ASH 2024 | The oral ATR inhibitor ceralasertib in patients with MDS or CMML

At this ASH, we had the opportunity to present an updated report on a trial that we’d been looking at of using an ATR inhibitor called ceralasertib in patients who have had MDS or CMML and progressed on prior therapy. This is the third iteration of this study. We initially enrolled a number of patients both with splicing factor mutant and splicing factor wild type disease. And we looked at the use of ceralasertib in that setting previously, giving it 14 days in a row and then having 14 days off. Our initial hypothesis was that we can use ATR inhibition, which exploits a synthetic lethality vulnerability of splicing factor mutant cells. And so we thought that by giving patients this, we’d be able to selectively put pressure on that splicing factor mutant cell, eliminate that clone and see some improvement in blood counts or blast reduction. Interestingly, we did see a number of responses. Actually, almost a third of patients responded to the treatment, but the responses were different from our expectations. So we saw a blood count improvement, we saw a few people with blast reduction, but many people had a stable mutation burden during their treatment. And so for this last arm of the study, we tried to understand what is it that we are actually doing with ATR inhibition? Somehow we’re achieving responses, particularly blood count responses. Is that dependent on the splicing factor mutation or is there something else going on? And at this year’s ASH, we present an update of the 14 patients who are enrolled to that part three of the study. Another thing that we did was we reduced the dosing. So instead of getting 14 days straight, we had patients get seven on, seven off, seven on, seven off. That resulted in the same amount of response. So we also had about a 30% response rate, but it was much better tolerated. So the need for platelet transfusions was markedly reduced. We think that it probably does cause some pressure on the malignant cells and then allow blood production by giving a little break. We also are in the process of looking at inflammatory markers. I think one of the big stories that continues to be presented in ASH and in MDS is this idea of dysregulated immune function and dysregulated growth factor experience. And so can you get some improvement in that inflammatory cytokines that are kind of contributing to cytopenias? And is that part of why we saw some improvement? Lastly, we tried to explore why our patients were progressing on this therapy. And we are in the process of understanding that, you know, many patients who progressed had a RUNX1 mutation. And at the time of progression, that RUNX1 mutation became a dominant clone. So is there something about RUNX1 biology that interacts with splicing and with ATR inhibition? So that work is ongoing, and hopefully we have an update soon.

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