Bosutinib, Blood Cancer Therapy, Safe and May Help Some With ALS

Stable disease reported in 5 of 9 patients treated for 12 weeks in Phase 1 trial

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Bosutinib, an inhibitor approved to treat a blood cancer, showed no unexpected safety concerns in people with amyotrophic lateral sclerosis (ALS), with some patients experiencing slower disease progression while on the therapy, results from a Phase 1 clinical trial showed.

Larger clinical trials are needed to confirm if bosutinib could be of benefit to people with ALS.

The study, “Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial,” was published in eClinicalMedicine.

Bosutinib is an oral therapy approved to treat a type of chronic myelogenous leukemia, for which it is marketed under the brand name Bosulif by Pfizer. It belongs to a class of medications called tyrosine kinase inhibitors, commonly called TKIs, and works by blocking the activity of two proteins needed for cell growth called Src and c-Abl.

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Preclinical research has suggested that bosutinib may be useful in treating ALS. A research team at Kyoto University, in Japan, in collaboration with Pfizer and other Japanese universities, launched a Phase 1 clinical trial called iDReAM (NCT04744532) to test the therapy in adults with ALS.

The trial’s main goals were to assess the therapy’s safety profile in this population, and determine the highest dose that could be given without unacceptable safety concerns.

“This is the first study to use a Src/c-Abl inhibitor, bosutinib, for patients with ALS,” the researchers wrote.

After completing a 12-week observation period, a total of 13 people were enrolled in the study and treated with bosutinib for another 12 weeks. All had a one- to three-point decline in their ALS Functional Rating Scale-Revised (ALSFRS-R) scores, a measure of disease severity and progression marked by declining scores, during the three months of observation.

They then were divided into four groups, each receiving a different dose — 100, 200, 300, or 400 mg per day. Trial participants also stopped using their regular ALS medications, including riluzole, while being treated with bosutinib.

Side effects related to treatment were reported by all 13 participants. The most common were diarrhea, constipation, and liver problems, and most were mild or moderate in severity.

All but one of the 10 people in the three lower dose groups completed the study (the lone discontinuation was for reasons unrelated to bosutinib’s use). However, all three patients in the 400 mg dose group stopped treatment early due to intolerable side effects.

“While patients with ALS receiving bosutinib experienced [side effects] with findings consistent with bosutinib’s known profile, no specific safety profiles or concerns in patients with ALS were observed in this study, and adverse events observed in ALS were also manageable by supportive care or dose modifications,” the researchers wrote.

On review by a safety committee, all in the 400 mg dosing group were deemed to have experienced dose-limiting toxicities, including two people with signs of liver damage and one with a severe rash. In the lower dose groups, no dose-limiting toxicities were observed.

An exploratory analysis of treatment efficacy was conducted in the three lower dose groups by comparing the change in their ALSFRS-R scores between the observation and treatment periods.

Five out of these nine patients showed stable or a slower decline in ALSFRS-R scores during the 12 weeks of treatment with bosutinib. A similar proportion showed no decline in tests of hand grip strength, and two had no decline in measures of lung function.

Stable ALSFRS-R scores may link with lower levels of nerve damage marker

In a post hoc analysis — designed and carried out after all trial data had already been analyzed — the researchers found that patients with a stable outcome on ALSFRS-R generally had lower levels of neurofilament light chain (NfL) in their blood. NfL is a marker of nerve damage.

Based on this finding, the scientists speculated that low initial NfL levels could be a marker of responsiveness to bosutinib treatment. However, they stressed that these results should be interpreted cautiously due to the small number of patients evaluated, and because low NfL levels are generally associated with slower disease progression in ALS.

“A subset of patients was found to respond well to bosutinib by appearing to maintain clinical stability during 12 weeks, and the treatment-responsive patients could be distinguished by plasma NFL levels, which may be a potential predictor of drug efficacy,” the researchers wrote.

In a further set of experiments, the researchers generated motor neuron cells from samples taken from each trial participant. Motor neurons are the nerve cells that control movement and are progressively lost in ALS.

Analyses of these cells showed that neurons from patients with low or high NfL levels showed differences in the expression of several genes, including several genes known to be related to ALS.

“The genes and pathways that distinguish these high and low groups may be the target molecules that enhance the efficacy of this study drug, as well as the ALS molecular pathophysiology underlying the NFL levels,” the researchers wrote. “Since they are exploratory findings in a small number of cases, further accumulation of case and laboratory data is needed.”