Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study
Gen Sobue,
Hirofumi Maruyama,
Keiko Imamura,
Yuishin Izumi,
Satoshi Morita,
Naohiro Egawa,
Takashi Ayaki,
Makiko Nagai,
Kazutoshi Nishiyama,
Yasuhiro Watanabe,
Ritsuko Hanajima,
Koji Fujita,
Naoto Takahashi,
Akiko Morinaga,
Ryosuke Takahashi,
Haruhisa Inoue,
Naoki Atsuta,
Osamu Kano,
Takehisa Hirayama,
Takao Kiriyama,
Hiroshi Kataoka,
Takahiko Tokuda,
Kazuma Sugie,
Takenobu Murakami,
Hitoki Nanaura,
Masahiro Nakamori,
Shotaro Haji,
Harutsugu Tatebe,
Riko Tabuchi,
Motoki Oe,
Mihoko Kobayashi,
Kasia Lobello
Affiliations
Gen Sobue
Aichi Medical University, Nagakute, Japan
Hirofumi Maruyama
Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Keiko Imamura
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
Yuishin Izumi
Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
Satoshi Morita
Department of Biomedical Statistics and Bioinformatics, Kyoto University, Kyoto, Japan
Naohiro Egawa
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Takashi Ayaki
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Makiko Nagai
Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan
Kazutoshi Nishiyama
Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan
Yasuhiro Watanabe
Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
Ritsuko Hanajima
Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
Koji Fujita
Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
Naoto Takahashi
Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
Akiko Morinaga
Pfizer Japan Inc, Tokyo, Japan
Ryosuke Takahashi
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Haruhisa Inoue
Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto, Japan
Naoki Atsuta
Department of Neurology, Aichi Medical University, Nagakute, Japan
Osamu Kano
Department of Neurology, Toho University Faculty of Medicine, Tokyo, Japan
Takehisa Hirayama
Department of Neurology, Toho University Faculty of Medicine, Tokyo, Japan
Takao Kiriyama
Department of Neurology, Nara Medical University School of Medicine, Kashihara, Japan
Hiroshi Kataoka
Department of Neurology, Nara Medical University School of Medicine, Kashihara, Japan
Takahiko Tokuda
Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan
Kazuma Sugie
Department of Neurology, Nara Medical University School of Medicine, Kashihara, Japan
Takenobu Murakami
Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
Hitoki Nanaura
Department of Neurology, Nara Medical University School of Medicine, Kashihara, Japan
Masahiro Nakamori
Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Shotaro Haji
Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
Harutsugu Tatebe
Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan
Riko Tabuchi
Pfizer R&D Japan GK, Tokyo, Japan
Motoki Oe
Pfizer R&D Japan GK, Tokyo, Japan
Mihoko Kobayashi
Pfizer R&D Japan GK, Tokyo, Japan
Kasia Lobello
Pfizer Worldwide Research and Development, Collegeville, Pennsylvania, USA
Introduction Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.Methods and analysis An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.Ethics and dissemination This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.Trial Registration number jRCT2051220002; Pre-results, NCT04744532; Pre-results
