By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a first-in-class oral inhibitor of activin A receptor type 1 (ACVR1) and Janus kinases (JAK) 1 and 2, as well as mutant JAK2, to treat myelofibrosis (MF) with anemia. It is the fourth JAK inhibitor approved for MF (after ruxolitinib, fedratinib, and pacritinib), but the first inhibiting ACVR1 and approved for adults with MF and anemia. It received an orphan designation and is distributed as Ojjaara.
INDICATIONS
Momelotinib can be prescribed to treat intermediate- or high-risk MF, including primary MF or secondary MF (post-polycythemia vera [PV] and post-essential thrombocythemia [ET]) in adults with anemia.1
DOSAGE
Prescribe 200 mg to patients to take orally once daily, with or without food.1 Lower the dose to 150 mg for patients with severe hepatic impairment (Child-Pugh Class C). Momelotinib is available as 100-mg, 150-mg, and 200-mg tablets.
POTENTIAL ADVANTAGES
In contrast to other approved JAK inhibitors, momelotinib inhibits ACVR1. Inhibition of this signaling pathway downregulates hepcidin expression, resulting in more iron for erythropoiesis, leading to alleviated transfusion burden and anemia.2,3 Momelotinib was associated with a reduced transfusion burden vs. ruxolitinib.4
POTENTIAL DISADVANTAGES
Momelotinib may be less effective than ruxolitinib in symptomatic improvement.1,4 Serious, possibly fatal, infections may occur with momelotinib.1 Momelotinib may reactivate hepatitis B infection. Thrombocytopenia, neutropenia, and hepatotoxicity may occur, which might require dose modifications.1
A long-term pool analysis of three Phase III trials (n = 725) with a median exposure of 11.3 months (range, 0.1-90.4 months) revealed the most common adverse reaction (any grade) as diarrhea 27%, thrombocytopenia (25%), anemia (23%), and neutropenia (7%).5 Thrombocytopenia was the most common reason for treatment discontinuation (4%). Other JAK inhibitors have been associated with higher risk of major adverse cardiovascular events, thrombosis, and malignancies.1
COMMENTS
The efficacy of momelotinib was established in the MOMENTUM trial and in a subpopulation of adults with anemia in the SIMPLIFY-1 trial.1,4,6 Study participants were adults with intermediate 1- (5%), intermediate 2- (57%), or high-risk (35%) MF, including primary MF, post-PV MF, or post-ET MF. MOMENTUM was a double-blind, randomized, active-controlled, 24-week trial that included 195 symptomatic and anemic adults who had received an approved JAK inhibitor.6 Researchers randomized 130 participants to momelotinib and 65 to danazol (300 mg twice daily).
The primary endpoint was the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v 4.0) Total Symptom Score (TSS) response rate at week 24. Response was defined as the proportion of subjects with a 50% or more reduction in MFSAF TSS over the 28 days immediately before the end of week 24. Some secondary outcomes included proportion of participants with reduction in spleen volume of 25% or more, transfusion independence rate (no transfusion or Hb < 8 mg/dL between weeks 12 and 24), and proportion with no transfusions during the 24-week treatment period. MFSAF TSS response rates were 25% vs. 9%, spleen volume reduction rates were 39% vs. 6%, and no transfusion rate during the 24-week treatment period (35% vs. 17%). Momelotinib was superior to danazol in these outcomes. Noninferiority was shown for transfusion independence (30% vs. 20%). Among those who did not achieve transfusion independence, participants treated with momelotinib required fewer units of blood.
SIMPLIFY-1 enrolled participants who were JAK treatment-naïve.1,4 Participants were randomized to momelotinib (n = 86) or ruxolitinib (20 mg twice daily; n = 95). Response rate for spleen volume reduction were similar — 31.4% for momelotinib vs. 32.6% for ruxolitinib. More participants treated with momelotinib were transfusion-independent (66.5% vs. 49.3%). However, a numerically lower percentage of participants treated with momelotinib achieved a MFSAF TSS reduction of ≥ 50% (25% vs. 36%).
CLINICAL IMPLICATIONS
MF is an uncommon, myeloproliferative neoplasm characterized by splenomegaly, scarring of the bone marrow, and progressively worsening anemia and thrombocytopenia.6 Symptoms include fatigue, cachexia, fever, night sweats, and bone pain. It is believed to be mediated by dysregulation of the JAK signaling pathway. Approximately 50% are living with a mutation of the JAK 2 gene.7 Generally, targeted treatment with a JAK inhibitor is considered for those with intermediate-risk disease.8 Ruxolitinib is the most commonly prescribed agent as fedratinib carries a warning for encephalopathy and gastrointestinal (GI) toxicity, and pacritinib is associated with a high incidence rate of adverse GI reactions (i.e., diarrhea).9,10
Momelotinib offers a first-in-class JAK inhibition, along with ACVR1 inhibition, that is specifically indicated for MF patients with anemia. The cost for a 30-day supply of momelotinib (200 mg once daily) is $26,900 vs. $17,020 for ruxolitinib (10 mg twice daily).
REFERENCES
1. GlaxoSmithKline. Ojjaara prescribing information. September 2023.
2. Tremblay D, Mesa R. Momelotinib for the treatment of myelofibrosis with anemia. Future Oncol 2022;18:2559-2571.
3. Chifotides HT, Bose P, Verstovsek S, et al. Momelotinib: An emerging treatment for myelofibrosis patients with anemia. J Hematol Oncol 2022;15:7.
4. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol 2017;35:3844-3850.
5. Verstovsek S, Mesa R, Gupta V, et al. Momelotinib long-term safety and survival in myelofibrosis: Integrated analysis of phase 3 randomized controlled trials. Blood Adv 2023;7:3582-3591.
6. Verstovsek S, Gerds AT, Vannucchi AM, 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;401:269-280.
7. National Organization for Rare Disorders. Primary myelofibrosis. Last updated June 24, 2020.
8. Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol 2023;98:801-821.
9. Celgene Corporation. Inrebic prescribing information.
10. CTI Biopharma. Vonjo prescribing information. February 2022.
Momelotinib can be prescribed to treat intermediate- or high-risk myelofibrosis.
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