Health Canada rejects masitinib application; reconsideration sought
Therapy is designed to block enzymes that drive ALS inflammation, nerve death
Health Canada has issued a notice of noncompliance-withdrawal saying it won’t approve the oral therapy masitinib as an add-on treatment for amyotrophic lateral sclerosis (ALS).
Its developer, AB Science, can submit a request for reconsideration within the next month, which it plans to do, it announced in a press release. As part of a reconsideration, which could take up to six months, new assessors will re-examine the decision based on available data.
AB first sought Health Canada’s approval in 2022, but the review was paused after a few months because the regulatory agency said it needed more information from AB. Health Canada resumed its review in May 2023 after a revised application was submitted.
The rejection comes less than a month after authorities in Europe delayed a ruling on masitinib.
The oral therapy is designed to block enzymes that drive inflammation and nerve death in ALS, which is expected to slow disease progression.
Outcomes of Phase 2/3 clinical trial
AB’s applications are based mainly on data from a Phase 2/3 clinical trial called AB10015 (NCT02588677). The study enrolled 394 people with ALS who were given one of two doses of masitinib (3 or 4.5 mg/kg) or a placebo as an add-on to the approved treatment Rilutek (riluzole).
After nearly a year, the rate of disease progression — measured by the ALS Functional Rating Scale Revised or ALSFRS-R — was 27% slower in those given the higher masitinib dose over a placebo.
This was observed in the patients with “normal” disease progression, defined as an ALSFRS-R decline of less than 1.1 points a month, who also had significantly slower declines in lung function and quality of life.
The greatest benefits, however, were seen in normal progressors with mild or moderate ALS. In these patients, masitinib slowed the rate of disease progression by 42% and extended survival by 25 months.
The basis for rejecting masitinib
In its notice, Health Canada highlighted three issues with the available data from the AB10015 study. First, the agency said changes in the study protocol were made late in the trial and weren’t sufficiently justified, leading to uncertainty about how reliable the results are. Second, the agency expressed concern that some statistical tests used to account for missing data could have biased the results, making it seem like masitinib was more effective than it really was.
In its press release, AB acknowledged that changes to the protocol were not data-driven and that they were within the normal range for a large clinical trial. The company also argued that many different statistical tests to account for missing data consistently indicate a clinical effect of masitinib.
The third issue raised by Health Canada is that, as part of its application, AB defined a new subpopulation of ALS patients, namely “patients with ALS prior to any loss of function.” In this subpopulation, overall survival was extended with masitinib compared to a placebo, but Health Canada said this finding isn’t reliable because the subgroup was defined after the study was already over, rather than being considered as part of its original design.
AB said the subpopulation was defined based on guidelines from European regulators and is logical given the push to start treating ALS as soon as possible. The company said improvements in overall survival seen in this subgroup are unlikely to be artificial because all the patients had access to the same supportive care, except that some were given masitinib and others got a placebo.
These counterarguments will form the basis of AB’s request for reconsideration, the company said.
The company is also conducting a global Phase 3 clinical trial (NCT03127267) to further support masitinib as an add-on treatment to Rilutek. The study will include 495 participants with mild to moderate ALS who were diagnosed less than two years before screening. They will receive daily masitinib (4.5 or 6 mg/kg) or a placebo for nearly a year while continuing Rilutek.
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