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Fierce Interviews Professor Amer Zeidan of Yale School of Medicine: Mesutoclax Poised to Reshape Treatment Landscape for High-Risk MDS and AML

Global biopharmaceutical authority Fierce recently conducted an exclusive in-depth interview with Professor Amer Zeidan of Yale School of Medicine, a leading expert in hematologic malignancies, providing a comprehensive analysis of a groundbreaking oral presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. The presentation highlighted breakthrough clinical data on mesutoclax, a novel BCL2 inhibitor, in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and its potential impact on the therapeutic landscape for myeloid malignancies.

Data showed that among evaluable treatment-naïve high-risk MDS patients, the regimen achieved a 100% overall response rate (ORR) and a 90% composite complete remission rate (composite CR). In treatment-naïve AML patients, it achieved an 82% composite CR rate and an 86.7% minimal residual disease negativity rate, demonstrating strong efficacy even in TP53-mutated patients, with a safety profile superior to current standard therapies. In this exclusive interview, Professor Zeidan drew upon his extensive clinical experience and industry insights to deeply analyze the long-standing unmet medical needs in high-risk MDS/AML, elucidate the core advantages of mesutoclax over existing BCL2 inhibitors, and outline future development pathways and clinical application prospects.

Dr. Zeidan is currently Professor of Internal Medicine at Yale School of Medicine, Director of the Hematologic Malignancies Program, Associate Director of the Hematology Clinical Trials Office at Yale Cancer Center, Director of Early Therapeutics in Hematology, and leads the Leukemia and Myeloid Malignancies Clinical Research Team within the Department of Medical Oncology and Hematology. With decades of dedication to clinical and translational research in hematologic malignancies, he is globally recognized as a leading authority in the field.

Below is the full transcript of the interview:

I. Unmet Medical Needs in High-Risk MDS

Fierce:

Your career has been dedicated to tackling some of the most challenging hematologic malignancies. Today, let’s start with a frequently overlooked disease—MDS, particularly high-risk MDS—and then move on to another aggressive myeloid malignancy, AML. You also chaired the oral abstract session on myeloid malignancies and transplantation at this year’s ASCO Annual Meeting. Could you begin by sharing your perspective on the current landscape of high-risk MDS and the unmet medical needs in this field?

Zeidan:

High-risk MDS remains a major challenge for us to this day. It is a common myeloid malignancy, with an incidence in the United States of approximately 4 cases per 100,000 people, resulting in roughly 20,000 new diagnoses annually. We typically categorize it into low-risk and high-risk groups, with the latter exhibiting a highly aggressive disease course.

Without treatment, their median survival is less than one year, so altering the disease trajectory and extending survival has always been our top priority. Currently,allogeneic stem cell transplantation is the only potentially curative approach for high-risk MDS. However, the median age at diagnosis for high-risk MDS is around 75 years, and most patients have comorbidities, meaning only a very small proportion are eligible for transplantation.

Therefore, we primarily rely on pharmacological therapies to manage these patients. Unfortunately, however, drug development for high-risk MDS has progressed very slowly, and we still largely depend onhypomethylating agents—available in both intravenous and oral formulations—which can extend survival by only about 6 to 9 months and do not offer a cure.

II. Azacitidine as the Long-Standing Standard of Care and Reasons for Treatment Failure

Fierce:

This is indeed very challenging, especially amid stalled progress in drug therapy development. We know that azacitidine has been the standard of care for high-risk MDS for over a decade, yet its composite complete response rate remains around 16%, and median patient survival is still measured in months. Why has this field failed to produce an innovative therapy surpassing azacitidine over so many years? What are the specific reasons behind treatment failure that prevent most patients from achieving durable remissions?

Zeidan:

This is a question our entire industry has been deeply reflecting on over the past few years. The issue lies in the fact that we placed high hopes on multiple Phase III clinical trials, but they all ultimately failed—none of the new drugs gained approval. Of course, there were some common problems across these unsuccessful trials.

I believe the most prominent issue is that some drugs appeared promising in early-phase Phase I and II clinical trials, but came with significant early-onset toxicity. When these agents advanced to larger Phase III trials, these toxicities became even more pronounced. Therefore, we now place strong emphasis on drug safety to ensure elderly patients can take these medications long-term without encountering severe complications.

