The developer of the add-on treatment masitinib for amyotrophic lateral sclerosis (ALS) has been given the go-ahead to ask Health Canada to reconsider its decision from earlier this year against approving the oral therapy.
Canada’s regulatory agency granted AB Science a right of review for masitinib — meaning the company now has 45 days to submit a new request for approval of the drug.
AB Science has already met with Health Canada to discuss the review process, the company said in a press release. As part of the review, the new assessors will revise the approval decision based on the available data. This can take up to six months.
“The main argument is about treatment missing data,” AB Science said in the release, noting that analyzes showed the therapy was “successful” in earlier studies.
Masitinib has been tested in nearly 400 ALS patients in a phase 3 trial
AB first asked Health Canada to approve masitinib in 2022. However, the agency halted its review after several months, citing a need for more information. The review then resumed in 2023 after a revised application was submitted, but the agency decided in February to reject that request.
Less than a month earlier, regulators in the European Union had delayed their decision on masitinib, which is now likely to be until June.
Masitinib is an oral therapy designed to block enzymes that cause inflammation and death of nerve cells in ALS. It is being studied as an add-on treatment to riluzole (sold as Rilutek among others), the only therapy to date shown to slow disease progression and prolong survival in people with the neurodegenerative condition.
“The recent failure of multiple phase 2 or 3 programs … dashed the community’s hopes of benefiting from new therapeutic advances and effectively set us back with riluzole, the only treatment with a modest effect demonstrated in the general ALS population,” said Albert Ludolf, MD , PhD, principal investigator of the phase 3 trial testing masitinib and also medical director of the department of neurology at the University of Ulm, Germany.
“We have to learn from [these] failed,” added Ludolph.
AB Science’s applications were supported by data from the AB10015 phase 3 study (NCT02588677), in which 394 ALS patients were randomly assigned to one of two doses of masitinib (3 or 4.5 mg/kg) or placebo given in addition to the standard ALS drug Rilutek.
The data showed that the higher dose of masitinib was significantly superior to placebo in slowing physical decline, as shown by a 27% reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) scores after one year.
These benefits were seen in patients with disease progression considered normal, meaning a decrease in ALSFRS-R of less than 1.1 points per month. A slower decline in lung function and quality of life was also found in these patients.
Overall, however, the data showed that patients with normal progression of mild to moderate ALS fared best, with masitinib slowing the rate of disease progression by 42% and extending survival by 25 months, or just over two years.
Health Canada cites 3 issues with data from key AB10015 studt
However, Health Canada rejected AB’s application, citing three limitations of the available data AB10015.
First, the one-year survey generated a lot of missing data. To impute or represent these missing values, the researchers used certain statistical tests — but the agency said the resulting data may have biased the results and made masitinib appear more effective than it was.
However, according to AB, sensitivity analyzes continued to support the efficacy of masitinib when missing data were treated as placebo, a recognized conservative approach to dealing with missing data. Re-randomization for more precise estimates of causal effects was also successful.
“A 48-week study inevitably generates a large number of missing data,” said Ludolph, who noted that “this situation is not unique to masitinib.”
“Masitinib posted results over a 48-week period that were positive when appropriate methodology was applied to treat missing data, and merits careful consideration,” Ludolph said.
Second, after AB10015 was completed, the developer created a new subgroup of study subjects that it called “pre-loss-of-function ALS patients.”
Among these patients, masitinib significantly prolonged overall survival compared with placebo. However, the agency said this finding is unreliable because this subgroup was not part of the original study design.
In its announcement, AB noted that the subgroup defined based on the mechanism of action of masitinib had a significant median overall survival benefit of more than 22 months, or almost two years, which is unlikely to be artificial because all patients had access to the same care.
Masitinib has published results over a 48-week period that were positive when appropriate methodology was used to treat missing data, and merits careful consideration.
Health Canada’s third problem was late changes to the study protocol that were not sufficiently justified, undermining the reliability of the data. While AB previously acknowledged that the protocol changes were not data-driven, the company said they were typical of such a large clinical trial.
In addition, the company also said there was a near-significant change in the secondary outcome of the Combined Assessment of Function and Survival (CAFS), a composite measure of survival-based outcomes, and the ALSFRS-R decline. This occurred even though the study was not statically powered for this outcome.
Finally, progression-free survival, the time from the start of the study to the earliest date of functional decline of at least nine ALSFRS-R points, did show a significant improvement in favor of masitinib, according to AB Science.
