Mesutoclax points to possible shift in high-risk MDS and AML (Sponsored)

Introduction to Episode

0:00You're listening to a sponsored episode of The Top Line.

0:10Welcome, everyone. You're listening to The Top Line, brought to you by Fierce Biotech. I'm your host, Stephanie Butler. So today, we want to talk about one of the datasets that's been drawing attention at ASCO 2026, and it's the study of the novel BCL2 inhibitor mesotoclax in MDS and AML, which reported striking early results. In MDS, mesotoclax achieved 100% ORR and a 90% composite CR. In AML, it achieved 82% CCR and 86.7% MRD negative, with potent activity in TP53 mutant.

0:49The regimen also demonstrated a favorable safety profile across treatment-naive MDS and treatment-naive AML and relapsed or refractory AML. In today's episode, we're going to take a broader look at what these early findings for MASCO 2026 mean for the evolving treatment landscape in higher-risk MDS and AML. We are incredibly privileged to be joined by a true leader in the field of hematologic malignancies. Our guest is Amir Zaidan, who is MBBS, MHS, Professor of Internal Medicine,

1:21Chief Division of Hematological Malignancies, Assistant Medical Director, Hematology, Clinical Trials Office, Director of Hematology, Early Therapeutics Research Leader, Leukemia, and Myeloid Malignancies, Clinical Research Team, Section of Medical Oncology and Hematology, Department of Internal Medicine at Yale School of Medicine and Yale Comprehensive Cancer Center, which is a phenomenal background and amazing to have you here joining us today. So welcome, Dr. Zaidan, and thank you for joining us. Yeah, thank you so much, Stephanie, for the kind introduction.

1:53I'm happy to be here with you today. Excellent. You have spent your career advancing treatment for some of the most difficult blood cancers, and today we're going to start with a disease that deserves more attention than it often gets, MDS, specifically higher-risk MDS. And then we're going to talk about another aggressive myeloid malignancy, AML, and we're going to discuss some of the updates from ASCO 2026, where you have chaired the oral abstract session for myeloid malignancies and transplant.

Higher Risk MDS

2:19So can you talk a little more first about the higher-risk MDS and the unmet needs that relate to that? Yeah, so higher-risk MDS continues to be a really big problem for us in the field. So higher-risk MDS is a common myeloid malignancy. The incidence of MDS in the U.S. is around 4 in 100,000. So it's a relatively rare malignancy, around 20,000 cases a year in the U.S. And we generally think of it as two kind of separate groups, lower-risk and higher-risk. The higher-risk patients generally have very aggressive course.

2:52Their average survival without treatment is less than a year. And therefore, trying to modify the disease course and improve survival has been very important for us. The only current way to achieve cure in higher-risk MDS is with a bone marrow transplant. However, because most patients with higher-risk MDS are older, they are in their mid-70s as a median age at diagnosis, and most of them have other comorbidities. Very few of them are able to proceed to transplant. And therefore, we are primarily managing them with drug therapies.

3:24The problem is that the drug therapy development has been slow in higher-risk MDS, and we are still primarily dealing with only what we call hypomethylating agents, which are drugs that have intravenous and oral versions, but they extend survival by around six to nine months, but they do not currently lead to cure. Yeah. That makes this a very difficult circumstance, especially with kind of a stalling in some of the drug treatment. Now, one of the things I know is, as a citadine, has been kind of the standard of care for higher-risk MDS for over a decade, right?

3:58But yet you just had talked about, you know, composite CR rates around 16%, and median survival still measured in months, right? So for a drug that has been in use that long, why hasn't the field moved beyond it, right? What are the specific mechanisms of failure that are leaving most patients without a durable remission? So this is a really great question, Stephanie. This is an area that we have been doing a lot of self-reflection in the field in the last couple of years. The reason for that is because we have a number of very important phase three trials

4:31that we are very optimistic about, but all of them end up being negative and not leading to drug approvals. Of course, there are a number of common themes that we have seen across some of those trials. I think some of the biggest themes that we have seen is sometimes the drug might appear to be active in early phase trials, phase one and phase two, but they are associated with significant early toxicities that once you go to the phase three trial, they show up more prominently than they were seen in the phase one trials.

