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November 28, 2022

Phase 1 clinical trial of bosutinib for amyotrophic lateral sclerosis (ALS); iDReAM study

A research group led by CiRA Professor Haruhisa Inoue conducted the iDReAM Study (iPSC-based Drug Repurposing for ALS Medicine Study), Phase 1 Dose Escalation Study of Bosutinib in Patients with Amyotrophic Lateral Sclerosis (ALS).

ALS is a disease caused by motor neuron degeneration that results in muscle atrophy and weakness. Although several medications are available that can alleviate the progression of ALS, no fundamental treatment has yet been established to halt the progression of the disease.

In previous studies, Inoue's group reported that the pathophysiology of ALS could be recapitulated and the drug efficacy could be evaluated using motor neurons generated from ALS patient induced pluripotent stem cells (iPSCs). Furthermore, this team has developed an induced motor neuron (iMN) system to screen compounds that can suppress motor neuron death and the accumulation of abnormal proteins, the core of the pathophysiology of ALS. Using the iMN system, the team tested various types of chemical compounds, including therapeutic drugs for other diseases, and found that the Src/c-Abl pathway is a potential therapeutic target for ALS. One of the Src/c-Abl inhibitors to show strong anti-ALS effects was bosutinib, which is used as a drug for the treatment of chronic myeloid leukemia. On the other hand, bosutinib is not approved for ALS in Japan and other countries, and its efficacy, safety, and appropriate dosage for ALS have not been established. Therefore, bosutinib is not currently available as a treatment for ALS.

In 2019, the research team, in conjunction with several hospitals in Japan, started a phase I clinical trial, the iDReAM Study, to evaluate the safety and tolerability of bosutinib in ALS patients as well as to assess its efficacy in an exploratory manner.

July 2008 Started generating iPSCs from ALS patients.
August 2012 Recapitulation of ALS pathophysiology and evaluation of drug efficacy using motor neurons generated from iPSCs derived from ALS patients are published.
May 2017 Compound screening was conducted using iMN system with iPSCs from ALS patients, and an ALS therapeutic target molecular pathway Src/c-Abl and therapeutic drug candidate bosutinib were identified.
September 2017 Conducted a preliminary meeting with the Pharmaceuticals and Medical Devices Agency (PMDA). Since then, preliminary meetings have been held a total of 4 times.
July 2018 PMDA consultation
February 2019 Approved by the Kyoto University Investigational Review Board (IRB).
Subsequent IRB approval for each investigational site.
March 2019 Clinical trial notification was submitted and the clinical trial was initiated.
September 2021 Clinical trial completed.
October 2021/
December 2021
Clinical trial results were presented at the WCN 2021 25th XXV World Congress of Neurology and the 32nd International Symposium on ALS/MND.
October 2022 Results published in THE LANCET Discovery Science, eClinicalMedicine.

To investigate the possibility of ALS-specific adverse events in 12 patients in this study, three ALS patients were first treated with a daily dose of 100 mg, and after the results were evaluated by the Safety Evaluation Committee, three other ALS patients were treated with a daily dose of 200 mg, then three other ALS patients were treated with a daily dose of 300 mg, and finally three other ALS patients were treated with a daily dose of 400 mg.

In the results, nine ALS patients who received bosutinib at daily doses of 100 mg to 300 mg completed the 12-week study; the three ALS patients who received 400 mg daily did not complete the study due to adverse events. Overall, adverse events included diarrhea and liver dysfunction. Based on the criteria specified in the study protocol, there were cases for which appropriate bosutinib dosing adjustments and management with supportive care were needed.

To explore the efficacy of bosutinib in ALS patients, the team examined changes in ALSFRS-R, a clinical score for measuring ALS symptoms; ALSFRS-R scores decrease as ALS symptoms progress. Although the number of participating patients was limited, five of the nine patients who took bosutinib for 12 weeks had reduced ALSFRS-R scores decline after taking bosutinib. Those who had a suppressed decrease in ALSFRS-R had a lower level of neurofilament L (NFL) in their blood prior to bosutinib administration.

The types of adverse events observed in ALS patients were similar to those seen in chronic myeloid leukemia (Bosulif tablets 100 mg package insert, revised June 2020), and bosutinib was found to be well tolerated at dose levels of 100 mg to 300 mg. Based on the criteria specified in the study protocol, there were cases for which appropriate bosutinib dosing adjustments and management with supportive care were needed. In an exploratory efficacy analysis, patients with lower blood NFL levels showed less decline in ALSFRS-R during the treatment period with bosutinib, and some patients showed a halt in ALS progression. However, due to the limited number of ALS patients participating in this trial, further investigation is needed. To further investigate the safety and efficacy of bosutinib, this team began the Phase II clinical trial for bosutinib in April 2022.

The results of this clinical trial were published online in THE LANCET Discovery Science, eClinicalMedicine on October 25, 2022.

Paper Details
  • Journal: eClinicalMedicine
  • Title: Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial
  • Authors: Keiko Imamura1, Yuishin Izumi2, Makiko Nagai3, Kazutoshi Nishiyama3, Yasuhiro Watanabe4, Ritsuko Hanajima4, Naohiro Egawa5, Takashi Ayaki5, Ryosuke Oki2, Koji Fujita2, Ryuji Uozumi6, Akiko Morinaga7, Tomoko Hirohashi8, Yosuke Fujii7, Takuya Yamamoto1, Harutsugu Tatebe9, Takahiko Tokuda9, Naoto Takahashi10, Satoshi Morita6, Ryosuke Takahashi5, Haruhisa Inoue1*
    *: Corresponding author
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    2. Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
    3. Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan
    4. Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
    5. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    6. Department of Biomedical Statistics and Bioinformatics, Kyoto University, Kyoto, Japan
    7. Pfizer R&D Japan G.K., Tokyo, Japan
    8. Pfizer Inc., New York, New York, USA
    9. Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan
    10. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

This research was supported by AMED under Grant Number JP18lk0201083h0003, and from iPS Cell Research Fund. The study drug bosutinib and the pharmacokinetic analysis for only patient-experienced SAEs are supported by Pfizer JAPAN INC. under the Clinical Research Collaboration Agreement. We appreciate patients and families for their willingness to participate in the study. The clinical trial part of this study was conducted in collaboration with Pfizer JAPAN INC., which provided the study drug without funding.

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