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      Evaluating the Safety, Efficacy, and Therapeutic Potential of Momelotinib in the Treatment of Intermediate/High-Risk Myelofibrosis: Evidence to Date

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          Abstract

          Myelofibrosis is a heterogeneous disorder with regard to both molecular pathogenesis and clinical phenotype, ranging from an initial fairly indolent condition in some through to an aggressive and debilitating scenario with profound constitutional symptoms, cytopenia frequently requiring transfusional support, and massive splenomegaly. Many advances have been made within the therapeutic arena, and an increasing array of novel agents are now available for disease management. Within this review, we focus on the current and predicted role of the JAK inhibitor momelotinib (Sierra Oncology) in myelofibrosis, with an emphasis on clinical trial evaluation, drug efficacyand safety, and discuss the suggested place in the therapeutic paradigm of myelofibrosis in 2020 and beyond.

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          Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

          Ross Levine, Martha Wadleigh, Jan Cools … (2005)
          Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.
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            SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis.

            Ruben Mesa, Jean-Jacques Kiladjian, John Catalano … (2017)
            Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.
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              MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis

              Paola Guglielmelli, Ayalew Tefferi, Terra Lasho … (2018)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ther Clin Risk Manag
                Journal ID (publisher-id): tcrm
                Journal ID (pmc): tcriskman
                Title: Therapeutics and Clinical Risk Management
                Publisher: Dove
                ISSN (Print): 1176-6336
                ISSN (Electronic): 1178-203X
                Publication date (Electronic): 25 September 2020
                Publication date Collection: 2020
                Volume: 16
                Pages: 889-901
                Affiliations
                [1 ]Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond , London, SE1 9RT, UK
                Author notes
                Correspondence: Donal P McLornan Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Tower, Great Maze Pond , London, SE1 9RT, UK Tel +44 20 7188 2742 Email donal.mclornan@nhs.net
                Article
                Accession ID: PMC7524184 Pmcid ID: PMC7524184 Pmc-uid ID: 7524184 Publisher ID: 258704
                DOI: 10.2147/TCRM.S258704
                PMC ID: 7524184
                SO-VID: 4ceabb0f-4417-4c8a-a82b-0e4df3086d6a
                Copyright © © 2020 Bassiony et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 22 May 2020
                Date accepted : 14 August 2020
                Page count
                Figures: 0, Tables: 7, References: 42, Pages: 13
                Categories
                Subject: Review

                Keywords: momelotinib,JAK inhibitors,myelofibrosis
                Data availability:
                Keywords: momelotinib, JAK inhibitors, myelofibrosis

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