5:01So one, I think, area where we had a lot of focus at is to make sure that the drugs have a safety profile that is good, that those patients who are generally older can take them for a prolonged period without having significant problem. Another area that has been a problem is the high incidence of TP53 mutations. So TP53 mutations are characterized by very aggressive disease course and early death and lack of success with many treatments. So this has been a setting where we've been looking for drugs

5:34that were for this important subgroup of patients. I mean, it's definitely a field with massive unmet need and an obviously poor development history. A drug with a 90% composite CR would be even more commercially significant. But that brings us then to arguably the most commercially significant gap in myeloid malignancies, which is there is no FDA-approved therapy for HRMDS patients, right? After azitazine fails, there's not one. So how large is this patient population

6:05and what does life look like for those patients today? And why has kind of this regulatory white space remained empty for so long? So you touched on several, I think, important points, Stephanie. The first one is that I mentioned some patients in the frontline setting being at high risk because they have TP53 mutations, which is around 20% of patients. But the second unmet clinical need that is a significant gap in management of MDS are patients with refractory and relapsed disease.

6:36As you mentioned, those patients have very limited survival. The median survival is less than six months once azacitidine or dicitabine stopped working. And one of the problems that we historically had is that those patients were not able to stay on trials long enough to kind of see a benefit from some of those drugs that were tested. So we currently only have one drug that is approved in the refractory relapsed higher risk MDS setting, which is an IDH inhibitor called Ivosidib. But this applies to less than 5% of patients who have the IDH1 mutation.

7:10For all the other patients, the 95%, we have no good treatment options in the relapsed refractory setting. And this is an area where we really need new, effective, and safe drugs.

BCL2 Inhibitors in MDS and AML

7:20So I want to kind of talk about BCL-2 inhibitors in kind of MDS and AML. You know, if you're a listener and you're familiar with Benotoclax from the AML world, you may ask, why should BCL-2 inhibitors work in MDS, right? So can you kind of explain to us the BCL-2 biology of HRMDS? You know, what makes these cells dependent on BCL-2 survival, signaling? And why do you believe BCL-2 inhibition is a scientifically compelling strategy in this disease?

7:53BCL-2 inhibition has become a very important strategy for management of patients with acute myeloid leukemia. And the first drug that has been approved in this space is Benetoclax. So Benetoclax is an oral drug. It's a BCL-2 inhibitor. What it does, it makes the leukemia cells die. It pushes them to die. And the way this drug has been used in patients with acute myeloid leukemia is in the combination with other drugs, such as azacitidine. So indeed, Benetoclax and azacitidine have been shown together

8:23to prolong the survival of older patients with acute myeloid leukemia. And pivotal trial called the Viali-A showed a survival improvement of 15 months with the combination compared to nine months with azacitidine alone. So because of the success in acute myeloid leukemia and because of the similarities with high-risk MDS, there has been an interest in exploring PCL-2 inhibitors in high-risk MDS. And indeed, this was done in a number of trials. One of them I have led in the lab's refractory setting

8:55where we added Benetoclax to azacitidine. And we show that patients achieved responses and transfusion independence. And in the front line, we have seen good activity. But once we have gone to the randomized phase 3 trial, which is called Verona, this trial randomized patients to receive azacitidine with Benetoclax compared to azacitidine with placebo. And it was a large global study of more than 500 patients. Unfortunately, that trial did not achieve its primary endpoint, which was the overall survival.

9:26The overall survival for both groups was around 21 months. And this was a big disappointment because many of us had a lot of hope that the Benetoclax would work. But I think kind of the silver lining of this is that there are other PCL-2 inhibitors that are showing promise in the disease and they are being advanced to subsequent testing, including one of them that was presented in ASCO 2025, which is Mesetoclax. I want to follow up a little bit on some of what you're talking about,

9:57because I know ASCO 2026 featured an oral presentation on Mesetoclax plus azacitidine in AML and MDS. And it was from InnoCare Pharma. And it's a distinction given to less than 9% of submitted abstracts, right? Among 10 efficacy-evaluable treatment-naive HRMDS patients, the majority of whom were high or very high risk by IPSSR. Mesetoclax plus the azacitidine produced 100% objective response rate per IWG 2006 criteria

10:29and a 90% composite CR rate near per IWG 2023 criteria. So in a disease where the standard of care achieves 16% composite CR, how do you interpret those numbers and what do they suggest about where this drug could go in MDS? You are absolutely right. So the data, I think, with Mesetoclax looks quite promising. So just to give a quick background. So Mesetoclax is an oral novel PCL2 inhibitor that appears to be more potent than Venetoclax.

