interestingly at the AUA and the SUO symposium this year, we've learned that... We can almost think about some of these intravesical chemotherapy agents almost being a little bit immunotherapeutic as well with the cytotoxic release of certain molecules, and that can stimulate the immune response as well, so it's very interesting.

I think Dr. Svatek is the one who made that comment at the SUO symposium, which is a really fascinating way to think about this, where we have these intravesical drugs such as gemcitabine and docetaxel, we have paclitaxel, we think of them as classic intravesical chemotherapy, just however, there may be an immunotherapeutic response as well, which is really fascinating, so I think your comments and your question is it's focused on a chemotherapy agent, however, I think there are other aspects, and other mechanisms of action as well.

Sam Chang: Yeah, with that dosing schedule similar to chemotherapy agents, I was wondering that. In terms of pre-human studies, obviously forms of paclitaxel have been given to adults and to humans for years, for decades. Tell me how the intravesical dosage was set up. Was it initial mice studies and then transferred to humans? Tell me a little bit about the transition from early development to actually this phase 3 trial.

Sunil Patel: Yeah, so great question. So very similar in what you hit the nail on the head there, using animal models, the mouse model, and then extrapolating the dosages into that initial phase 1, looking at the efficacy, really, of that, and then looking at the adverse events, but that was... The initial studies were looking at some of the animal models, the classic models that we've been looking at, specifically BBN models as well.

Sam Chang: As you look at these, clearly your early signal with a CR of 75%, having CRs, and then a minimal side effect profile, so at least in terms of absorption in the bloodstream, seems minimal with this formulation that you've come up with. Any other unique side effect signals that you've seen so far, or seems to be very well tolerated thus far?

Sunil Patel: It seems to be very well tolerated thus far, but it seems very similar to a lot of the other intravesical chemotherapy agent side effects and adverse events, specifically fatigue, instillations, some hematuria as well. Unlike some of the other chemotherapy agents given intravesically, we haven't seen any hair loss, which alludes to some systemic absorption, so that may be a good sign, but very classic and similar to the other intravesical chemotherapy agents. Nothing really unique that we've noted yet.

Sam Chang: That's great to hear. I guess the last question is, as this space gets more and more attention as we talked about, tell me about... Are they still looking for sites for enrollment, or are they capped off with sites and just going to wait to see these results? Where are we in terms of enrolling either new sites and/or new patients?

Sunil Patel: So, great question. New patients and sites are both on a need. So the U.S. I believe, we're still looking to get two more sites active, and for patients... As you can imagine, in this current era we have a lot of, which is a nice place to be, and you probably see this in your practice as well, we're having a lot more options for patients to provide clinical trials, and there are certain specifics in terms of inclusion criteria, exclusion criteria, right, and so when we have our patients on clinical trials, some we hope to get on this trial but they don't qualify, so we're seeing that the enrollment's going okay, however, we need to increase the enrollment, and there's still areas for improvement for two more sites in the U.S. as well, so I think we can utilize and get more people interested in this study. Specifically for our patients, right, I think that'd be the best thing.

Sam Chang: Right, so if people are interested in enrolling, should they contact you? What's the best way then if sites are interested in possibly starting this trial?

Sunil Patel: Yeah, that's great. They are more than happy to, or we're more than happy for them to reach out to me and I can always forward information to Fidia, which is the pharmaceutical company, the parent company, and we can help utilize the communications and contacts and get everyone set up. But yeah, I'm more than happy to field any of those questions or even an interest in, take a phone call if needed, just to talk about the logistics of starting and setting up the trial, our early experience with our patients. I'm happy to do that.

Sam Chang: Oh, that's fantastic. Sunil, thanks again for not only today's presentation but thanks for all your efforts. It's really gratifying for me personally to see someone who early in their stage of career has really tackled the clinical trials aspect and has done a great job for not only the patients, but actually for the next steps in terms of research, so good luck and really appreciate all your efforts.

Sunil Patel: I appreciate the time, Dr. Chang. I appreciate your mentorship as well.