Hello. My name is Richard Stone. I’m from the Dana Farber Cancer Institute in Boston, Massachusetts. And I’m here at the iwAL meeting, in beautiful Nice, France, with my colleagues, Dr David Sallman from H. Lee Moffitt Cancer Center in Tampa. And Dr Thomas Cluzeau, who works right here in Nice. So we just came from a session. We discussed, potential next blockbuster therapies in AML. And we had a lot of discussion about one of the more difficult topics in AML, which is how to make strides in the very difficult subtype of p53 mutant AML. And we heard about a couple of drugs in this regard, namely, eprenetapopt and magrolimab, which are drugs in classes of refolding agents and anti-CD47 agents, respectively. So I’ll start with Dr Cluzeau and ask what your impression of the development of the p53 refolding agents is?

So thank you for the question. So, yes, so it’s complicated for the for eprenetapopt, as you know, we performed two Phase II studies with David, one in the US and one in France and we combined the results. The results were really promising. Based on the combined results, with a long follow up, we observed an overall response rate around 70% and a median overall survival at 12 months and for some patients could obtain, it was a small population, of course, but some patients could obtain a deep CR before allo stem cell transplantation. The median overall survival is not reached, so maybe some patients could be cured, we don’t know, but could be cured using this drug. But as you know, in the MDs setting, the Phase III clinical trial was negative. So there is some… we could discuss about this clinical trial, but we don’t know where we will go with this drug in the future. There is a Phase I study combining azacitidine plus venetoclax plus eprenetapopt with also some promising results with high response rates, and with median overall survival around nine months in tp53 AML patients. So it seems to be a really interesting drug in this setting. Maybe what we learn about eprenetapopt is the mechanism of action. So as you said, this is a reconfirming agent. But it’s not only, the mechanism is not only the unique mechanism of action, there is other mechanism of action. The drug-induced oxidative stress, the drug-induced ferroptosis. And maybe it’s also what we learn about this drug. Maybe we know now, some pathways to target tp53-mutated patients.

David Sallman. Do you think that… well, how can, first, how can you explain the relatively high response rates did not translate into a positive Phase III trial. As best we know. I mean, the, what we know is that the AZA plus or minus eprenetapopt study was quote a negative study that you only heard about that in a press release. Do you have some further comments as to why it might not be, uh, moving forward?

Yeah, hopefully, I mean, and really the world needs sort of the full mature data set. This is the first, you know, prospective Phase III trial, and I think just actually a lot of the discussion afterwards, you know, from Mark Levis and others and Amer Zeidan is that we really do need to focus our efforts specifically on this patient population and really take out from both MDS and AML cohorts, this group so that we can really move the move the field forward. I think, you know, based on the press release your P value 0.13, you know, probably 3, 4 more patients, and then we have a positive, Phase III trial, I think, you know, open label study. I think, in retrospect, was probably the wrong action.

And my concern is was there, a disparity number of patients, you know, leaving the control arm because they knew they could get venetoclax. And I think actually, around the time, the study wasn’t as clear as of now, does, HMA venetoclax improve or not improve outcome. So I think with a relatively borderline powered study of 150 patients. Did we lose more patients in the control arm and also did patients, you know, treat differently? In the Phase II studies that we presented, actually, essentially one patient had a dose reduction of azacitidine, was there different.. drug holding dose reductions of AZA somewhat from the AZA venetoclax experience. And could that have dropped our CR rate, which was sort of in the low forties, down to the 33%. Also the control arm did behave better than what we hypothesized. similar to you could argue in the pevonedistat trial again, MDS study. But, you know, nobody could beat a CR rate of 30 something percent, which was reported. So I think there’s a little bit of challenges in design.

Maybe a little bit of under powering. My hope is, at least in the Phase III Magro studies, which we’ll talk about, is there, 500 patient, double blind, placebo controlled studies, And that that may solve at least some of the issues that we had in the APR experience. I think one other study is Dr M… at my institution published the post-transplant maintenance study in JCO recently. And actually the one year-two year overall survivals were quite remarkable. Now is it that we captured a group of patients that had the optimal clearance, cytogenetic remission, engrafted, no GvHD, and we get them on maintenance. That’s actually what I do off study, all the time. And was it truly the combination or not? I’d love for that to go into a randomized, CT in study, but whether or not that can happen based on, you know, company band with this is a question. Do you think, Dr Cluzeau, that complete remission rate is the right end point for p53…studies and p53 mutant patients? Given that remission may not be deep or durable, even if that trial had met a CR rate endpoint, would have been used. Would it have been important?