11:01And the drug is actually being tested in a large global trial that is being conducted in China and being expanded to include other countries, including the U.S. We are actually opening this trial at Yale University. And the Mesetoclax basically have several advantages in the way it was designed so that it can overcome some of the issues that were seen with Venetoclax. For example, the metabolites that result from Venetoclax can stay around in the circulation and can induce prolonged myelosuppression.

11:33And this issue seems minimized with Mesetoclax so it does not have the same issue with these metabolites that will stick around and cause significant myelosuppression. Also, the drug seems to have a better pharmacokinetic profile where it does not seem to be affected as much by food or other drug-drug interactions, which is a very important issue in management of myeloid malignancies because we often use antifungals and other medications that can require adjustment with Venetoclax. So there are a number of advantages that Mesetoclax has, which we were excited about.

12:08And once, indeed, once the drug entered clinical testing, we are already seeing promising results. You highlighted the CR rate. Of course, you know, this is still relatively a small number of patients and an early cutoff of data. But I think even within the small number of patients who see such a high complete response rate, which comparatively is much higher than what you would expect with is a by itself or even is a Venetoclax from what was seen in Verona. So I think if these numbers continue to trend in the same direction,

12:40this would be, I think, very positive in use about the efficacy of the drug. And we certainly look forward to seeing additional data and longer follow-up of this trial. Now, that's definitely really promising. I kind of want to follow up a little bit on some of what you're talking about. So if Venetoclax already works name out, right, and it does, what is the scientific argument for Mesetoclax? Like when you look at its pharmacological profile, the BCL-2 potency, the three times PK exposure advantage, the strict BCL-XL selectivity, the absence of azole DDI risk, you know,

13:13what specific clinical problems does that profile then address that Venetoclax has not actually solved? Yeah, and I think all of what you mentioned is on target because I think these advantages leads to a more potent inhibition, but at the same time, more target selectivity and avoiding the early toxicity. As I mentioned, one of the problems that we have in drug development with MDS, in high-risk MDS, is drugs that cause early toxicity and early discontinuation and early risk of infection. So beyond the efficacy data that was presented in ASH, the safety profile, the time-to-count recovery

13:49among those patients who were treated with Mesetoclax looks good. So if this data continues to be in the same direction, I think this would be very promising that those kind of preclinical advantages that were seen with the drug are actually translating into real clinical benefit for the patients. These are really great developments in this space. I mean, this is some really encouraging information for something that has been really difficult, especially over the past few years. But I'd love to hear you talk a little bit more about how does Mesetoclax compare to Venetoclax

14:19in AML, considering a CCR rate of more than 80 percent and MRD negative rate of more than 80 percent for Mesetoclax. Yeah, the abstract that was presented in ASCO 2026 looks at both high-risk MDS as well as acute myeloid leukemia, and it does include patients in the frontline and the transfusion and, sorry, and the refractory lab setting. And actually, the most kind of advanced data and the highest number of patients were included in the frontline treatment-naive acute myeloid leukemia patients, where more than 40 patients

14:52were treated in that setting. And the data, similar to what we just discussed with high-risk MDS, looked actually quite good. The complete response rate was much higher, more than 70 percent, compared to what was seen with Isavin in Vialli A, which was around 37 percent. And as I mentioned, I think what was quite interesting is the safety profile with this drug in terms of the risk of infections, early death, tumor lysis syndrome. All of these things that are a concern with Venetoclax seem to be much less of an issue with Mesetoclax.

