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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to talk today to Dr. Mark Markowski, who is an Assistant Professor at Johns Hopkins University in Baltimore. Thank you so much for being here with me today, Dr. Markowski.

Mark Markowski: Thanks for having me.

Alicia Morgans: Wonderful. So I wanted to talk with you about a relatively newer compound, VERU-111, which has been evaluated, I think, by some groups for the last number of years and had a recent presentation at GU ASCO 2022. So first, as we start to dig into that, can you tell me a little bit about the compound? And then we can get into the study results.

Mark Markowski: Sure. VERU-111, also called sabizabulin, is a novel, oral alpha, and beta-tubulin inhibitor. And we just conducted a phase one/two study in men with metastatic castration-resistant prostate cancer. The phase one trial was a dose-finding trial and the primary endpoint was safety. And it's always challenging when you have a new compound, particularly an oral dose, compound to determine what is the best way to dose the drug, how often to give it, do you give drug holidays, et cetera. And so it was a really unique trial design where we initially started with patients going on for one week. So they would take the drug daily for one week and then get two weeks off. If that was found to be safe, they would then do two weeks on, one week off, and then eventually daily. And so we really tried to ramp up our dose escalation to give patients the best chance of responding to the drug and also determining how best we should dose it moving forward.

Alicia Morgans: Well, and that's so important as you said with these oral agents because we do have a little bit of control, but we do need to advise obviously the patient to take the drug when he needs to take it. So what did you ultimately find was the best schedule?

Mark Markowski: So we found that patients did quite well with daily dosing on a continuous basis. And we were increasing the dose levels and found that 63 milligrams per day was the recommended phase two dose. We did not find a maximum tolerated dose. Patients did okay at 72 milligrams and also at  81 milligrams. But we did start to see some adverse events, particularly GI events, so we decided to move forward for phase two at 63 milligrams per day.

Alicia Morgans: Well, and that makes some sense, of course, in terms of your dose finding. But let's dig in a little bit to the events, the adverse events, that helped to shape that dose, because that is of course the purpose of this study. And with an oral agent, GI events are relatively common for a lot of our agents.

Mark Markowski: So we did see GI toxicity here, and I think diarrhea and nausea were very common, mostly low grade. We did see one or two grade three adverse events in terms of nausea and diarrhea and also fatigue. And those were the main side effects that we observed. What was interesting, because the mechanism of action does target the microtubules, we did not see any neuropathy nor did we see any neutropenia, which we commonly see with other taxane-based chemotherapies. And so that was an interesting finding. So most patients tolerated the drug well, except for GI toxicity. But those were managed conservatively with a dose reduction, dose holiday, or supportive care.

Alicia Morgans: Well, that is really interesting, as you mentioned, because we do see with our taxane chemotherapies, for example, that we have to think about cytopenias, we have to think about infection risk, particularly important, of course, in the era of the COVID pandemic. And then neuropathy can be a dose-limiting event, particularly for docetaxel. So this seems to really be quite a different approach to delivering something that's targeting those microtubules.

Mark Markowski: Yeah, absolutely. And so I think it will be interesting to see in the phase three study that's ongoing, what that toxicity profile looks like. So in the phase one/two study, we treated about 80 patients and we did not see neutropenia or neurotoxicity. But we'll see, as we dose more patients, are we going to start to see kind of more taxane-based toxicities or not? Perhaps this is just going to be localized to the GI tract, which has been pretty manageable.

Alicia Morgans: Okay. Well, great. Well, what would your message be then to folks who are thinking about VERU-111 and trying to keep an eye out for it as it does continue to move forward through the pipeline?

Mark Markowski: So I think this is a novel oral agent that is not directly targeting the androgen receptor pathway. We do see preliminary activity, the RPFS in the phase one/two study was about 11 months, which is pretty impressive given the prior treatments of the patients on the study. So I think it's going to be interesting to see in the phase three study what the efficacy looks like here. And this may be in another oral drug that's available to patients in place of chemotherapy or an intravenous form of chemotherapy as they go through their treatment course.

Alicia Morgans: Well, thank you so much for sharing your expertise, letting us know a little bit about this abstract, and also giving us an understanding of what we can look forward to in the future. Thank you so much for your time today.

Mark Markowski: Thanks again for having me.