ASH 2024 | A Phase Ib study of PRT503, a PRMT5 inhibitor, in R/R splicing factor-mutated myeloid malignancies

So this was a Phase Ib escalation dose expansion study of PRT503, which is a PRMT5 inhibitor in patients with relapsed/refractory myeloid malignancies. So the background is that PRMT5 is an enzyme that’s really important to regulate normal splicing. And as you probably know, splicing factor mutations are very common in patients with myeloid malignancies, especially myelodysplastic syndrome, but also enriched in patients with secondary AML. So patients who had a prior MDS and then progressed to AML. And with currently available therapies, including intensive chemotherapy, as well as venetoclax-based combination therapies, outcomes are still not as good as we hoped they would be. Especially in a relapsed/refractory setting, there’s no established standard of care for those patients. So we then conducted a, so there was a dose escalation study that was done previously and previously presented, I think like two or three years ago at ASH of this compound. And that trial included a cohort of patients with MDS as well as myelofibrosis. And interestingly, the best responses were seen in patients with splicing factor mutations. And that then led to a dose expansion phase dedicated to patients with myeloid malignancies, MDS, AML, as well as MDS-MPN overlap, who had a splicing factor mutation. And in this trial that involved a total of 42 patients, 35 of MDS and MDS-MPN overlap, as well as 7 AML patients, we could show that one, the PRT503 is safe in patients with these conditions and that toxicity was mostly limited to hematologic adverse events as well as low-grade nausea and diarrhea. And we did see an efficacy signal, especially in patients with SRSF2 mutations, which included a CR with incomplete hematologic recovery in a patient with AML as well as several patients with hematologic improvement in the MDS cohort. So that’s encouraging in a setting where there’s really no established standard of care. And we’ll see. The qualitative studies are still in process and hopefully we’lll learn something from those, why patients with SRSF2 mutations seem to be responding better. And so the presentation at this year’s ASH really shows the clinical data as well as some qualitative studies. And hopefully this provides some proof of concept that targeting PRMT5 can be a therapeutic strategy in this context.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.