Momelotinib versus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: an efficacy/safety analysis in the Japanese subgroup of the phase 3 randomized SIMPLIFY-1 trial

Kazuya Shimoda¹, Norio Komatsu², Itaru Matsumura³, Kazuhiko Ikeda⁴, Masayuki Hino⁵, Michihiro Hidaka⁶, Yoshinobu Maeda⁷, Takeshi Kondo^{8

9}, Tomoaki Fujisaki¹⁰, Keita Shoshi¹¹, Kyoichi Azuma¹¹, Ryuichi Fukushima¹², Jun Kawashima¹³, Hiroshi Kosugi¹⁴

Affiliations

¹ Hematology, Diabetes, and Endocrinology, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan. kshimoda@med.miyazaki-u.ac.jp.
² Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan.
³ Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
⁴ Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan.
⁵ Department of Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
⁶ Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.
⁷ Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
⁸ Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
⁹ Blood Disorders Cente, Aiiku Hospital, Sapporo, Japan.
¹⁰ Department of Hematology, Matsuyama Red Cross Hospital, Matsuyama, Japan.
¹¹ Clinical Development (Oncology), Japan Medical and Development, GlaxoSmithKline K.K., Tokyo, Japan.
¹² Biostatistics, Japan Medical and Development, GlaxoSmithKline K.K., Tokyo, Japan.
¹³ Sierra Oncology, Inc., San Mateo, USA.
¹⁴ Department of Hematology, Ogaki Municipal Hospital, Ogaki, Japan.

PMID: 39110143
PMCID: PMC11362197
DOI: 10.1007/s12185-024-03822-z

Clinical Trial

Momelotinib versus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: an efficacy/safety analysis in the Japanese subgroup of the phase 3 randomized SIMPLIFY-1 trial

Kazuya Shimoda et al. Int J Hematol. 2024 Sep.

. 2024 Sep;120(3):314-324.

doi: 10.1007/s12185-024-03822-z. Epub 2024 Aug 7.

Authors

Affiliations

¹ Hematology, Diabetes, and Endocrinology, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan. kshimoda@med.miyazaki-u.ac.jp.
² Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan.
³ Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
⁴ Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan.
⁵ Department of Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
⁶ Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.
⁷ Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
⁸ Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
⁹ Blood Disorders Cente, Aiiku Hospital, Sapporo, Japan.
¹⁰ Department of Hematology, Matsuyama Red Cross Hospital, Matsuyama, Japan.
¹¹ Clinical Development (Oncology), Japan Medical and Development, GlaxoSmithKline K.K., Tokyo, Japan.
¹² Biostatistics, Japan Medical and Development, GlaxoSmithKline K.K., Tokyo, Japan.
¹³ Sierra Oncology, Inc., San Mateo, USA.
¹⁴ Department of Hematology, Ogaki Municipal Hospital, Ogaki, Japan.

PMID: 39110143
PMCID: PMC11362197
DOI: 10.1007/s12185-024-03822-z

Abstract

Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF.

Keywords: Japan; Momelotinib; Myelofibrosis; Phase 3; Ruxolitinib.

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Conflict of interest statement

