Momelotinib May Fill Treatment Gap for Anemia in Myelofibrosis


Momelotinib for the treatment of patients with myelofibrosis may address concerns with the development of cytopenias, an issue no approved therapy has been able to solve.

The development of cytopenias is a common occurrence in patients with myelofibrosis (MF), yet the available treatment options for MF may not currently be sufficient for the prevention or resolution of the condition. With no FDA-approved therapy available to address cytopenias, the field has a significant unmet need. Based on results observed with momelotinib in multiple studies, the drug is a candidate for filling in this treatment gap.

“Amenia is a tremendous burden for patients, particularly for those who are receiving transfusions. This is a very dynamic variable. We [thoroughly] considered how to best analyze the impact as well as the difference seen from momelotinib.”

The Issue of Anemia in MF

Anemia and transfusion dependency are considered to be the most common cytopenias and were shown to be associated with poor prognosis and survival outcomes. In fact, anemia is the number one correlate to patients developing progressive disease just 1 year after being diagnosed with MF. The percentage of patients who progress 1 year after diagnosis is 64%, and other indications of progressive disease, like splenomegaly and constitutional symptoms, occur in 46% and 34% of patients, respectively.

In terms of prognostic risk score, anemia scores high among risk factors, especially if the anemia is moderate to severe. Specifically, patients with anemia or transfusion dependency are automatically ranked as intermediate-2 or high-risk on the Dynamic International Prognostic Scoring System plus (DIPSS-plus) model.

Therapies approved by the FDA for the treatment of MF include ruxolitinib (Jakafi), a JAK1/2 inhibitor, and fedratinib (Inrebic), a JAK2 inhibitor. In the COMFORT-1 study of ruxolitinib versus placebo (NCT00952289), more than a 35% reduction in spleen size was achieved in 41.9% of patients, compared with only 0.7% of patients in the placebo arm. But, high hemoglobin (Hgb) levels and exacerbated anemia were also seen, which led to dose reduction in 31% of patients. In the SIMPLIFY-1 study of momelotinib versus ruxolitinib, dose reductions were necessary for 56% of patients and 54% of patient in the overall population required red blood cell (RBC) transfusions. Treatment with fedratinib led to dose reductions in 24% of patients in the JAKARTA-1 trial(NCT01437787), and 51% of patients in the overall population required RBC transfusions. Notably, once doses of ruxolitinib were reduced and transfusions were done in the SIMPLIFY-1 study, partial Hgb recovery was observed.

Although it was difficult to manage anemia in SIMPLIFY-1 in the ruxolitinib treatment arm, a different result was observed with momelotinib.

Momelotinib and Anemia in MF

The earliest evidence that momelotinib was a valid option to manage anemia in MF was seen in the phase II GS-US-352-1672 trial, which evaluated 41 transfusion-dependent participants.

Transfusion independence rate was the primary end point in this study. At 8 weeks, 39% of patients showed transfusion independence and at 12 weeks 41% of patients were transfusion independence. Of the 78% of patients who did not become transfusion independent, the need for transfusion was still reduced by more than 50% for at least 8 weeks. In addition, treatment with momelotinib had a positive impact on hepcidin, hematocrit, Hgb, and serum iron levels.

Later, in the SIMPLIFY-1 study, in addition to showing non-inferiority to ruxolitinib in terms of splenic response and symptomatic benefit, momelotinib also demonstrated a statistically significant transfusion dependence rate of 66% compared to 49% in the ruxolitinib arm (P < .001), in the overall population of patients. Among those who were transfusion-dependent at baseline, momelotinib led to a ≥12-week transfusion independence rate of 49.1% versus 28.8% in the ruxolitinib arm (P = .0299).

SIMPLIFY-1 (NCT01969838) was an international randomized, double-blind, active-controlled phase III study that included patients with primary MF, post-polycythemia vera, or post-essential thrombocytopenia MF. In addition to assessing splenic response rate, the secondary end points of the study were response rate in total symptom score, rate of RBC transfusion, transfusion independence rate, and transfusion dependence rate.

Patients in the study received 200-mg momelotinib orally once daily in the experimental arm. In the comparator arm, 20-mg ruxolitinib was administered orally twice daily.

To be eligible for enrollment, patients were required to be in need of MF therapy based on investigator opinion, be classified as intermediate-2 or high-risk, have acceptable laboratory values 14 days prior to first dosing in the study, and have a life expectancy of at least 24 weeks.

Durable Anemia Response

Whether momelotinib can maintain transfusion independence in patients with MF is an important question. A Kaplan-Meier analysis showed that with a follow-up period of more than 3 years, the median time to loss of transfusion independence was still not reached with momelotinib treatment.

Further Confirmation

During the crossover period in SIMPLIFY-1, patients who were originally receiving ruxolitinib began to show robust improvements in Hgb levels with momelotinib. These results were seen in both the previously treated and treatment naïve groups.

Momelotinib in the MF Landscape

Momelotinib has been evaluated in more than 20 phase I-III studies. Over 1200 individuals have been treated with the drug and about 820 of them were patients with MF who were treated in the SIMPLIFY-1 and SIMPLIFY-2 studies. Some patients have been receiving momelotinib for 8 years or more.

The success of momelotinib in the MF treatment landscape is believed to be related to its mechanisms of action which helps to decrease hepcidin transcription through ACVR1 inhibition. In doing this, momelotinib restores homeostasis and boosts hemoglobin, which, in turn, has multiple anemia benefits.

“Momelotinib’s immediate and sustained anemia benefits are underpinned by its unique biology and manifested overall significant reduction in transfusion burden compared to ruxolitinib,” said Mesa. “These anemia benefits combined with momelotinib’s ability to achieve presently comparable benefits for symptoms and splenomegaly will provide an important addition to the myelofibrosis armamentarium. Momelotinib will likely be used in patients with largely cytopenic secondary myelofibrosis, but I believe it [will also] have a frontline roll in cytopenic patients suffering from anemia transfusion dependence at presentation.”


Mesa, Ruben. Unmet Need in Myelofibrosis: Addressing Anemia & Transfusion Dependency. Webcast. Sierra Oncology website. Accessed May 14, 2020.

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