Heartache for Syndax
Response rates in relapsed NPM1-mutant AML look slightly worse than before, but QTc prolongation could be the real worry.
Response rates in relapsed NPM1-mutant AML look slightly worse than before, but QTc prolongation could be the real worry.
Syndax is due an approval decision soon in one genetic leukaemia subtype, but results in a larger niche have just disappointed investors. The group’s stock closed down 26% on Tuesday following pivotal topline data from the Augment-101 trial of its menin inhibitor revumenib in relapsed/refractory NPM1-mutant AML.
Response rates have waned a little versus the phase 1 portion of the same study, but investors are likely more concerned about side effects, particularly the heart rhythm issue of QTc prolongation, which was seen at high rates. These results leave the door open for Kura’s rival menin inhibitor ziftomenib, whose Komet-001 trial in second-line NPM1m AML is set to read out early next year.
Kura, which has long claimed that ziftomenib has a better safety and tolerability profile, ended the day up 6%.
NPM1m vs KMT2Ar
NPM1 mutations are seen in around 30% of AML patients, while KMT2A-rearranged disease, where revumenib has a December PDUFA date, affects around 10%. Taken together, the addressable market is worth almost $2bn, Syndax has estimated.
The latest results come from the phase 2 portion of Augment-101, which enrolled 84 patients with relapsed/refractory NPM1m AML. The primary efficacy endpoint is complete remission plus CR with partial hematologic recovery (CRh).
Among 64 evaluable patients, the CR/CRh rate was 23%. This has waned slightly since phase 1, when Syndax reported CR/CRh of 27% in NPM1m disease – but only in 11 patients.
Meanwhile, 35% of 20 NPM1m patients receiving a 600mg dose of Kura’s ziftomenib in the phase 1 portion of Komet-001 achieved a CR with full count recovery.
QTc prolongation and differentiation syndrome
Toxicity has always been a worry with menin inhibitors, and Syndax’s latest data drop did nothing to dispel those concerns. QTc prolongation was seen in 21% of patients (19% at grade 3, 2% at grade 4). In the phase 1 portion 13% of patients experienced grade 3 QTc prolongation across the two genetic subtypes.
Differentiation looked in line with earlier updates, with 13% of patients experiencing this side effect (11% at grade 3, 2% at grade 4).
Meanwhile, Kura saw a 20% rate of differentiation syndrome in Komet-001, but only 5% at grade 3, and no cases of drug-induced QTc prolongation.
Kura has abandoned plans for ziftomenib monotherapy in relapsed KMT2Ar disease, but the two companies are also facing off in first-line AML, where combos are the name of the game. Other menin inhibitors include Johnson & Johnson’s bleximenib and Sumitomo’s enzomenib, both of which will feature at the upcoming ASH meeting.
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