Robert Doebele: Yes, if I can understand your question, well, we haven’t changed any of the other inclusion exclusion other than copy number. So that’s unlikely to change the number of prior lines of therapy. We know that MDM2 gene amplification as a whole carries a worse prognosis. But again, we don’t think that the change in copy number is going to necessarily affect the kind of clinical status of the patients in terms of prior lines of therapy or other, I think meaningful clinical characteristics.
Mitchell Kapoor: Okay, great. Thanks, that’s helpful. And then on MANTRA-4, just wanted to understand a little bit of the rationale for the pushback. I know you had mentioned that FDA recommendations were some of the reasons, but could you just comment a little bit more on why that might be?
Avanish Vellanki: Sure. We’ll turn that one over to Richard.
Richard Bryce: So, I mean, there was nothing contentious there. Broadly speaking, I mean, I won’t go into to the fine detail, but broadly speaking, there was some help for — there were some helpful suggestions around the essentially the inclusion criteria and some stopping rules, which we were very happy to implement and incorporate into the protocol. So, that was essentially it, nothing major or contentious at all.
Mitchell Kapoor: Okay, great. Thank you all very much.
Operator: Our next question is from the line of Tony Butler with EF Hutton. Please go ahead.
Tony Butler: Thanks very much. Two very brief questions, if I may. One is, what is the rationale or may I ask, the rationale for utilizing a PDL-1 antibody? I mean, I recognize you’ve got a supply agreement with Roche’s versus a PD-1 antibody. And I say this, really — for a couple of reasons, but one is in your K, you do make a comment about nonclinical data in immunocompetent mouse models in CRC with CDK into a loss did demonstrate some common control activity with an anti PD-1? So, that’s question one. And the second question is in patients that actually respond to milademetan, let’s assume that these are in liposarcoma patients and then at some point progress. Do they progress because there’s a second site mutation? Do you have a — do you know, or do you have a hypothesis as to where that exists? Or is there some other explanation? Thank you very much.
Avanish Vellanki: Thanks for the question, Tony. So, I’ll turn both those. I’ll turn the first part of the first question, the non-clinical rationale for the IO combination with Mila to Bob before turning it, asking Richard to comment on the reason for the PD-L1 versus the PD-1. Let’s address that first question first. Bob?
Robert Doebele: Yes. So in terms of patients progressing on milademetan, and I think this could apply to our MANTRA study with liposarcoma patients or really any patients. I would say we are not expecting second site mutations within MDM2. The binding pocket that our drug binds to is the same pocket that p53 binds to. So a mutation there we believe would be likely to disrupt binding with p53. So that’s, I think unlikely, but something we can look at. The expected resistance pathway, and there’s been some both preclinical and clinical evidence for this is the emergence of p53 mutations. There could be other mechanisms as well. And we have the ability to monitor and look at those resistance mechanisms through these of CDKN2A analysis.
Avanish Vellanki : And I believe that was your second question, Tony. So let’s, on the first part, I think you were asking about the nonclinical support that we have for the combination of an IO agent and milademetan, is that right?
Tony Butler : Yes. But in K, Avanish, it says an anti-PD-1. So I’m trying to split anti PD1 from PD-L1 and if there was a rationale for one over the other, because you have chosen atezo in the MANTRA-4 study.
Robert Doebele: Yes, we — as you know, PD-1 and PD-L1, really target two sides of the same binding interaction. So we don’t see a meaningful difference between the two clinically or pre-clinically. That’s the short answer.
