And so, I think that’s really why we’ve been able to go after MEK in a unique way that we think certainly preclinically is really kind of living up to the full potential of MEK as a target. And you’re right, conceptually, MEK is a great target to really target any mutation in RAS and really achieve that kind of universal-RAS activity. Let me see if Brett wants to add anything on your first question, and then we can talk about the second question.
Brett Hall: Yeah, just really quickly €“ Hi, Mark. So I would add the strength, our core thesis is that deep cyclic inhibition within novel engagement mechanism that prevents or resist the CRAF-bypass and other bypass mechanisms is critical. And, I think, here is where a good example of the existing MEK inhibitors their strength becomes their weakness, right. There’s 24/7 chronic inhibition sustainably induces these adaptive resistance mechanisms that basically is kind of like having a snowplow where the snow builds up in front of the plow and eventually just slows down the ability for that truck to be effective and remove snow, very similar with MEK inhibitors. And we can avoid that or reduce that significantly by the deep cyclic inhibition approach, where we reset the pathway every day, as well as the novel mechanistic engagement that actually resisted the build up in the first place.
And, I think, those 2, the 1, 2 punch of deep cyclic inhibition with IMM-1-104 really stands apart from the other MEK inhibitors.
Mark Breidenbach: Okay. I guess, I’m also just wondering if you included any of the more conventional MEK inhibitors in your screen against humanized 3D tumor models, if you saw any sort of difference there.
Benjamin Zeskind: Yeah, this is a good question. Yeah, so we haven’t guided on that at this point. But what we have actually run and we’ve already mentioned that we do see a nice read through of the 3D-TGA into in vivo. And we did publish, for example, in the head-to-head comparison of IMM-1-104 versus binimetinib in the NRAS Q61R SK-MEL-2 model, where we saw a mid-cycle regressions with 104, but really very minimal to no effect with full dose binimetinib.
Mark Breidenbach: Okay. Great. And then with respect to the timing on expansion cohorts?
Benjamin Zeskind: Yeah, thanks for that second question, Mark. So, given that that RP2D stands for Recommended Phase 2 Dose, I’ll ask Scott to confirm this with his decades of clinical experience. But I think it’d be hard to start the Phase 2 until we have the recommended Phase 2 dose.
Scott Barrett: I think Mark is asking in the spirit €“ can you hear me?
Mark Breidenbach: Yes. We can.
Scott Barrett: Right. In the spirit of dose optimization, we’re proactively volunteering to have a dose evaluation phase, where we’re calling internally Phase 1b. And so, we’ll come up with candidate dose or dose, RP2 dose candidates, and then evaluate them further to make sure that we’ve selected the definitive one before we start Phase 2a. So, yes, in answer to your question, Mark, we plan to complete dose escalation before we formally evaluate 2 or more dose candidates.
Mark Breidenbach: Got it. Thank you.
Benjamin Zeskind: Thanks. That’s a great point. And I first heard about the project optimists from Scott and his team, years before it sort of got the popular and gained a lot of prominence and attention. So we’ve been very, very focused on that from the early days. But thanks, again, Mark, for your questions. And let’s go on to the next question, please.
Operator: Thank you. One moment for next question. Our last question comes from the line of Michael Schmidt from Guggenheim Partners.
Michael Schmidt: Hey, guys, thanks for taking my question. Just maybe a quick follow-up on the Phase 1 study. Based on the enrollment criteria, what tumor histologies would you expect to enroll predominantly? And based on that, as we think ahead towards you reaching more efficacious or higher doses in the study, where would you expect to see early clinical activity? Thanks so much.
