Health Canada agrees to reconsider request for masitinib approval

Regulatory agency rejected add-on treatment for ALS earlier this year

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by Steve Bryson, PhD |

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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 the approval of the oral therapy.

The Canadian regulatory agency granted reconsideration eligibility to AB Science for masitinib — meaning the company now has 45 days to file a new request seeking the drug’s approval.

AB Science already has met with Health Canada to discuss the reconsideration process, the company announced in a press release. As part of the reconsideration, new assessors will re-examine the approval decision based on available data. This could take up to six months.

“The pivotal argument is on the treatment of missing data,” AB Science stated in the release, noting that analyses show the therapy was “successful” in earlier research.

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AB first asked Health Canada to approve masitinib in 2022. However, the agency paused its review after a few months, citing a need for more information. The review was 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 now is likely by June.

Masitinib is an oral therapy designed to block enzymes that drive inflammation and nerve cell death in ALS. It’s being investigated as an add-on treatment to riluzole (sold as Rilutek among others), the only therapy proven to date to slow disease progression and extend survival in people with the neurodegenerative condition.

“The recent failure of numerous phase 2 or 3 programs … have dashed the community’s hopes of benefiting from new therapeutic advances and have effectively set us back with riluzole being the only treatment with a proven modest effect in the overall ALS population,” said Albert Ludolph, MD, PhD, principal investigator of the Phase 3 trial that tested masitinib, and also medical director of the neurology department at the University of Ulm, in Germany.

“We should learn from [these] failures,” Ludolph added.

AB Science’s applications were supported by data from the AB10015 Phase 3 trial (NCT02588677), in which 394 ALS patients were randomly assigned one of two doses of masitinib (3 or 4.5 mg/kg) or a placebo, given on top of the standard ALS medication Rilutek.

Data showed that the higher masitinib dose significantly outperformed the placebo at slowing physical decline, as indicated 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 deemed normal, meaning an ALSFRS-R decrease of less than 1.1 points a month. Slower declines in lung function and quality of life also were found for these patients.

Overall, however, data showed that normal progressors with mild or moderate ALS achieved the best outcomes, with masitinib slowing the rate of disease progression by 42% and extending survival by 25 months, or just longer than two years.

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Health Canada had cited 3 issues with data from key AB10015 studt

Health Canada nevertheless rejected AB’s application, citing three limitations to the available AB10015 data.

First, the year-long study generated a great deal of missing data. To impute, or represent, these missing values, the researchers used certain statistical tests — but the agency said the resulting data could have biased the results and made masitinib appear more effective than it was.

According to AB, however, sensitivity analyses continued to support masitinib’s efficacy when the missing data were considered a placebo, a recognized conservative approach to dealing with missing data. Rerandomization, for more precise estimates of causal effects, also was successful.

“A 48-week study inevitably generates a large number of missing data,” Ludolph said, who noted that “this situation is not unique to masitinib.”

“Masitinib has published results over a 48-week period, positive when appropriate methodology to treat missing data is applied, and it deserves careful consideration,” Ludolph said.

Second, after AB10015 was completed, the developer created a new subgroup of study individuals it dubbed “patients with ALS prior to any loss of function.”

Among these patients, masitinib significantly extended overall survival versus the placebo. However, the agency said this finding was unreliable because this subgroup wasn’t part of the study’s original design.

In its release, AB noted that the subgroup, defined based on masitinib’s mechanism of action, had a significant median overall survival benefit of more than 22 months, or nearly two years, which was unlikely to be artificial because all patients had access to the same care.

Masitinib has published results over a 48-week period, positive when appropriate methodology to treat missing data is applied, and it deserves careful consideration.

Health Canada’s third issue was late-in-the-trial changes to the study protocol that were not sufficiently justified, undermining the data’s reliability. While AB previously acknowledged that the protocol changes were not data-driven, the company said they were typical for such a large clinical trial.

Further, the company also stated that 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 ALSFRS-R decline. This occurred despite the study not being statically powered for this outcome.

Lastly, progression-free survival, the time from the study’s start to the earliest date of a functional decline of at least nine ALSFRS-R points, did show significant improvement in favor of masitinib, according to AB Science.