Another challenging issue isthe high prevalence of TP53 mutations. Patients harboring TP53 mutations have highly aggressive disease, high early mortality, and poor responses to most treatment regimens. Thus, we have been actively seeking effective therapies specifically for this critical patient subgroup.

III. Patient Population After Azacitidine Failure and Unmet Therapeutic Needs

Fierce:

There is indeed a significant unmet medical need in this area, and prior drug development efforts have not been successful. A therapy achieving a 90% composite complete remission rate would carry enormous commercial value. This leads directly to the most commercially significant treatment gap in myeloid malignancies—Currently, there is no therapy approved by the U.S. FDA for high-risk MDS patients who have failed azacitidine treatment. How large is this patient population? What is their current survival outlook? And why has this regulatory gap persisted for so long?

Zeidan:

You’ve raised several critical questions. First, as I mentioned earlier, approximately 20% of treatment-naïve patients are considered high-risk due to TP53 mutations. However, another major unmet clinical need in MDS management involvespatients with relapsed/refractory MDS. As you noted, once azacitidine or decitabine therapy fails, these patients have a median survival of less than six months.

Historically, a key challenge has been that these patients are often too frail to complete clinical trials, causing many investigational agents to fail to demonstrate clear benefit. Currently, in the relapsed/refractory high-risk MDS space, we have only one approved drug—ivosidenib, an IDH1 inhibitor—but it is applicable to fewer than 5% of patients who harbor IDH1 mutations. For the remaining 95% of patients, there are no effective treatment options, making this an area of urgent need for novel, safe, and effective therapies.

IV. Biological Rationale for BCL2 Inhibitors in Myelodysplastic Syndromes

Fierce:

Next, let’s discuss the application of BCL2 inhibitors in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). If you’re familiar with venetoclax in the AML space, you might wonder: why would BCL2 inhibitors be effective in MDS? Could you explain the BCL2 biological mechanism in high-risk MDS? What makes these tumor cells dependent on the BCL2 survival signaling pathway? And why do you consider BCL2 inhibition a scientifically sound therapeutic strategy for this disease?

Zeidan:

BCL2 inhibition has become an important strategy in AML treatment, with venetoclax being the first approved drug in this class. It is an oral BCL2 inhibitor that works by inducing apoptosis in leukemia cells. In AML, venetoclax is typically used in combination with agents such as azacitidine.

In fact, the combination of venetoclax and azacitidine has been shown to extend survival in older patients with AML. The pivotal VIALE-A clinical trial demonstrated a median overall survival of 15 months in the combination group, compared to just 9 months in the azacitidine-alone group. Given the success of BCL2 inhibitors in AML and the biological similarities between high-risk MDS and AML, researchers began exploring their use in high-risk MDS.

Multiple clinical trials have investigated this approach. I personally led a trial in patients with relapsed or refractory disease, which showed that the combination of venetoclax and azacitidine could induce remission and achieve transfusion independence. Promising efficacy was also observed in treatment-naïve patients. However, when we moved into the randomized Phase III VERONA trial—enrolling more than 500 patients randomized to receive either azacitidine plus venetoclax or azacitidine plus placebo—the study unfortunately did not meet its primary endpoint of overall survival, with both groups showing a median survival of approximately 21 months.

This outcome was disappointing for many, as we had high hopes for venetoclax. However, it is encouraging that other BCL2 inhibitors are showing strong promise in this disease and are advancing in clinical development, including mesutoclax, which will be presented at the 2026 ASCO Annual Meeting.

V. Interpretation of Breakthrough Data for Mesutoclax in High-Risk MDS Treatment

Fierce:

We understand that the 2026 ASCO Annual Meeting will feature an oral presentation on mesutoclax combined with azacitidine for the treatment of AML and MDS. Oral presentations are among the highest academic honors awarded at ASCO, granted to fewer than 9% of all submitted studies each year. Among evaluable, treatment-naïve patients with high-risk MDS—most of whom had IPSS-R high or very high risk—mesutoclax plus azacitidine achieved, according to IWG 2006 criteria,100% overall response rate (ORR), with a 90% composite complete remission rate (composite CR). In a disease where standard therapy achieves only a 16% composite complete remission rate, how do you interpret these data? What do they suggest about the future development trajectory of this drug in the MDS space?

