SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis

This study evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared to ruxolitinib in JAKi-naïve patients with myelofibrosis.

A total of 432 patients with high-risk, intermediate-2 risk, or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive either momelotinib (200 mg once daily) or ruxolitinib (20 mg twice daily or per label) for 24 weeks. After this period, all patients could transition to open-label momelotinib. The primary endpoint was achieving a ≥ 35% reduction in spleen volume at 24 weeks. Secondary endpoints included symptom response rates and the impact on red blood cell (RBC) transfusion requirements.

The results showed that 26.5% of patients in the momelotinib group and 29% in the ruxolitinib group achieved a ≥ 35% reduction in spleen volume at 24 weeks, meeting the criteria for noninferiority (P = .011). However, a ≥ 50% reduction in total symptom score was observed in 28.4% of momelotinib-treated patients and 42.2% of ruxolitinib-treated patients, failing to meet the noninferiority threshold (P = .98).

Momelotinib demonstrated advantages in transfusion-related outcomes, with significant improvements in transfusion rates, transfusion independence, and transfusion dependence (all nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in both groups were thrombocytopenia and anemia. Grade ≥ 3 infections were observed in 7% of momelotinib-treated patients and 3% of ruxolitinib-treated patients. Peripheral neuropathy occurred in 10% of momelotinib-treated patients (all grade ≤ 2) and 5% of ruxolitinib-treated patients (all grade ≤ 3).

In conclusion, momelotinib was noninferior to ruxolitinib in terms of spleen volume reduction but did not achieve noninferiority for symptom improvement. However, momelotinib was associated with a reduced need for RBC transfusions, suggesting potential benefits in managing transfusion-dependent myelofibrosis patients.