OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Momelotinib – Ojjaara®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Momelotinib	1056634-68-4	C23-H22-N6-O2

ANNOTATED BIBLIOGRAPHY

References updated: 28 December 2023

Abbreviations: JAK, Janus kinase; STAT, signal transducer activator of transcription.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase inhibitors such as momelotinib).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not momelotinib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2023/216873Orig1s000IntegratedR.pdf

  (Integrated FDA review of the data on safety and efficacy of momelotinib that formed the basis of its approval, mentions that ALT elevations arose in 22- 31% of patients, were above 5 times ULN in 0.5-2.0%, and that among 448 patients treated, there were 8 cases of suspected drug induced liver injury, 3 of which were considered probable or highly likely: 2 women and 1 man, ages 59, 77 and 54 years, with onset after 59, 112 and 54 days, and peak ALT 1178, 483 and 308 U/L, Alk P 617 566, and 83 U/L, bilirubin 7.0, 2.3 and 4.0 mg/dL, and all improving once momelotinib was stopped, one with apparent reactivation of hepatitis B with evidence of cirrhosis).
• Verstovsek S, Courby S, Griesshammer M, Mesa RA, Brachmann CB, Kawashima J, Maltzman JD, et al. A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia. Leuk Res. 2017;60:11–17. [PMC free article: PMC8170698] [PubMed: 28622623]

  (Among 39 patients with polycythemia or essential thrombocythemia treated with momelotinib [100 or 200 mg] once daily for 24 weeks, only 2 patients had a cytological response while 80% of patients had adverse events including headache, dizziness, somnolence, nausea and fatigue; no mention of ALT elevations or hepatotoxicity).
• Mesa RA, Kiladjian JJ, Catalano JV, Devos T, Egyed M, Hellmann A, McLornan D, 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. [PMC free article: PMC6553796] [PubMed: 28930494]

  (Among 432 patients with high or intermediate risk myelofibrosis treated with momelotinib [200 mg, once daily] or ruxolitinib [20 mg, twice daily] for 24 weeks, spleen size decreased in 26.5% vs 29% and adverse events arose in 92% vs 95%, serious adverse events in 23% vs 18%, resulting in discontinuations in 13% vs 6%, and peripheral neuropathy in 10% vs 5%, while there were no hepatic serious adverse events or deaths; no mention of ALT elevations ).
• Harrison CN, Vannucchi AM, Platzbecker U, Cervantes F, Gupta V, Lavie D, Passamonti F, 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. [PubMed: 29275119]

  (Among 156 patients with myelofibrosis and an inadequate response to or intolerance of ruxolitinib treated with momelotinib [200 mg once daily] or “best available therapy” for 24 weeks, reduction in spleen size [by 35% or greater] was achieved in 7% vs 6% and adverse events arose in 97% vs 89%, serious adverse events in 35% vs 23%, peripheral neuropathy in 11% vs none, deaths in 6% vs 8%, and there were no hepatic deaths or serious adverse events noted; no mention of ALT elevations).
• Coltro G, Vannucchi AM. The safety of JAK kinase inhibitors for the treatment of myelofibrosis. Expert Opin Drug Saf. 2021;20:139–154. [PubMed: 33327810]

  (Extensive review of the mechanism of action, rationale for use, current status, and safety of JAK kinase inhibitors for myelofibrosis including 2 FDA approved agents [ruxolitinib and fedratinib] and 2 in clinical development [pacritinib and momelotinib], focusing on common hematologic and gastrointestinal adverse events and special concerns on increased rates of infections, peripheral neuropathy and secondary cancer including lymphomas; no discussion of hepatotoxicity and ALT elevations mentioned only for fedratinib).
• Verstovsek S, Gerds AT, Vannucchi AM, Al-Ali HK, Lavie D, Kuykendall AT, Grosicki S, et al; MOMENTUM Study Investigators. 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(10373):269–280. [PubMed: 36709073]

  (Among 195 patients with intermediate or high risk symptomatic myelofibrosis treated with momelotinib [200 mg once daily] or danazol [300 mg twice daily] for 24 weeks, symptom improvement occurred in 25% vs 9% and transfusion independence in 30% vs 20%, while adverse event rates were similar 94% vs 95%, serious adverse events 35% vs 40%, discontinuations in 18% vs 23%, fatal outcome in 12% vs 17%, and ALT elevations in 7% vs 8%).
• Gerds AT, Verstovsek S, Vannucchi AM, Al-Ali HK, Lavie D, Kuykendall AT, Grosicki S, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023;10:e735–e746. [PubMed: 37517413]

  (Among 82 patients who continued on or were crossed over to open-label momelotinib after participation in a controlled trial [Verstovek 2023], rates of symptom improvement [45-50%] and transfusion independence [55-60%] increased while “there were no new safety signals”, no liver related serious adverse events or fatalities, although therapy was discontinued in one subject because of ALT and AST elevations [no details given]; no mention of rates of ALT elevations).