Zeidan:

Absolutely correct—the data for mesutoclax appear highly promising. Let me briefly introduce this agent: mesutoclax is a novel oral BCL-2 inhibitor with greater in vitro potency than venetoclax. Currently, a large global clinical trial is underway, expanding to include other countries and regions such as the United States, and we at Yale University have also launched this trial.

Mesutoclax was designed with multiple advantages that address certain limitations of venetoclax. For example, venetoclax produces metabolites that circulate in the body for an extended period, leading to prolonged myelosuppression, whereas mesutoclax significantly mitigates this issue and does not generate long-acting metabolites that cause severe myelosuppression.

Moreover, mesutoclax has superior pharmacokinetic properties and is less affected by food or drug–drug interactions. This is critically important in the treatment of myeloid malignancies, where we frequently need to use antifungal agents—drugs that interact with venetoclax and necessitate dose adjustments. It is precisely these advantages that make us highly optimistic about mesutoclax, and indeed, it has already demonstrated encouraging results since entering clinical trials.

You just mentioned the response rate data. Of course, the current number of patients remains small, and the data are still early. However, even within this limited cohort, we are observing such high rates of complete remission—far exceeding those achieved with azacitidine alone and even surpassing the efficacy seen in the VERONA trial with azacitidine plus venetoclax. If these findings are validated in larger-scale studies, they would provide strong evidence of the drug’s efficacy. We are eagerly awaiting more data and long-term follow-up results from this trial.

VI. Pharmacological Advantages and Clinical Value of Mesutoclax Compared to Venetoclax

Fierce:

This is indeed very encouraging. Given that venetoclax has already demonstrated efficacy in AML, where does mesutoclax’s scientific advantage lie? From a pharmacological standpoint—its stronger BCL-2 inhibitory potency, three-fold higher pharmacokinetic exposure, strict selectivity for BCL-XL, and absence of azole-related drug interaction risks—what specific clinical challenges unmet by venetoclax do these features address?

Zeidan:

All the points you mentioned are highly accurate. These advantages not only deliver more potent inhibition but also enhance target selectivity and reduce early toxicity. As I noted earlier, in drug development for MDS—particularly high-risk MDS—compounds that cause early toxicity, lead to premature treatment discontinuation, or increase early infection risk often struggle to succeed.

Beyond the efficacy data presented at the ASCO annual meeting, mesutoclax also showed an excellent safety profile, with treated patients experiencing shorter recovery times for blood cell counts. If these results hold up consistently, they will demonstrate that the advantages observed in preclinical studies can truly translate into meaningful clinical benefits for patients.

VII. Efficacy of Mesutoclax in AML

Fierce:

This represents a truly exciting advancement in the field. For a disease that has seen little progress over the past few years, this news is genuinely uplifting. Could you elaborate further on mesutoclax’s performance in AML—specifically, its composite complete remission rate exceeding 80% and its MRD-negative rate also surpassing 80%? How does this compare with venetoclax?

Zeidan:

The abstract presented at the 2026 ASCO Annual Meeting covered both high-risk MDS and AML, including treatment-naïve as well as relapsed/refractory patients. Among these,The data for treatment-naïve AML patients are the most mature, with the largest number of enrolled patients—over 40 cases.。

Similar to the high-risk MDS data we just discussed, the results in AML are also very impressive, with a complete remission rate exceeding 70%, far higher than the 37% observed with azacitidine plus venetoclax in the VIALE-A trial. Moreover, and even more noteworthy, the safety profile of the mesutoclax regimen shows significantly lower rates of concerning adverse events commonly associated with venetoclax-based therapy—such as infections, early mortality, and tumor lysis syndrome.

Thus, based on the current data, mesutoclax not only translates into superior efficacy but also offers an improved safety profile. Of course, we still need to await data from randomized controlled trials. It is understood that a randomized registrational study of mesutoclax in AML is about to commence.