Kazuya Shimoda has employment/leadership position/advisory role with AbbVie, PharmaEssentia, Sumitomo Pharma, GSK, a honoraria role with Novartis and Takeda, received research funds AstraZeneca, PharmaEssentia, Meiji Pharma, and received subsidies/donations from Chugai Pharma, Kyowa Kirin, AbbVie, Daiichi Sankyo, Otsuka, Eisai, Shionogi and Asahi Kasei Medical. Norio Komatsu has employment/leadership position/advisory role with PharmaEssentia Japan; received fees from Takeda Pharmaceutical Co., Ltd., Novartis Pharmaceutical, Japan Tobacco Inc.; received researched funds from Takeda Pharmaceutical Co., Ltd., PerseusProteomics Inc., Meiji Seika Pharmaceutical Co., Ltd., PharmaEssentia Japan; received donated fund laboratory from Otsuka Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Sumitomo Pharmaceutical Co., Ltd., PharmaEssentia Japan, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. Itaru Matsumura received fees from Novartis Pharmaceutical KK, Bristol-Myers Squibb Co., Ltd., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Astellas Pharmaceutical Inc., Janssen Pharmaceutical KK, AbbVie GK., Takeda Pharmaceutical Co., Ltd., Onopharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd.; received research funds from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Novartis Pharmaceutical KK, Astellas Pharmaceutical Inc., AbbVie GK., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Alexion, Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical KK; received subsidies/donations from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Shionogi &Co., Ltd.; Asahi Kasei Pharmaceutical Co., Eisai Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AbbVie GK., Onopharmaceutical Co., Ltd., Sanofi KK., Mitsubishi Tanabe Pharmaceutical Corporation. Kazuhiko Ikeda received fees from Novartis, Kyokuto, PharmaEssentia Japan, Japan Blood Product Organization, Nippon Shinyaku, Otsuka, Ortho Clinical Diagnostics, Zeria, Takeda, Ono; received research funds from Kyowa-Kirin, Daiichi Sankyo, Kyokuto, Hokuyo-Denki; received reagents from GenDx. Masayuki Hino received fees from Novartis, Bristol Myers Squib, Otsuka, Kyowa-Kirin; received research funds from Labcorp Drug Development; received subsidies/donations from Chugai, Kyowa-Kirin, Otsuka, Takeda, Taiho, Sekisui Medical. Michihiro Hidaka has no COIs to declare. Yoshinobu Maeda received fees from Kyowa Kirin Co., Ltd., Novartis Pharmaceutical Co., Ltd.; received research funds from Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co. Ltd; received subsidies/donations from Otsuka Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co. Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Kirin Co. Ltd. Takeshi Kondo received fees from Pfizer, Otsuka Pharmaceuticals Co., Ltd., Novartis, Astellas. Tomoaki Fujisaki has no COIs to declare. Keita Shoshi has employment/leadership position/advisory role with GSK KK. Kyoichi Azuma has employment/leadership position/advisory role with GSK KK. Ryuichi Fukushima has employment/leadership position/advisory role with GSK KK. Jun Kawashima was employed in a leadership position/advisory role by Sierra Oncology and GSK at the time the analysis was conducted; holds stock with Gilead Sciences, GSK. Hiroshi Kosugi has no COIs to declare.

Figures

**Fig. 1**
Patient disposition in the Japanese subpopulation. ^aThe study was prematurely discontinued by the sponsor closing the study, which was not related to momelotinib treatment [12]. MMB, momelotinib; OL, open-label; RUX, ruxolitinib

**Fig. 2**
Percent change from baseline in A SRR and B TSS at Week 24. Dashed lines indicate the threshold response. MMB, momelotinib; RUX, ruxolitinib; SRR, splenic response rate; TSS, total symptom score

**Fig. 3**
Mean hemoglobin levels during the double-blind and open-label phases to Week 48. Hgb, hemoglobin; MMB, momelotinib; RUX, ruxolitinib

See this image and copyright information in PMC

References

1. Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89–101. - PMC - PubMed
1. Titmarsh GJ, Duncombe AS, McMullin MF, O’Rorke M, Mesa R, De Vocht F, et al. How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am J Hematol. 2014;89:581–7. 10.1002/ajh.23690 - DOI - PubMed
1. Hultcrantz M, Ravn Landtblom A, Andréasson B, Samuelsson J, Dickman PW, Kristinsson SY, et al. Incidence of myeloproliferative neoplasms—trends by subgroup and age in a population-based study in Sweden. J Intern Med. 2020;287:448–54. 10.1111/joim.13019 - DOI - PMC - PubMed
1. Verstovsek S, Yu J, Scherber RM, Verma S, Dieyi C, Chen CC, et al. Changes in the incidence and overall survival of patients with myeloproliferative neoplasms between 2002 and 2016 in the United States. Leuk Lymphoma. 2022;63:694–702. 10.1080/10428194.2021.1992756 - DOI - PubMed
1. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: From bench to clinic. Signal Trans Targeted Therapy. 2021;6:402.10.1038/s41392-021-00791-1 - DOI - PMC - PubMed

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Momelotinib versus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: an efficacy/safety analysis in the Japanese subgroup of the phase 3 randomized SIMPLIFY-1 trial

Affiliations

Momelotinib versus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: an efficacy/safety analysis in the Japanese subgroup of the phase 3 randomized SIMPLIFY-1 trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Research Materials