MOMENTUM Clinical Trial

Building MOMENTUM for Patients with Myelofibrosis

The MOMENTUM Clinical Trial is a randomized, double-blind, Phase 3 trial to evaluate the activity of momelotinib versus danazol in symptomatic, anemic subjects with myelofibrosis (MF). The target enrollment for this clinical trial is 180 patients globally.

Evaluating the Investigational Drug Momelotinib

Momelotinib is an orally-bioavailable inhibitor of Janus kinase1 (JAK1), Janus kinase2 (JAK2), and Activin A receptor, type I (ACVR1) with a differentiated therapeutic profile in myelofibrosis. Data from more than 820 clinical trial subjects suggest that momelotinib can markedly improve constitutional symptoms and splenomegaly while also substantially addressing the chronic anemia and transfusion dependency associated with the disease.

Myelofibrosis Biology: JAK1, JAK2 & ACVR1 Drive MF Disease Hallmarks

Momelotinib’s unique ability to alleviate anemia and reduce or eliminate transfusion dependency contrasts with other JAK inhibitors which have high rates of hematological toxicity and can worsen cytopenias. This anemia benefit is achieved through direct inhibition of ACVR1 leading to a decrease in circulating hepcidin. Hepcidin is often markedly elevated in myelofibrosis and contributes to an iron restricted anemia. By lowering hepcidin, a corresponding increase in serum iron occurs with consequent clinically relevant increases in hemoglobin and red blood cells due to increased iron availability for erythropoiesis. Momelotinib has also been shown to stabilize, and in some cases ameliorate, thrombocytopenia.

Myelofibrosis Anemia: Reducing Hepcidin Restores Red Blood Cell Production

In addition to this differentiated anemia benefit, momelotinib therapy elicits significant improvements in constitutional symptoms and splenomegaly, by variously decreasing aberrant inflammatory cytokine signaling, mutant hematopoietic stem cell proliferation and RBC sequestration, consistent with potent inhibition of JAK1, JAK2 and the downstream JAK-STAT pathway.

In contrast to other JAK inhibitors, very low rates of thrombocytopenia and other hematological toxicities, also allow maximal momelotinib dose intensity to be sustained during chronic therapy, further supporting the compound’s unique potential for benefit in MF.

Myelofibrosis Biology: Momelotinib Uniquely Inhibits All Three Disease Drivers

 MOMENTUM Trial Overview

MOMENTUM is a randomized, double-blind, active control trial intended to confirm the differentiated clinical benefits of momelotinib versus danazol in subjects who have previously received an approved JAK inhibitor therapy for MF, including either ruxolitinib or fedratinib. Subjects must be symptomatic with a Myelofibrosis Symptom Assessment Form v4.0 (MFSAF) Total Symptom Score (TSS) of ≥ 10 at screening, and be anemic with hemoglobin (Hgb) < 10 g/dL.

For subjects with ongoing JAK inhibitor therapy at screening, JAK inhibitor therapy must be tapered over a period of at least 1 week, followed by a 2-week non-treatment washout interval that concludes prior to randomization.

Subjects will be randomized 2:1 to orally self-administer blinded treatment, momelotinib plus placebo or danazol plus placebo. Subjects randomized to receive momelotinib who complete the randomized treatment period to the end of Week 24 may continue to receive momelotinib in the open-label extended treatment period to the end of Week 204 (a total period of treatment of approximately 4 years).

Subjects randomized to receive danazol may cross-over to momelotinib open-label treatment in the following circumstances:

  • at the end of Week 24 if they complete the randomized treatment period; or
  • at the end of Week 24 if they discontinue treatment with danazol but continue trial assessments and do not receive prohibited medications including alternative active anti-MF therapy; or
  • at any time during the randomized treatment period if they meet the protocol-defined criteria for radiographically-confirmed symptomatic splenic progression.

Trial Objectives:

Primary Endpoint:

  • To determine the efficacy of momelotinib versus danazol assessed by improvement in MFSAF TSS in subjects with primary myelofibrosis (PMF), post-PV myelofibrosis (MF), or post-ET MF who were previously treated with an approved JAK inhibitor therapy, including either ruxolitinib or fedratinib.

Key Secondary Endpoints:

  • To compare the effect of momelotinib versus danazol on transfusion independent (TI) status at Week 24.
  • To compare the splenic response rate (SRR) for subjects treated with momelotinib versus danazol.
  • In addition, the trial will investigate several other secondary and exploratory endpoints, including the duration of symptomatic improvement, the effect of momelotinib treatment on other measures of transfusion burden and patient reported outcome metrics.

 

Chief Investigator

Dr. Srdan Verstovsek, MD
Anderson Cancer Center
Houston, Texas, USA