(Guest Lecture) Mezigdomide (CC-92480) | Paul Richardson, MD | ASH 2022

Hello, everyone. My name is Dr. Paul Richardson. It's my pleasure to present on behalf of my colleagues some preliminary results from our dose expansion phase of the CC92480MM001 study, where we evaluated the novel cerebron E3 ligase modulator, the mesigdemide, as it's called, which is a so-called cell mod in combination with dexamethasone in patients with relapse and refractory multiple myeloma. Now, just by way of introduction, Mezi, as we like to call it, is a very potent orally bioavailable agent that has remarkable tumor acidal and immune stimulatory effects compared to other drugs that are broadly immunomodulatory, such as, for example, pomalidomide and lenalidomide. However, I think it's important to recognize that mesigdemide is different. Preclinical and translational data show this very clearly, and above all, as a pharmacologic activity, it's different in its structure and it induces 100% closure of what we call the active cerebron state, which is the key target. And in this slide, I try to show how this molecule binds in the E3 ligase complex and by so doing leads to highly active and targeted degradation of key transcription factors that control the pathobiology of myeloma, including icaros and allos, as these proteins are described. And this results not only in targeted programmed cell death in the myeloma cell, but above all, in profound immune stimulation. And this is really quite important because it leads to the increased activity that we see. Now, in terms of this study, this composed of two parts, the phase one dose escalation, which we completed and established what we call a recommended phase two dose, the one milligram given daily three weeks on and one week off. And the phase two portion that we're going to focus on today describes the combination of mesigdemide with dexamethasone in a large cohort over 100 patients with relapsed refractory disease. Now, in the first part of the study, we demonstrated that if you gave one milligrams three weeks on one week off with dexamethasone, we saw a response rate of 55%, which is very encouraging, but this was a relatively small number of patients. So we had to be careful and make sure could this be reproducible in a larger cohort of patients. So with that in mind, the eligibility of the patients was they all had to have relapsed and refractory myeloma. They had to have three or more prior lines of therapy. And what was important to note is they had to be refractory to immunomodulators, proteasome inhibitors, and CD38 antibodies. And then above all, we allowed patients who'd had prior exposure to BCMA treatment. Now, this I think was an important cohort. In any event, the primary intent was to establish the response rate and then to look at safety, tolerability, progression-free survival, time to response and duration of response. And we also did an exploratory examination of what we call pharmacodynamics to better understand how the drug was actually working on tumor cells. Now, these are the baseline characteristics of the patients. 101 patients were enrolled overall. As you can see, slightly more men than women. And importantly, the median age was 67, but we had a range from 42 all the way up to a patient aged 85. Importantly, about a third of patients had high-risk cytogenetics, 37%. And interestingly, and very importantly, 40% had extramodular disease. Now, in terms of prior therapy, about 30% had received prior BCMA treatment. All of the patients were relapsed in refractory and all were triple-class refractory. This describes the patient disposition and treatment exposure. And what you can see here is that few patients discontinued due to adverse events. And really, there was minimal treatment-related mortality, in fact, only in one or two cases at most. Now, in that context, the mortality leading to treatment discontinuation is noteworthy for the following. We only had one patient pass from complications of COVID-19. And this, particularly as we were enrolling patients during the peak of the pandemic, was an important and unfavorable observation. Now, what about actual treatment-related adverse events? Well, the important thing to share here is that neutropenia was the most frequent hematologic significant event. These proved manageable. Infections also did occur, but again, generally very manageable. And the amount of pneumonia we saw, approximately 13 cases of significant pneumonia and only three that were considered potentially life-threatening. So, these were an important signal because it's really relatively lower than we see, for example, with some antibody-based approaches. Otherwise, the most important side effect noted was fatigue, but again, generally manageable. Now, in terms of response rates, this is where the response rate data landed. We saw 41% response rate overall. Importantly, in those patients with extramedullary disease, it was 30%. And then, excitingly, in those patients who had had prior anti-BCMA therapy, we saw a 50% response rate, which we thought was really quite encouraging, given the fact that those patients are particularly refractory. Now, what do we know about progression-free survival? Well, the data are very early, but so far, I think it's reasonable to say so good. The median progression-free survival is around four and a half months. And if we look at duration of response, I think this is perhaps more informative. If you achieve very good partial response or better, with early follow-up, we've got a median DOR of at least nine months. And if you achieve a PR or better, it's at least five months. So, these data, again, are expected to continue to improve with time. Now, what about the pharmacodynamics? Well, this was a very important part of the trial. What we sought to do was understand where levels of ALS and ICAROS might be in patients prior to treatment and then during treatment, and specifically focusing on tumor ALS, and especially grateful to patients for being willing to undergo serial bone marrows to establish this. We saw that patients who had received prior pomalidomide, for example, as their prior treatment, and in fact were refractory to it, very interestingly, we were able to show that with mesignomide, you're able to restore that response. And it truly reflected an improvement in the effects of mesignomide on the ALS target. And you can see that summarized in this slide. And what you can see is that the ALS regimen, the ALS staining in the slide on the left, is very intense. And what you can see here is that when they receive the eight days of therapy, and this is markedly reduced. So showing that the mesignomide is able to degrade the ALS even after pomalidomide has failed to do so. And then when we looked at this in a more comprehensive fashion, looking at what we call peripheral blood immunophenotyping on the right of this slide, you can see that NK cells proliferating were active in the context of exposure to mesignomide. T cells that were proliferating were active and increased. And what's so interesting as well is to see the preferential effects on both CD4 positive and CD8 positive cells. So in conclusion, mesignomide clearly showed that it's the most potent novel cell mod that we have to date. It clearly is very active in combination with dexamethasone and doing so in an incredibly vulnerable population. There's a manageable safety profile. And now we're evaluating this drug in combination with other standard treatments as part of larger phase one, two, and phase three studies. I just want to close by especially acknowledging our patients and families, as also the clinical study teams at all of the sites, our sponsor, Celgene, as part of Bristol Myers Squibb. And then similarly, just to acknowledge the international platform that this study is built on, incorporating countries not just from the United States, but also from the United Kingdom, Korea, Spain, Denmark, Finland, France, Greece, Canada, Belgium, and Australia. Thank you very much.