ASH 2025 | Zilurgisertib with/without ruxolitinib in patients with anemia due to MF: Phase I/II final results

So zilurgisertib is an ALK2 inhibitor, ACVR1/ALK2 from Incyte, small molecule inhibitor, extremely potent for this target. And it was being developed for anemia of myelofibrosis, both alone and in combination with a stable dose of ruxolitinib in those who had been on ruxolitinib but were anemic. And also, actually, there was a frontline arm where you could start, where patients could start with zilurgisertib and ruxolitinib in combination. These are JAK inhibitor naive patients. Really, all the different subgroups of patients that you would typically include in a trial. So either prior JAK inhibitor exposed or like I said they’re on ruxolitinib and they need something for anemia so those patients get it as an add-on and then patients who are JAK inhibitor-naive and are starting with both from the get-go. 

But however this drug even though being extremely potent pre-clinically, did not give us the kind of responses we would have expected it to in the trial. We saw some patients in both the monotherapy and the add-on arms that were able to have hemoglobin improvements, but we didn’t really see transfusion dependence to independence conversion. And at this point, this agent is actually not being developed any further for myelofibrosis anemia. 

But perhaps a takeaway from this is that, you know, there are agents, for example, like momelotinib, which are good for anemia of myelofibrosis and are approved. And we think that that stems from inhibition of ALK2/ACVR1. But this one, given that it was such a potent inhibitor, at least in vitro, of the same target, not having that much efficacy, would make us wonder if, the agents that do have efficacy, perhaps also have additional mechanisms beyond ALK2/ACVR1 inhibition.

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