Ami Fadia: Got it. Okay. Just with regards to safety, you mentioned that you dosed up to 40 milligrams per kg in sort of the preclinical models before you started to see some safety. What type of safety emerged at that point? And what was that €“ and then maybe what duration of treatment?
Steve Kelsey: Okay. So this is very species-specific. So mice, we just see weight loss. The tox species were mice and monkeys. And obviously, the monkey is a little bit more representative of what happens in humans. And there, we saw very clearly wild-type RAS-mediated toxicity, predominantly gastrointestinal toxicity and some suppression of myeloid hemopoiesis. Now interestingly, in the human study so far, we have seen some GI toxicity. It’s not €“ it’s a little bit diverse in terms of the exactly which part of the GI track is affected and how that manifests itself. So sometimes, we’ve seen nausea, sometimes we’ve seen diarrhea. Sometimes we’ve seen loss of appetite, for instance. It’s a constellation of gastrointestinal effects that almost €“ well, all of them have either been grade 1 or grade 2 and very easily manageable.
But the predominant toxicity, the one that’s coming through with the increased frequency is skin rash, which we were not able to detect in the preclinical toxicities largely because that we’re limited by what we can detect in those species. But it is interesting, the one organ in which we showed €“ in our JPMorgan presentation, we show that it is the one organ where the clearance of the drug is slightly delayed compared with the other organs, nowhere near as much as tumor, by the way, but it is the clearance of the drug from skin is slower than from, for instance, colonic epithelia or other organs in the body. So it maybe the tissue kinetics of 6236 are contributing to the skin rash. And that makes it the pattern of toxicity a little different in humans compared to the preclinical species.
Ami Fadia: Understood. Okay. Please remind me €“ I don’t know if you mentioned exactly what dose the patient was on, the patient that had to pause the dose and then restart at a lower dose?
Steve Kelsey: I don’t remember. I’ll have to take that off-line. I’m sorry, I don’t remember.
Ami Fadia: Okay.
Mark Goldsmith: I think we have time for one more question. Is that right?
Steve Kelsey: Tremendous. Another speaker. I think there’s one other person.
Operator: Our last question comes from Jay Olson with Oppenheimer. Your line is now open.
Jay Olson: Oh, hey, thank you for the update and for taking the questions. We had a couple on 6236. What are you expecting to be the minimally effective dose? Is there any saturation of target occupancy that could lead to a plateau of efficacy? And what dose would you see that plateau? And then since the AE table excluded events that occurred in fewer than four patients, can you just comment on what those AEs were and if any of them were grade 3 or 4? Thank you.
Steve Kelsey: Well, it’s easy to answer the second question, we see no grade 3 or grade 4 events other than that one bowel perforation that we described, which was a grade 4 AE and also a serious adverse event. But as we said, the bowel perforation was most likely due to the efficacy of the drug not due to the toxicity of the drug on the gastrointestinal epithelium.
Mark Goldsmith: Sort of question about MAD…
Steve Kelsey: There is no plateau in our dose response. We continue to see increases in efficacy up to the point where the drug becomes intolerable due to inhibition of multi-RAS. So there is no expectation of a plateau as we continue to dose-escalate. And this makes €“ this is really important because this compound so far, everything we know about RMC-6236 does not follow the paradigm for Project Optimus. We continue to see increase in efficacy as we see increase in toxicity. They are absolutely related to each other, but we are seeing efficacy at doses that are tolerable. And that is incredibly important both for the platform and for the further development of the compound.
