Leukemia drug decelerates amyotrophic lateral sclerosis (ALS) progression

A research team led by Professor Haruhisa Inoue of the Center for iPS Cell Research and Application (CiRA) at Kyoto University, Professor Yuishin Izumi and Lecturer Koji Fujita of the Department of Neurology at the University of Tokushima Hospital, Former Professor Ryosuke Takahashi and Former Clinical Lecturer Naohiro Egawa of the Department of Neurology at Kyoto University Hospital, Professor Kazutoshi Nishiyama and Clinical Associate Professor Makiko Nagai of the Department of Neurology at Kitasato University Hospital, Professor Ritsuko Hanajima and Associate Professor Yasuhiro Watanabe of the Department of Neurology at Tottori University Hospital, Professor Kazuma Sugie of the Department of Neurology at Nara Medical University Hospital, Professor Osamu Kano of the Department of Neurology at Toho University Omori Medical Center and Professor Hirofumi Maruyama of the Department of Neurology at Hiroshima University Hospital conducted a phase II study of bosutinib, a drug approved for treatment of chronic myelogenous leukemia, in patients with amyotrophic lateral sclerosis (ALS).

The research group announced the preliminary results showing that bosutinib decelerated the disease progression in at least 13 of 26 ALS patients who participated in the trial. Inoue of CiRA, said, "We were able to confirm a certain level of effectiveness, although the results fluctuated among the patients. We are examining all possibilities, including phase III trials, with a view to submitting an application for approval to deliver the drug to patients as soon as possible." The integrated report of the clinical trial results will be published shortly.

ALS is caused by the death of motor neurons, resulting in progressive muscle weakness and atrophy. Patients die of respiratory muscle paralysis within 2−5 years of onset. The number of patients in Japan is estimated at 9,000−11,000. Although drugs that can decelerate the progression of the disease are available, radical treatments remain to be developed.

Inoue and his colleagues have previously generated motor neurons and ALS mice from ALS patients induced pluripotent stem (iPS) cells and identified a therapeutic drug candidate that reduces motor neuron death in ALS. In motor neurons from ALS patients, autophagy is impaired due to phosphorylation of Src/c-Abl, resulting in the accumulation of misfolded proteins and the death of motor neurons.

The research group screened existing drugs and found that bosutinib, a therapeutic drug for chronic myelogenous leukemia, was effective in inhibiting phosphorylation. Thus, they began investigating bosutinib as a treatment for ALS. A phase I (physician-initiated) trial conducted from March 2019 to September 2021 identified no safety findings or concerns and suggested stabilization of motor dysfunction in some patients after 12 weeks of treatment. They also found that plasma neurofilament light (NFL) in the blood may be an ALS progression marker.

In this phase II study, bosutinib was administered for a longer period to a larger number of patients than in the phase I study. A total of 26 patients (13 each receiving 200 or 300 milligrams orally once daily after meals) participated in the study at 7 sites. The planned observation, treatment, and follow-up periods were 12, 24, and 4 weeks, respectively. The data from the clinical trials of edaravone, which is currently used as a treatment for ALS, and data from JaCALS, a registry of ALS patients, were used as the control group. Patients who developed ALS within 2 years and showed a decrease of 1−4 points in ALSFRS-R (ALS assessment score, a 48-point scale with points decreasing with muscle weakness) during the observation period were included. In each dose group, they compared the total ALSFRS-R score change from baseline at week 24 of bosutinib treatment to the external control data and found that the decrease in ALSFRS-R score in the bosutinib-treated group was significantly smaller compared to that in the placebo group of the edaravone trials.

Inoue said, "In both 200 mg and 300 mg groups, 95% confidence interval (CI) was achieved, meaning that the results of 95 out of 100 repeats should be probabilistically the same. However, compared with edaravone, we could not achieve 80% CI, although the ALSFRS-R decline was suppressed."

The comparison with JaCALS data, conducted as an exploratory evaluation, suggested the efficacy of bosutinib. Furthermore, it has been reported that the value of NFL, an ALS biomarker, remains constant on average after the onset of the disease. In the current trial, plasma NFL levels measured during the observation period before initiation of the bosutinib administration and during the treatment period showed that the mean NFL level of the patients after the bosutinib treatment was lower than the mean level before initiation of the treatment. However, since some patients showed a spontaneous decrease in NFL during the observation period, the research group will carefully evaluate the NFL changes in future analyses. The NFL will be one of the measures to evaluate ALS. When the median NFL value was used as a threshold to divide the patients into two groups, the ALSFRS-R decrease was larger in the high NFL group, while the ALSFRS-R change was smaller in the low NFL group. Inoue added, "Bosutinib may be more effective in patients with low NFL."