Miguel Zugman: Thank you so much.
Tian Zhang: So, we're going to talk a little bit about the results that you're presenting here at GU ASCO, the CBM588 trial with Nivo/Ipi. So, tell us a little bit about the study and its inception and how it came to be.
Miguel Zugman: Great. Yes, this is a phase one dose-escalation study with a standard three-plus-three design. And the primary endpoint was to assess the safety and viability of the new formulation of CBM588 in patients with advanced renal cell carcinoma. So in our previous studies with CBM588, we used a sachet formulation which had to be mixed with water. But this new formulation involves a capsule that must be refrigerated, but much easier to use.
Tian Zhang: Great. And what's the patient population that you were really picking for this particular dose escalation part of the trial?
Miguel Zugman: So, patients for this study were first-line metastatic clear cell renal cell carcinoma patients with or without sarcomatoid features. They had to be candidates for nivolumab and ipilimumab, so no previous autoimmune diseases were allowed. And they needed adequate performance and organ function status.
Tian Zhang: And you mentioned the formulation was a little different. So, now kept at room temperature or any special handling for this particular probiotic?
Miguel Zugman: Yeah. So, previously we used powder that had to be mixed with water, but the new formulation involves capsules that must be refrigerated. So ideally, the patient must keep them in their fridge and we give them frozen bags to transport from clinic to their homes.
Tian Zhang: Is that difficult, or do you think most people can handle it in real world settings?
Miguel Zugman: I think it's manageable. I don't see any issues coming along, and that has not been an issue discussed by the research team at all.
Tian Zhang: Good. What were the highlights of the trial findings? What did you see?
Miguel Zugman: So, we were happy that no dose immunotoxicities occurred. So with only 12 patients, we were able to achieve the highest dose planned, and that was actually 10 times higher than those used in the previous CBM588 studies. But we also looked at some correlative analysis that involved microbial shifts between those level one to two and those level one to those level three. And we saw enrichment of certain bacterial toxins and the depletion of other. And one additional analysis that we did was based on the serum MAdCAM-1 levels, which is a new biomarker for dysbiosis. And a recent study published in Nature Medicine actually proposed a cutoff of 180 nanograms per mL of sMAdCAM-1 levels. And we tried to see that in our cohort of patients, and we found that three out of four responders actually had sMAdCAM-1 levels above that cutoff, but also five out of eight patients that did not respond also had higher sMAdCAM-1 levels. Of course, all these are very small numbers, but when we look at the data side by side, there is a trend that patients in the responder group seem to have higher MAdCAM-1 levels at baseline, but also longitudinally at cycle three that tended to be similar or even higher. While for non-responders, in general, those MAdCAM-1 levels seem lower.
Tian Zhang: And so, do you think the serum marker will eventually help you pick out patients who might respond or not? And would you add that in as a prospective stratification marker?
Miguel Zugman: Yes, that's one of the hopes moving forward with microbiome-directed therapies. We're always striving to understand better the mechanism behind this very encouraging clinical signals that we find in our studies. And so, different groups have proposed different measures, and this is one of the most promising tools that we have to use in the future. Similarly, another tool that we plan to use in future studies is the TOPOSCORE, which is a measurement of ecological network composition of the microbiome population in the gut, instead of more focused in single strain bacterium that didn't really pan out in our previous studies.
Tian Zhang: Okay. What are some of the ongoing trials and progress with CBM588?
Miguel Zugman: So, that's a very exciting topic. We have one study that has just been activated at City of Hope, led by Dr. Wesley Yep, and the combination of CBM588 with pembrolizumab in the adjuvant setting. Our study is still enrolling a few more patients for the dose-expansion cohort, led by Dr. Chehrazi-Raffle. And what's coming next that it's even more important is the SWOG BioFront. So, this is going to be a national study led by the cooperative group, and the idea is to enroll patients in first-line metastatic RCC, and they will be able to choose any regimen decided by the attending physicians. So it can be either TKI combinations with immunotherapy, or just IO-IO combination with CBM588. And based on this larger national effort, we probably will be able to consolidate and really understand and see if there's a role for CBM588 with standard care therapy in renal cell carcinoma.
Tian Zhang: Great. Yeah, I hope so too. A lot of great trials ongoing, and especially in the ramp up phase for BioFront. I know a lot of sites are looking forward to participating. Any thoughts? A lot of our patients are coming into our clinics asking for what they can do now to optimize their gut microbiome. Any thoughts there? What advice would you give them?
Miguel Zugman: So, I think we should be really cautious on advising our patients regarding their motivation of self-modulated microbiome. So I would advise against using over-the-counter probiotics, that's for sure. We saw different studies showing that these can be... We have contradictory clinical effects out of it, so it's very context dependent. But what we can advise for sure also other physicians is that we should avoid unnecessary antibiotics when possible. We should also be very mindful when prescribing proton-pump inhibitors, which can also affect the microbiome composition. And just advising on a healthy, fiber-rich diet is a reasonable and safe approach. And of course, I think enrolling patients in clinical trials to find better ways of doing this kind of microbiome modulation is the safest and most appropriate way of moving the field forward.
Tian Zhang: I think those are great takeaways. Any final thoughts about this particular study or going forward that you would like to add for our UroToday audience?
Miguel Zugman: Well, I have one more study that I designed while still at City of Hope with Dr. Monty Pal. So, we'll be launching a new study that we actually called Remix Study. It's going to test a new probiotic, a live biotherapeutic compound called EXL01, and it's based on Faecalibacterium prausnitzii. The design will be very similar to the previous CBM588 studies, and this is a partnership with a French company. So, we're very excited about that program. And I'm also excited by the fact that I'm moving back to Brazil where I'll start a new position at Einstein in São Paulo.
Tian Zhang: Congratulations on this particular study, and Monty is always thinking outside the box, so great work doing your next one. And good luck with your career efforts in Sao Paulo.
Miguel Zugman: Thank you so much.