ASH 2024 | Findings from a Phase I/II trial of nuvisertib in the treatment of R/R myelofibrosis

Nuvisertib or TP-3654 is a novel PIM1 kinase inhibitor that has been tested in relapsed/refractory patients with myelofibrosis. This is a Phase I/Phase II ongoing study. We’re very excited to present this data as it is the third year in a row that this data has been accepted as an oral presentation. Up to this date, we have enrolled 74 patients on the dose escalation. And currently, we are enrolling patients in the 720 milligram BID dose, which is expected to be the RP2D. We presented 18 evaluable patients on that dose level. And the patients have shown a significant spleen volume reduction and much more impressively they have shown significant improvement in their symptom score reduction. In addition, those symptom reductions happened early on in the treatment as soon as four weeks and they were sustained. Another very important characteristic of this study is that it enrolls patients with myelofibrosis with a platelet count as low as 25,000, which is very different than many other studies that are enrolling right now, other drugs in development for patients with myelofibrosis. What is very particular about this drug, the PIM1 kinase inhibitor, nuvisertib, is that it is not associated with significant cytopenias and in some instances actually can improve cytopenias in patients, such as improving hemoglobin and improving platelet count. So far we have tested many of those levels and there has been no DLT. And the most common side effects of this drug are GI toxicity such as nausea, vomiting and diarrhea. However, most of these side effects were grade 1 and grade 2. We had less than 4% grade 3 GI side effects and most of these side effects were transient. and they happened early on in the trial and then they subsided soon after that. Many of the patients have been on the study for more than a year. Actually one of my patients went and got stem cell transplantation and she’s now a year and a half post-stem cell transplant doing very well. We are excited about this new therapy because it’s a novel mechanism of action and currently we are enrolling on additional arms. So there’s the monotherapy arm, there’s a second arm that is enrolling patients with ruxolitinib in addition to ruxolitinib, and the third arm enrolling patients in addition with momelotinib. And why we’re excited? Because in mouse model, a combination of a PIM1 kinase inhibitor and JAK inhibitor has shown synergy in spleen volume reduction and improvement in bone marrow fibrosis, as well as improvement in count. So nuvisertib or TP-3654 seems to be a great partner for other JAK inhibitors, especially that it could potentially prevent cytopenias in that patient population.

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