8. Efficacy of Mesutoclax in Relapsed/Refractory AML

Fierce:

We are very much looking forward to the release of these data. I’d like to follow up with a question about relapsed/refractory AML, particularly in the patient population whose disease has progressed after venetoclax-based therapy—a group that continues to grow. What efficacy has mesutoclax demonstrated in these patients? From a biological perspective, is it plausible for one BCL-2 inhibitor to achieve meaningful responses in patients who have developed resistance to another BCL-2 inhibitor?

Zeidan:

That’s another critically important question. Resistance or relapse after venetoclax-based therapy in AML represents a major clinical challenge today, with a median overall survival of only about four months in these patients. Therefore, there is an urgent need for novel therapeutic options in this setting.

Although the number of enrolled patients with relapsed/refractory AML remains relatively small, the data show encouraging efficacy, including responses observed even in patients previously treated with venetoclax, along with a favorable safety profile.

I’ve always believed that although observing drug efficacy in the relapsed/refractory setting is promising, The optimal time to develop this class of drugs has always been in first-line treatment—because intervening early in the disease course yields the longest duration of remission. Therefore, although mesutoclax does demonstrate efficacy in the relapsed/refractory setting, I believe its most significant breakthrough will come in first-line treatment, whether for AML or high-risk MDS.

Nine: Safety Profile of Mesutoclax and Its Clinical Implications

Fierce:

You just mentioned safety, and I’d like to delve deeper into this topic. For elderly patients with AML and MDS, safety is a critical factor determining whether a drug can be widely adopted in clinical practice. In this Phase I study,no dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. More importantly,in treatment-naïve AML patients, both the 30-day and 60-day mortality rates were zero。

. Additionally, the duration of grade 4 cytopenias was very short: grade 4 neutropenia lasted only 10 days, and grade 4 thrombocytopenia lasted only 6 days. Moreover, the incidence of cytopenias during post-remission therapy was also significantly reduced. What accounts for this excellent safety profile? Compared with venetoclax, how might this drug be integrated into current clinical practice?

Zeidan:

Your summary of the safety data is very accurate. We need to remember that in the VIALE-A trial, the early mortality rate (typically defined as 30- to 60-day mortality) with venetoclax was approximately 7%, meaning roughly 1 in every 10 patients died due to complications related to myelosuppression and infection. In contrast, in early data from over 40 treatment-naïve AML patients treated with mesutoclax, there were no early deaths, no cases of tumor lysis syndrome, and myelosuppression was not a major issue.

Most patients were able to achieve blood count recovery within a reasonable timeframe. All of this suggests that patients can better tolerate the drug and adhere to the full course of treatment. If these findings are confirmed in randomized controlled trials, they would indicate a potential advantage of mesutoclax over venetoclax.

10. The Impact of Mesutoclax on the Future Treatment Landscape for AML and MDS

Fierce:

This is truly exciting. Finally, I’d like to ask you to take a step back and view this from an industry-wide perspective: how do you envision these data ultimately reshaping the future treatment of AML and MDS patients, especially those at high risk?

Zeidan:

In the AML space, more than 14 drugs have been approved since 2017. Yet despite this progress, outcomes remain suboptimal—particularly for older patients who cannot tolerate intensive chemotherapy—with median survival under two years, and most patients eventually relapsing and succumbing to the disease. Clearly, we need better therapies.

Moreover, there are practical clinical challenges to address, such as drug–food interactions and interactions with other commonly used medications—issues that are particularly cumbersome in real-world practice. Patients may be taking multiple drugs prescribed by cardiologists or primary care physicians, and managing all these drug interactions can become a significant burden. Therefore, a best-in-class BCL-2 inhibitor that is more effective, safer, and has fewer drug interactions would hold substantial clinical value.

And in high-risk MDS, one could say we have long been in atherapeutic desertStatus: For a long time, there have been almost no new drugs launched. We have been searching for effective therapeutic agents, and the early data for mesutoclax in treatment-naïve high-risk MDS patients looks very promising.

I hope these data continue to demonstrate robust efficacy and safety, and that we can establish a new pathway for this drug in the treatment of high-risk MDS, ultimately delivering better therapeutic benefits to our patients.

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