Syndax Pharmaceuticals has stopped a pivotal cancer clinical trial early for efficacy—which sent the biotech’s share price down 9%. The negative reaction to superficially positive news reflects the failure to live up to efficacy expectations and the emergence of a safety concern.
Massachusetts-based Syndax helped set investor expectations for its inhibitor of the menin-KMT2A interaction, revumenib, when it shared data from the phase 1 portion of a trial called AUGMENT-101 late last year. The phase 1 clinical trial reported a 27% complete remission rate (CR/CRh) in people with KMT2A-rearranged acute leukemia. The median duration of complete remissions was 9.1 months.
Now, Syndax has reported top-line data from a pivotal portion of AUGMENT-101. The results were good enough for Syndax to stop the KMT2A-rearranged acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) cohorts early but not good enough to satisfy investors.
The CR/CRh rate in the pooled KMT2Ar AML and ALL cohorts was 23%, down four percentage points on the earlier readout. The pivotal figure is above the 20% that Syndax CEO Michael Metzger identified as the regulatory bar on a conference call with investors in August. But, as Metzger said, “people have done better than that, somewhere between 20% and 30%.”
The median duration of CR/CRh, 6.4 months, was shorter than in the phase 1 trial too. There is scope for the figure to change, though, as Metzger explained on a call with investors to discuss the pivotal data.
“6.4 months includes about half of the patients still on therapy and in remission, so we do think it’s a bit early days,” the CEO said. “There are several patients still continuing on and we expect that to elongate over time.”
The safety results featured a finding that was worse than in the earlier study. Nobody had grade 3 or worse differentiation syndrome (DS) in the phase 1 leukemia cohorts. In the pivotal portion of the trial, 15% of patients had grade 3 and 1% had grade 4 DS. Neil Gallagher, M.D., Ph.D., president, head of research and development, addressed the DS cases on the call to discuss the pivotal data.
“Overall, it’s manageable. No patients actually discontinued as a result of differentiation syndrome. As we’ve discussed the data with investigators, they’re pretty nonplussed by it. For them, it’s expected, it’s easily managed,” Gallagher said.
Syndax sees the interim data providing a path to approval. The biotech aims to file for approval from the FDA by the end of 2023, putting revumenib on a parallel track to the Incyte-partnered graft-versus-host disease candidate axatilimab.
One concern for revumenib is that the efficacy in KMT2A acute leukemias, which affect around 6,000 people a year, is a pointer to how the candidate may fare in the more prevalent and competitive mNPM1-mutant AML space. Asked in August whether analysts should use the KMT2A as a proxy for the upcoming mNPM1 readout, Metzger said “it’s reasonable to think that [the results] would be roughly the same.”
A 23% CR/CRh rate in mNPM1 may be uncompetitive against Kura Oncology, which linked its rival drug candidate ziftomenib to a 30% complete response rate in AML patients with the mutation. Kura started a registration-directed study in AML early this year.
Shares in Syndax fell 9% to $13.21 in premarket trading. The stock has traded above $20 for most of the past year.