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ISSUE 4 AUGUST
New drug

Momelotinib for myelofibrosis

Active ingredient: momelotinib

Brand name (sponsor): Omjjara (GlaxoSmithKline)

Presentation: 100 mg, 150 mg and 200 mg film-coated tablets

Route of administration: oral

Approved indication: treatment of disease-related splenomegaly or symptoms in adult patients with moderate to severe anaemia who have primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis and who are Janus kinase (JAK) inhibitor–naive or have been treated with ruxolitinib


Background:
Myelofibrosis is a chronic myeloproliferative neoplasm that causes bone marrow to become dense and rigid, and to produce abnormal, immature blood cells. Myelofibrosis is characterised by splenomegaly, constitutional symptoms (e.g. fatigue, fever), and cytopenias, particularly anaemia. Momelotinib is an oral drug with a once-daily administration; it joins other Janus kinase (JAK) 1 and 2 inhibitors (e.g. ruxolitinib) but has additional inhibitory activity against activin A receptor type 1 (ACVR1), a key regulator of iron metabolism.

Mechanism of action:
Momelotinib is a first-in-class inhibitor of JAK1, JAK2 and ACVR1.1 JAK1 and JAK2 are involved in the pathogenesis of myelofibrosis through dysregulated cytokine signaling. ACVR1 is a key regulator of hepcidin production; by suppressing hepcidin, momelotinib increases iron availability, thereby improving erythropoiesis and reducing the need for blood transfusions.

Clinical trials:
Momelotinib was evaluated in three phase 3 trials (SIMPLIFY-1, SIMPLIFY-2 and MOMENTUM).

SIMPLIFY-1 compared the safety and efficacy of momelotinib versus ruxolitinib in patients with myelofibrosis who had never received a JAK inhibitor (n=432).2 Momelotinib was noninferior to ruxolitinib in achieving 35% or more spleen volume reduction from baseline at week 24 (26.5% versus 29%). However, it did not meet noninferiority for symptom improvement; 28.4% of patients treated with momelotinib had a total symptom score reduction of 50% or more, compared with 42.2% of patients treated with ruxolitinib. Superior anaemia-related outcomes were observed in the momelotinib group, with reduced transfusion requirements.

SIMPLIFY-2 compared momelotinib with best available therapy,3 which included, but was not limited to, ruxolitinib, anagrelide, corticosteroids, hematopoietic growth factors, immunomodulating drugs, androgen, interferon alpha, or no treatment. Patients (n=156) had previously been treated with ruxolitinib and either needed red blood cell transfusions or ruxolitinib dose reduction due to haematological toxicity (e.g. anaemia). The trial showed that momelotinib was not superior to best available therapy (mostly ruxolitinib) for spleen volume reduction at week 24 (7% versus 6%). However, patients who received momelotinib demonstrated improvements in anaemia-related endpoints and symptom scores. Momelotinib was also associated with reduced transfusion dependence compared with best available therapy.

MOMENTUM compared momelotinib with danazol in patients with symptomatic and anaemic myelofibrosis who had previously been treated with a JAK inhibitor (mostly ruxolitinib) (n=195). At week 24, momelotinib was superior to danazol in symptom improvement (25% versus 9%), and spleen volume reduction by 35% or greater from baseline (22% versus 3%), and was noninferior to danazol for transfusion independence (30% versus 20%).1 There was a trend toward improved overall survival in the momelotinib group compared with the danazol group over a median follow-up of 39 and 42 weeks, respectively.4

Adverse effects:
Across the 3 trials, the most frequently reported adverse effects were diarrhoea (26.8%), nausea (19.4%), thrombocytopenia (25% of patients and the most common reason for treatment discontinuation [4%]), anaemia (23.4% of patients, although momelotinib also showed benefits in reducing the need for blood transfusions) and neutropenia (6.8%). Adverse effects were noncumulative and generally manageable.4

Peripheral neuropathy (14.8%) and infections such as pneumonia (55.4% overall) were also reported.4

Dosage and administration:
The dose of momelotinib is 200 mg taken orally once daily. Dose reduction may be required for thrombocytopenia, neutropenia, hepatotoxicity or other nonhaematological toxicities.5

Precautions and practice points:
Momelotinib carries risks of serious infections, haematological toxicities (including thrombocytopenia and neutropenia), hepatotoxicity and peripheral neuropathy. Monitoring of full blood count, including platelets, and liver function is recommended before starting treatment and during treatment. Also consider cardiovascular risk and the potential for secondary malignancies, particularly in patients with predisposing factors (e.g. 65 years or older). Momelotinib should not be started in patients with active infections. It may interact with other drugs via cytochrome P450 (CYP) enzymes, particularly CYP3A4, and transporters such as P-glycoprotein, BCRP, OATP1B1 and OATP1B3.5

Use in pregnancy and breastfeeding:
Momelotinib is classified as a category D drug and should not be used during pregnancy or breastfeeding.

Place in therapy:
Momelotinib is a promising treatment option for patients with intermediate- or high-risk myelofibrosis, particularly those with anaemia or transfusion dependence, because of its unique mechanism of action. It may be preferred in patients who are intolerant to or have suboptimal responses to other JAK inhibitors (e.g. ruxolotinib), especially when anaemia is a dominant clinical issue.

This new drug comment was finalised on 27 June 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

Australian Prescriber welcomes Feedback.

 

References

  1. Verstovsek S, Gerds AT, Vannucchi AM, Al-Ali HK, Lavie D, Kuykendall AT, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet 2023;401:269-80.
  2. Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients With Myelofibrosis. J Clin Oncol 2017;35:3844-50.
  3. Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol 2018;5:e73-e81.
  4. Verstovsek S, Mesa R, Gupta V, Lavie D, Dubruille V, Cambier N, et al. Momelotinib long-term safety and survival in myelofibrosis: integrated analysis of phase 3 randomized controlled trials. Blood Adv 2023;7:3582-91.
  5. Therapeutic Goods Administration. Australian Product Information - OMJJARA momelotinib (as dihydrochloride monohydrate) 100 mg film-coated tablet bottle. Department of Health, Disability and Ageing; 2024. [cited 2025 Jun 3]
 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

Report all suspected adverse reactions to new drugs to enable continued monitoring of their benefit–harm balance.

 
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