Data shows momelotinib benefits anemia, reduces transfusion burden in myelofibrosis

Post hoc analysis of the single-arm Phase 2 (NCT02515630) and Phase 3 studies of SIMPLIFY-1 (NCT01969838), SIMPLIFI-2 (NCT02101268), and MOMENTUM (NCT04173494) showed that, Momelotinib is associated with anemia-related benefits in most patients and reduces transfusion burden compared with JAK inhibitor-naïve and MF-experienced patients. Published findings showed that across four trials, more than 77% of patients treated with molotinib had a reduction in red blood cell (RBC) transfusion requirements during treatment compared with baseline.

This[post hoc analysis] demonstrates that in all 3 Phase 3 clinical trials of molotinib in myelofibrosis to date, transfusion intensity remained unchanged or improved from baseline in at least 75% of molotinib-treated patients. These results provide evidence highlighting the sustained anemia benefit of molotinib in the majority of patients. In September 2023, the U.S. Food and Drug Administration (FDA) approved molotinib for the treatment of adult patients with moderate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis and anemia. This regulatory decision is supported by data from a subgroup of patients with anemia treated during MOMENTUM and SIMPLIFY-1.

1. Principle and design of post hoc analysis

Although the transfusion-independent response rate data for MOMENTUM, SIMPLIFY-1, and SIMPLIFI-2 highlight the anemia benefit of molotinib in myelofibrosis, this post hoc analysis was designed to better characterize the relative anemia benefit associated with this drug. As a proof-of-concept, the researchers first assessed time-dependent transfusion burden in patients treated in the phase 2 studies and then used results from the three phase 3 studies for further analyses. They collected data on red blood cell units transfused and transfusion-related hemoglobin (Hb) levels at baseline during the 24-week study period and before starting molotinib. Baseline was defined as 56 days before enrollment in the Phase 2 study and 84 days before enrollment in the Phase 3 trial. Patients in the phase 3 study who received treatment for less than 14 days were excluded from the analysis.

Time-dependent transfusion burden per patient (defined asThe number of red blood cell units administered over 28 days) and mean transfusion intensity at baseline and during treatment were tracked. Patients were also grouped based on red blood cell unit strength at baseline and during treatment; bins included those who received bins. 0 units, more than 0 units and less than 1 unit, more than 1 unit and less than 2 units, more than 2 units and less than 3 units, more than 3 units and less than 4 units, or more than 4 units every 28 days.

Second, PhasePhase 2 results

This open-label, translational biology, Phase 2 study enrolled patients with transfusion-dependent intermediate- and high-risk myelofibrosis, defined as receiving at least 4 units of red blood cells within 8 weeks before the first dose of study treatment. All patients received 200 mg of molotinib once daily for 24 weeks. Transfusion-independent response at week 24 (defined as no red blood cell transfusions during any period of at least 12 weeks during the study) was the primary endpoint.

Post hoc analysis of the phase 2 study showed that patients with known transfusion status (n = 40) were all transfusion-dependent at baseline, whereas in the entire group (n = 41), 88% of patients were unaware of the JAK inhibitor. The average hemoglobin level in this group was 83 g/L, and 71% had hemoglobin levels of at least 80 g/L. At baseline, patients' mean red blood cell transfusion requirement was 3.2 units (range, 1.5-6.0) every 28 days, which decreased to 1.7 units (range, 0-6) during treatment (mean change, 1.5; standard deviation [SD], 1.3).

In addition, 85% of patients experienced a reduction in red blood cell transfusion intensity during treatment compared with baseline. Among patients without transfusions (n=9), 78% were independent responders to transfusions.

SIMPLIFY-1: This Phase 3, double-blind, double-dummy study enrolled patients with JAK inhibitors, including patients with de novo, moderate-1, moderate-2, or high-risk myelofibrosis and palpable splenomegaly at least 5 cm below the left costal margin, who were randomly assigned in a 1:1 ratio to receive either molotinib plus placebo or ruxolitinib plus placebo twice daily. After the 24-week double-blind treatment phase, all patients were eligible to receive open-label molotinib for an additional 216 weeks. Spleen response rate is the primary endpoint of the trial, and transfusion-independent response rate at week 24 is a key secondary endpoint

MOMENTUM: This Phase 3 trial was a double-blind, placebo-controlled study enrolling symptomatic patients with JAK inhibitors experiencing myelofibrosis who were randomized 2:1 to receive molotinib plus placebo or danazol plus placebo. Total symptom score response rate was the trial's primary endpoint, and transfusion-independent response rate was a key secondary endpoint.

SIMPLIFY-2 trial: included myelofibrosis patients with JAK inhibitors who were randomly assigned in a 2:1 ratio to receive molotinib or best available therapy (BAT), with 88.5% of patients taking ruxolitinib. Splenic reaction rate was the primary endpoint, and transfusion-independent reaction rate was a key secondary endpoint.

Reference materials:https://www.onclive.com/view/post-hoc-data-show-anemia-benefits-reduced-transfusion-burden-with-momelotinib-in-myelofibrosis