Amyotrophic lateral sclerosis (ALS) is a progressive disease affecting motor neurons and causing them to degenerate, resulting in muscle atrophy and weakness. Although disease progress varies, the disease is typically fatal within a few years after onset. Several drugs have been shown to alleviate the progression of ALS, but no treatment has thus far demonstrated the ability to halt disease progression completely.

In 2017, the research team led by Inoue, using brain cells generated from amyotrophic lateral sclerosis (ALS) patient-specific iPS cells, reported that bosutinib–an approved drug for chronic myeloid leukemia treatment--showed neuroprotective effects via cell-based assays and mouse models of ALS. Given their findings, investigator-initiated clinical trials were initiated to develop bosutinib as a therapeutic drug for ALS treatment to realize the medical potential of their discovery.

From 2019 to 2021, an exploratory Phase 1 clinical trial--the iPSC-based Drug Repurposing for ALS Medicine (iDReAM) study--was conducted. Although the number of patients were limited, no ALS-specific adverse events were observed with bosutinib, some patients indicated suppression of disease progression, and potential markers of disease suppression were identified.

In 2022, a multicenter, open-label Phase 2 trial was started with more participants (26 patients) and extended treatment duration (24 weeks) compared to the Phase 1 trial. While the results did not meet one of the two secondary endpoints, both primary endpoints and the other secondary endpoint in the pre-defined efficacy criteria that were set based on the results of a previous ALS trial were met. No ALS-specific adverse events were observed.

Based on the favorable results from these Phase 1 and 2 trials, the next steps are now being considered.

The Phase 2 study was conducted by: Professor Haruhisa Inoue, Center for iPS Cell Research and Application (CiRA), Kyoto University; Professor Yuishin Izumi and Lecturer Koji Fujita, Department of Neurology, University of Tokushima Hospital; Former Professor Ryosuke Takahashi and Former Hospital Lecturer Masahiro Egawa, Department of Neurology, Kyoto University Hospital; Professor Kazutoshi Nishiyama and Clinical Associate Professor Makiko Nagai, Department of Neurology, Kitasato University Hospital; Professor Ritsuko Hanashima and Associate Professor Yasuhiro Watanabe, Department of Neurology, Tottori University Hospital; Professor Kazuma Sugie, Department of Neurology, Nara Medical University Hospital, Professor Osamu Kano, Department of Neurology, Toho University Medical Centre Omori Hospital and Professor Hirofumi Maruyama, Department of Neurology, Hiroshima University Hospital, and their research teams. The trial was conducted in collaboration with the Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS), a multicentre registry of ALS patients (President Hajime Sobue, Aichi Medical University; Associate Professor Naoki Atsuta, Central Secretariat). Pharmacokinetic analysis was conducted in collaboration with Professor Naoto Takahashi, Akita University Graduate School of Medicine.

This research was financially supported by the Japan Agency for Medical Research and Development (AMED) and the iPS Cell Research Fund. This Phase 2 trial was conducted under a collaboration agreement between Pfizer Japan, Inc. and Kyoto University, with advice and support from Pfizer Japan, Inc., including providing investigational drugs, safety information, trial design, and trial conduct management.