15:26So it does seem, based on the data so far, that the profile of the drug is translating into improved efficacy as well as better safety profile. Of course, we have to see the randomized data, and I believe the sponsor has announced that they are embarking on the randomized registrational studies in acute myeloid leukemia. Yeah, it'd be really interesting to see that data as it comes out. I want to follow up for relapsed refractory AML, right, and specifically for this growing population

15:56who have progressed on Venetoclax-based therapy. What did the Mesetoclax show, right? And is it biologically plausible that a BCL2 inhibitor can generate meaningful responses in patients who have already become resisted to another BCL2 inhibitor? Yeah, and again, I think this is a very important point because BCL2 inhibitor resistance or refractory disease and relapsed disease after Venetoclax-based therapy is actually a very challenging clinical scenario where the median survival has been shown in the range

16:28of a few months, like around four months. So this has been an area where we really needed drugs. And again, although the number of patients who are included in the relapsed refractory setting was somewhat small, the data looks encouraging, including among patients who have received prior Venetoclax. We are seeing responses in terms of the clinical activity and the safety profile looks good. So I think we generally always love to see activity in the relapsed refractory setting. But in my view, the best setting to develop these drugs is always in the frontline setting

16:59because this is where you attack the disease in a way that leads to the longest duration. So I believe while the drug is certainly active in the relapsed refractory setting, I think the kind of the most significant advancement is going to be in the frontline setting, both in AML as well as in at-risk MDS. No, that's a great point. And you had mentioned kind of the safety. So I want to follow up on that. The safety is the practical filter for drug adoption in elderly AML and MDS patients, right? So on this phase one study of 78 patients, you know, there was no dose limiting toxicities.

17:32Maximum tolerated dose was never reached. And critically, you know, zero deaths within 30 or 60 days in the newly diagnosed AML population. There was also a very short duration of grade 4 cytopenia, just 10 days of grade 4 neutropenia and six days of grade 4 thrombocytopenia. In the meantime, there is a much lower incidence of cytopenia during post-remission. You know, what drives that profile? What does it mean clinically for how this drug would fit into practice compared with the venetococlx?

18:02Yeah, and I think you summarized the safety data very well. One of the things to remember with venetococlx, for example, in Vialli A study is that early mortality, which is generally defined as 30 to 60-day mortality in those patients, around 7%. So around 1 in 10 patients who die from generally complications related to myelosuppression and infection. So here we have an early data cutoff of more than 40 patients and there were no early deaths. There were no tumor lysis syndrome and myelosuppression was generally not a big issue.

18:34Most patients achieved count recovery within a reasonable time frame. So all of these translate into patients being able to tolerate the drug better and to stay on the drug better. And if these data continue to kind of hold true in a randomized setting, I think they could potentially signal an advantage over venetococlx. It's very exciting and, you know, I just kind of want to close out, like, as you step back from all this data, right?

Future of AML and MDS Treatment

18:59What do you think that this may ultimately mean for the future treatment of patients with AML and MDS, and especially in the high-risk cases? Yeah, so in AML, we have seen the approval of more than 14 drugs since the year 2017 for AML. Still, the outcomes, especially in older patients who cannot tolerate intensive chemo, continue to be not great. The median survival is this 10-2 years. Most patients will relapse and eventually die from AML. So there's certainly a clear need for better drugs.

19:30And there are also other logistical factors, such as drugs that don't interact with food as much, that drugs that don't interact with other medications that these patients often take, because these can become like a headache. You know, the patients get drugs from their cardiologist, from their primary care, etc. So trying to manage all these drug interactions logistically can become a problem. So I think having a better in-class PCL2 inhibitors that are more effective, that are safer, and have less drug effect and less drug interactions,

20:02all of these, I think, could be important points. Now, in high-risk MDS, we have been in a therapeutic desert, basically. There was no drugs really in high-risk MDS, and we are looking for drugs that are active. And the early data from the high-risk MDS treatment-naive patients looks really promising. So I am hopeful that these data will continue to be as robust as they are in terms of the efficacy and the safety. And hopefully, we can work with the sponsor towards the registrational pathway for this drug in high-risk MDS.

20:34And hopefully, this will translate into better benefits for our patients. It's really promising that we're getting some movement in an area that there hasn't been much development in over the past, as you mentioned, I think 10 years. So this has been a fantastic, exciting conversation. I am really looking forward to see where this goes. When we talk next year, hopefully, about where all of this has come and where the date is. But I really want to thank you, Dr. Zaidan, for such a great conversation and taking the time to speak with us today. And thanks to all of you for joining us on this episode of The Top Line.

21:04I'm your host, Stephanie Butler. And that is the bottom line from The Top Line. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler. I'm your host, Stephanie Butler.

21:35I'm your host, Stephanie Butler.