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Background: The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis. In this updated analysis, we report duration of week 24 responses and new responses with momelotinib through week 48., Methods: MOMENTUM is an international, double-blind, randomised, phase 3 study done at 107 sites across 21 countries. Patients were 18 years or older with primary, post-polycythaemia vera, or post-essential thrombocythaemia myelofibrosis, previously treated with an approved Janus kinase (JAK) inhibitor for 90 days or more (≥28 days with haematological complications), and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (2:1) to either the momelotinib group (200 mg orally once per day) or danazol group (300 mg orally twice per day) through week 24 via non-deterministic biased coin minimisation and an interactive response system. Stratification factors were Total Symptom Score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), transfusion burden (0 units vs 1-4 units vs ≥5 units), and study site. After week 24, all patients initially randomly assigned to either group who remained on the study received open-label momelotinib. The primary endpoint, which has already been reported, was Myelofibrosis Symptom Assessment Form TSS response rate at week 24. Predefined secondary endpoints were duration of week 24 TSS and transfusion independence responses, safety, and survival, which are summarised post hoc at the week 48 data cutoff (May 17, 2022). TSS, transfusion independence, and splenic responses at week 48 were defined post hoc and assessed in all evaluable patients who entered the open-label period and provided sufficient data. The timing of this updated analysis was defined post hoc after all patients had the opportunity to complete their week 48 assessments, as most patients entered an extended access study (NCT03441113) after week 48. This study is registered with ClinicalTrials.gov, number NCT04173494, and is now complete., Findings: Between April 24, 2020, and Dec 3, 2021, a total of 195 patients were randomised (130 [67%] in the momelotinib group and 65 [33%] in the danazol group). 93 (72%) of 130 patients in the momelotinib group and 41 (63%) of 65 in the danazol group entered the momelotinib open-label extension period. Median follow-up was 48·4 weeks (IQR 40·6-55·7). Among TSS-evaluable patients at week 48, 30 (45%) of 67 patients in the momelotinib group who continued treatment and 15 (50%) of 30 in the danazol group who crossed over were responders. TSS responders at any time during the open-label period by week 48 were 46 (61%) of 75 evaluable patients in the momelotinib group who continued and 19 (59%) of 32 in the danazol group who crossed over, including most week 24 responders plus new responders after week 24. No new safety signals emerged with long-term follow-up. The most common non-haematological treatment-emergent adverse events in momelotinib-treated patients over the entire study period as of the data cutoff were diarrhoea (45 [26%] of 171) and asthenia (28 [16%]); the most common grades 3-4 treatment-emergent adverse events were thrombocytopenia (33 [19%]) and anaemia (19 [11%]). Serious treatment-emergent adverse events were reported in 79 (46%) of 171 patients, and fatal treatment-emergent adverse events were reported in 30 (18%); two fatal treatment-emergent adverse events were considered possibly related to momelotinib (rotaviral enteritis and Staphylococcus pneumonia)., Interpretation: Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia., Funding: Sierra Oncology, a GSK company., Competing Interests: Declaration of interests ATG reports consulting fees from AbbVie, Bristol Myers Squibb, Constellation/MorphoSys, CTI Biopharma, Imago Biosciences/Merck, Incyte, Pharma Essentia, Sierra Oncology/GSK, and Telios. SV reports consulting fees from GSK. AMV reports payment or honoraria from AbbVie, AOP Health, Bristol Myers Squibb, GSK, Incyte, Novartis, and Roche. HKA-A reports research grants from Bristol Myers Squibb and Incyte; honoraria from AbbVie, Bristol Myers Squibb, GSK, and Novartis; and advisory board participation with AbbVie, Bristol Myers Squibb, GSK, and Novartis. DL reports consulting fees from AbbVie, Medisson, and Takeda; payment or honoraria from AbbVie, Novartis, Roche, and Takeda; travel support from AbbVie; and advisory board participation with AbbVie and Medisson. ATK reports consulting fees from CTI Biopharma, GSK, and Imago Biosciences; payment or honoraria from Bristol Myers Squibb, Incyte, and MorphoSys; travel support from AbbVie and MorphoSys; and advisory board participation with Incyte. AI reports payment or honoraria from Bristol Myers Squibb, GSK, Incyte, Novartis, and Pfizer; and advisory board participation with AOP Health, Incyte, and Novartis. YTG reports consulting fees from AstraZeneca, GSK, Novartis, and Pfizer; and payment or honoraria from AbbVie. MLF reports consulting fees from AbbVie, GSK, Novartis, and Sierra Oncology; payment or honoraria from Bristol Myers Squibb and Novartis; and travel support from AbbVie. DM reports a research grant from Imago Biosciences; payment or honoraria from AbbVie, Bristol Myers Squibb, Jazz Pharma, and Novartis; participation on a data safety monitoring board for the UK ALL-RIC trial; and a leadership or fiduciary role as a member of the EBMT Scientific Council and chair of the EBMT Chronic Malignancies Working Party. S-SY reports grants or contracts from Roche-Genentech, Kyowa Hakko Kirin, and Yuhan Pharma; payment or honoraria from Celgene, Janssen, and Novartis; and advisory board participation with Amgen, Antengene, and Takeda. VG reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Constellation Biopharma, CTI Biopharma, GSK, Novartis, Pfizer, and Sierra Oncology; payment or honoraria from Bristol Myers Squibb/Celgene and Novartis; and advisory board participation with AbbVie, Bristol Myers Squibb/Celgene, CTI Biopharma, Pfizer, Roche, and Sierra Oncology. J-JK reports advisory board participation with AbbVie, AOP Health, Bristol Myers Squibb, GSK, Incyte, and Novartis. FP reports grants or contracts from Bristol Myers Squibb; consulting fees from AbbVie, AOP Orphan, Bristol Myers Squibb/Celgene, Kartos, Karyopharm, Kyowa Kirin and MEI, Novartis, Roche, Sierra Oncology, and Sumimoto; and payment or honoraria from AbbVie, AOP Orphan, Bristol Myers Squibb/Celgene, Novartis, and Roche. CNH reports payment for study conduct and advisory board participation, related to the present manuscript; consulting fees from DISC, Galecto, and Keros; payment or honoraria from Bristol Myers Squibb, CTI Biopharma, GSK, Novartis, and Sierra Oncology; advisory board participation with AOP, Keros, Sumimoto, and Telios; and a leadership or fiduciary role with EHA, HemaSphere, and MPN Voice. SO reports consulting fees from AbbVie, Bristol Myers Squibb, Cogent, Constellation, CTI Biopharma, Geron, Incyte, Protagonist, and Sierra Oncology. BJK and RD employment and stock/stock options with Sierra Oncology, a GSK company. JY reports employment and stock or stock options with GSK. JK reports employment and stock or stock options with Sierra Oncology, a GSK company; and stock or stock options with Gilead. RM reports consulting fees from AbbVie, Blueprint, Bristol Myers Squibb, CTI, Genentech, Geron, GSK, Incyte, MorphoSys, Novartis, Sierra Oncology, and Telios. All authors received medical writing support related to the present manuscript, funded by GSK. SG, MCL, ME, NG, AP, S-EL, and LO declare no other competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)