So maybe a complete remission is not the best primary endpoint for tp53. Because as we know, for example, azacitidine plus venetoclax, there is a significant increase of complete remission rate, but there is no benefit in overall survival at the end. So for this very poor patient, I think the overall survival is the best primary endpoint.

Yeah, I completely agree. I mean, actually, how we had originally written even the Phase II studies was an OS endpoint, I think based on early Phase I data and sort of, speed, often needed in industry trials is sort of switched to that CR endpoint. But yeah, we agree that CR is almost an irrelevant endpoint. I do think true CR with molecular clearance. Those patients, you know, overall do have, uh, you know, better outcomes. But given the OS is so short like that clearly needs to be it. And that’s, you know, both the endpoint and the pivotal magrolimab plus azacitidine p53 AML study that we discussed a little bit, the ENHANCE-2 trial. But even in MyeloMATCH, I think we’re appreciating that and really the endpoint in the sort of randomized Phase II trial is also OS. So I think we now know OS is the key. Can we have early predictors such as, VAF clearance? I think those are interesting questions to look at.

So let’s indeed segue into magrolimab, which is certainly the most favorite nation now for p53 mutant patients. The results that you have presented, several times. So, Dr Sallman, could you briefly review how magrolimab another CD47 and other anti-CD47 antibodies are supposed to work? And what are the developmental pathways for this, this drug?

Yeah, sort of. The basic concept is that cancer cells, one of their ways to avoid the innate immune system, and macrophages is through over expression of of CD47. This is actually not specific to AML in MDS patients, but it’s actually seen, you know, throughout cancer, many solid tumor models have have similarly shown that, and then at the same time have this upregulation of protein… signals. This is sort of maybe, you know, a defense mechanism that should lead to clearance of the cancer cells, but it, because of CD47 at the same time, it’s abrogated. So essentially any inhibitor of the CD47 sirp alpha… sirp alpha being expressed on the macrophages can block this. And if there is a pro signal allow for, antibody-dependent cellular phagocytosis to occur. I think what’s really relevant at the same time is it’s not effective enough. Even though in preclinical models, monotherapy at activity and clinical studies single agent essentially has no complete remission. And so thus you need to add it to agents that can ideally induce a prophagocytic signal, azacitidine being shown to do that with calreticulin. We talked a little bit about triplet combinations where venetoclax-azacitidine can actually further lead to that upregulation. But essentially, you get this combination, this block of… phagocytosis, this allowing of it to eat the cancer cell. And then you get this synergy. I do think, is this truly the main mechanism? Is it LSC eradication? I really hope, in these randomized trials, can we see differences not just at the time of complete remission, but earlier endpoints where maybe we can see immune, microenvironment changes, or a superior LSC eradication that may speak to truly what is the predominant MOA in our patients.

So Dr Cluzeau, to pick up on this.. I guess we’re not using AZA-ven or AZA along with anti-CD47 to help bust the mitochondria open and kill the cell. We’re using it to change the immunological… in a sense, but still the cell has to die. So the question is, can a macrophage eat a p53 mutant cell successfully and kill it? What do you think about this? Are you optimistic? In other words, based on what you know about the biology.

So based on the first results using the CD47 antibody, yes, we are optimistic, but I’m young and I know I know we were disappointed with a lot of drugs before, especially in the p53 mutated, with venetoclax with pevonedistat, with HDAC inhibitors. So yes, for me, it seems to be really promising, but we need to await the results of the Phase III study because we know with eprenetapopt. Unfortunately, the Phase III was negative, but it seems to be promising. And this is a new also mechanism of action. So maybe it will be the one.

I think we can all agree. It’s good to be young and optimistic.

That’s a great thing. So, I think we’ve had a good discussion today about these interesting agents which might be able to change the natural history of p53 mutant AML and MDS, something that is surely needed. I hope you’ve enjoyed this discussion, and we’ll listen to other discussions at this exciting, iwAL meeting. Thank you.