Syndax Pharmaceuticals, based in Massachusetts, has made a significant decision to prematurely conclude a pivotal cancer clinical trial, leading to a 9% dip in the biotech company’s stock price. Surprisingly, the negative market response comes on the heels of what initially appeared to be positive news. This paradoxical reaction can be attributed to a shortfall in meeting efficacy expectations and the emergence of safety concerns.
The genesis of this situation can be traced back to Syndax’s release of data from the phase 1 segment of a trial named AUGMENT-101 in late 2022. In that phase 1 clinical trial, Syndax reported an impressive 27% complete remission rate (CR/CRh) in individuals suffering from KMT2A-rearranged acute leukemia. Furthermore, the median duration of complete remissions reached 9.1 months.
Fast forward to the present, and Syndax has unveiled top-line data from a pivotal phase of the same trial, AUGMENT-101. While these results were promising enough to prompt Syndax to halt the KMT2A-rearranged acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) cohorts prematurely, they did not quite meet investor expectations.
In the pooled KMT2A-rearranged AML and ALL cohorts, the CR/CRh rate stood at 23%, marking a four-percentage-point decrease compared to the earlier phase 1 results. Syndax CEO Michael Metzger had previously mentioned a regulatory benchmark of 20%, which was surpassed, but as he acknowledged, others have achieved success rates ranging from 20% to 30%. The median duration of CR/CRh, at 6.4 months, was also slightly shorter than observed in the phase 1 trial. Metzger, however, pointed out that this figure may evolve over time, as a considerable number of patients are still undergoing therapy and remain in remission.
Concerns arose in the safety domain, with findings indicating a deterioration compared to the earlier study. Notably, there were no instances of grade 3 or worse differentiation syndrome (DS) in the phase 1 leukemia cohorts. In the pivotal trial, however, 15% of patients experienced grade 3 DS, while 1% had grade 4 DS. Neil Gallagher, M.D., Ph.D., President and Head of Research and Development, addressed the DS cases, assuring that they are manageable and did not lead to treatment discontinuation. Investigators, too, expressed minimal concern, deeming it an expected and easily manageable occurrence.
Syndax remains optimistic, viewing the interim data as a pathway to regulatory approval. The biotech firm intends to submit its application to the FDA by the end of 2023, putting its candidate, revumenib, on a parallel course with the Incyte-partnered axatilimab for graft-versus-host disease. However, one point of contention is whether revumenib’s efficacy in KMT2A acute leukemias, affecting approximately 6,000 individuals annually, can be indicative of its performance in the more widespread and competitive mNPM1-mutant AML arena. Metzger indicated that it might be reasonable to anticipate similar results, but the landscape is uncertain.
With a 23% CR/CRh rate in mNPM1 AML, revumenib may face tough competition from Kura Oncology, which reported a 30% complete response rate with its drug candidate ziftomenib in AML patients harboring the mutation. Kura initiated a registration-directed study in AML earlier this year.
While the stock of Syndax experienced a 9% premarket decline, trading at $13.21, it’s important to note that the company had predominantly traded above $20 throughout the past year. This development signifies both challenges and opportunities on the horizon for Syndax Pharmaceuticals.