Table 1.

Synopsis of clinical trials evaluating momelotinib and the anemia benefits it elicited in MF patients

Study title	ClinicalTrials. gov Identifier	Phase	Population studied	Anemia benefits	Duration	References
A phase 1/2, open-label, dose-escalation study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of orally-administered CYT387a in PMF, post-PV MF or post-ET MF	NCT00935987 Core study	1/2	166 intermediate- and high-risk MF patients	Of 41 anemia-evaluable patients: 70% (23/30) became transfusion-independent by IWG-MRT criteria (2006) Median duration of transfusion-independence: 9.6 months	11/2009–04/2012	[92]
An open-label phase 2 extension study evaluating the long term safety, tolerability, and efficacy of orally-administered CYT387a in PMF, post-PV MF or post-ET MF	NCT01236638 Extension of the core study NCT00935987	Extension of core phase 1/2 study	120 intermediate- and high-risk MF patients	Of 111 anemia-evaluable patients: 75% (54/72) and 68% became transfusion-independent (for ≥ 8 weeks) at 8 and 12 weeks, respectively; 28% (11/39) of the patients with Hb < 10 g/dL had a median increase of 2.4 g/dL at 8 and 12 weeks Median duration of 8-week anemia response: 7.7 months	11/2010–06/2014	[93]
Seven-year follow-up study of 100 patients with PMF, post-PV MF or post-ET MF, treated with CYT387a  in a phase 1/2 clinical trial	NCT00935987 (part of the larger phase 1/2 trial with the same study identifier)	7-year follow-up of the phase 1/2 trial	100 intermediate- and high-risk MF patients treated at the Mayo Clinic	51% of the patients became transfusion-independent, and 44% of the patients had improvement in anemia	7 years	[94]
A phase 1/2, open-label study evaluating twice-daily administration of CYT387a in PMF, post-PV MF or post-ET MF	NCT01423058	1/2	61 intermediate- and high-risk MF patients	Of 29 transfusion-dependent patients at baseline, 51.7% (15) achieved transfusion-independence for ≥ 8 weeks; 27% (3/11) transfusion independent patients had a Hb increase of ≥ 2 g/dL for ≥ 8 weeks	08/2011–06/2014	[89]
A phase 2, open-label, translational biology study of momelotinib in transfusion-dependent subjects with PMF, post-PV MF or post-ET MF	NCT02515630	2	41 transfusion-dependent MF patients	41% (17/41) of the patients became transfusion-independentb 78% (21/27) of the transfusion-dependent patients had ≥ 50% decrease in RBC transfusion requirements for ≥ 8 weeks 49% transfusion-independence response rate at any time during the study in the evaluable population after ≥ 12 weeks of follow-up	01/2016–08/2017 Extension study: 04/2014–12/2018	[67]
SIMPLIFY-1: A phase 3, randomized, double-blind active-controlled study evaluating momelotinib versus ruxolitinib in subjects with PMF, post-PV MF or post-ET MF	NCT01969838	3 Randomization period: 24 weeks	432 JAK inhibitor-naïve patients who had high-risk, intermediate-2 risk or symptomatic intermediate-1 risk MF and platelet counts  ≥ 50 × 109/L	At week 24: 66.5% of the patients in the momelotinib arm became transfusion-independentc versus 49.3% in the ruxolitinib arm (at baseline, 24.7% and 24% were transfusion-dependent, respectively) 83% of the patients treated with momelotinib required ≤ 4 units of RBCs versus 62% on ruxolitinib Median RBC transfusion rate was 0 units/month with momelotinib versus 0.4 units/month with ruxolitinib At week 48: 75% of the patients treated with momelotinib only became transfusion-independent versus 67% of the patients who were in the ruxolitinib arm and crossed over to momelotinib Odds of remaining transfusion-independent were 9.3 times higher for momelotinib-treated patients versus ruxolitinib-treated patients Median duration of transfusion-independence was not reached with momelotinib after follow-up of ≥ 3 years	12/2013–05/2019 Extension study: 05/2018 (onset) Ongoingf	[91, 95, 98]
SIMPLIFY-2: A phase 3, randomized study to evaluate the efficacy of momelotinib versus BAT in anemic or thrombocytopenic subjects with PMF, post-PV MF or post-ET MF who were treated with ruxolitinib	NCT02101268	3 Randomization period: 24 weeks	156 anemic or thrombocytopenic patients with MF, post-PV MF or post-ET MF previously treated with ruxolitinibd 104 patients received momelotinib, and 52 patients received BAT (89% ruxolitinib); 56% (58/104) and 52% (27/52) were transfusion-dependent in the momelotinib and BAT/ruxolitinib arm, respectively; no platelet count was set	At week 24: 43% (45/104) of the patients treated with momelotinib became transfusion-independentc versus 21% (11/52) in the BAT/ruxolitinib arm Median RBC transfusion rate was 0.5 units/month with momelotinib versus 1.2 units/month with BAT/ruxolitinib At week 48: 55% of the patients treated with momelotinib from the onset became transfusion-independent versus 40% who were in the BAT/ruxolitinib arm and crossed over to momelotinib During the entire treatment period: 40% (42/104) of the momelotinib-treated patients versus 27% (14/52) in the BAT/ruxolitinib cohort did not require RBC transfusions Median duration of transfusion independence with momelotinib was > 1 year at any time during the study	06/2014–04/2019 Extension study: 05/2018 (onset) Ongoingf	[91, 96]
MOMENTUM: A randomized, double-blind phase 3 study of momelotinib versus danazol in symptomatic, anemic subjects with PMF, post-PV MF or post-ET MF, previously treated with JAK inhibitorse	NCT04173494	3 Randomization period: 24 weeks	180 patients with MF, post-PV MF or  post-ET MF Eligible patients were anemic (Hb < 10 g/dL) and symptomatic (TSS ≥10) at baseline (platelet count ≥ 25 x 109/L); and patients had been previously exposed to an approved JAK inhibitor	Proportion of transfusion-independentc patients at week 24; and cumulative transfusion burden and Hb improvement RBC transfusions will be recorded at 4-week intervals until week 48 and up to the end of week 204 (open label treatment period)	02/2020 Ongoing	[90]

BAT best available therapy, ET essential thrombocythemia, Hb hemoglobin, IWG-MRT International Working Group-Myeloproliferative Neoplasms Research and Treatment, JAK Janus kinase, MF myelofibrosis, PMF primary myelofibrosis, PV polycythemia vera, RBC red blood cell, TSS Total Symptom Score

^aCYT387: former name for momelotinib

^bAbsence of RBC transfusion for ≥ 12 weeks at any time on the study

^cAbsence of RBC transfusion and no Hb level < 8 g/dL in the  12 weeks preceding the end of the randomized treatment period (week 24)

^dPatients were previously exposed to ruxolitinib for ≥ 28 days and required RBC transfusions while treated with ruxolitinib or a dose reduction to < 20 mg twice daily due to grade 3 or worse anemia, thrombocytopenia or bleeding

^eOngoing international, registration-track, pivotal phase 3 trial, sponsored by Sierra Oncology, Inc. (Vancouver, Canada)

^fSubjects remaining on momelotinib treatment from studies NCT01969838, NCT02101268, NCT02124746, and NCT04173494 were permitted to enroll in an additional extended access study (NCT0344113), which is currently ongoing