The developer of masitinib, an add-on treatment for amyotrophic lateral sclerosis (ALS), has been given permission to ask Health Canada to reconsider its decision earlier this year against approval of the oral treatment.
Canadian regulators have granted AB Sciences review status for masitinib. That means the company now has 45 days to submit a new application for approval of the drug.
AB Sciences has already met with Health Canada to discuss the review process, the company announced in a press release. As part of the review, the new evaluator will reconsider the approval decision based on available data. This may take up to 6 months.
“A crucial discussion concerns the treatment of missing data,” AB Science said in a release, noting that analysis showed the therapy had been “successful” in previous studies.
Masitinib was tested in approximately 400 ALS patients in a phase 3 trial.
The AB first asked Health Canada to approve masitinib in 2022, but the agency suspended the review several months later, citing a need for more information. The review was then resumed in 2023 after a revised application was submitted, but the authorities decided to reject the application in February.
Less than a month later, European Union regulators postponed a decision on masitinib, now likely until June.
Masitinib is an oral therapy designed to block the enzyme that causes inflammation and nerve cell death in ALS. This is as an add-on treatment to riluzole (sold specifically as Rilutek), the only treatment proven to date to slow disease progression and extend survival in patients with neurodegenerative diseases. being researched.
“A number of recent phase 2 or phase 3 program failures have dashed community hopes of benefiting from new therapeutic advances, with riluzole proving moderately effective across the ALS population. It has become the only treatment and we are effectively regressing,” said Albert Rudolph. , MD, is the principal investigator of the phase 3 trial testing masitinib and medical director of the Department of Neurology at the University of Ulm, Germany.
“We have to learn from [these] It was a failure,” Rudolph added.
AB Science's application was supported by data from the AB10015 Phase 3 study (NCT02588677). In this trial, 394 ALS patients were randomly assigned to one of two doses of masitinib (3 or 4.5 mg/kg) given in addition to standard ALS or a placebo. Ta. A drug called Rilutek.
Data show that high-dose masitinib is significantly more effective than placebo in slowing the decline in physical function, as evidenced by a 27% reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) scores after 1 year. It was shown that
These benefits are seen in patients whose disease progression is considered normal, meaning a decline in ALSFRS-R of less than 1.1 points per month. These patients also showed a gradual decline in lung function and quality of life.
However, overall the data show that normally progressing patients with mild or moderate ALS achieved the best outcomes, with masitinib slowing the rate of disease progression by 42% and increasing survival by 25 months, or 2 It was extended by a little more than a year.
Health Canada cited three issues with data from the main AB10015 study
Nevertheless, Health Canada rejected AB's application, citing three limitations on the available AB10015 data.
First, the 1-year study generated a large amount of missing data. To impute or represent these missing values, the researchers used specific statistical tests, but the resulting data may bias the results and make masitinib appear more effective than it actually is. Officials said it may have been.
However, according to the AB, sensitivity analyzes continue to support the efficacy of masitinib even when missing data are considered as placebo, which is recognized as a conservative approach to dealing with missing data. Re-randomization to more accurately estimate causality was also successful.
“A 48-week study inevitably generates a large number of missing data,” Rudolph said, adding that “this situation is not unique to masitinib.”
“Masitinib has published results over 48 weeks that are positive and merit careful consideration if appropriate methodology to address missing data is applied,” Rudolph said.
Second, after the completion of AB10015, the developers created a new subgroup of study subjects, which they named “ALS patients before loss of function.”
In these patients, masitinib significantly prolonged overall survival compared to placebo. But officials said the findings were unreliable because this subgroup was not part of the study's original plan.
AB said in a release that this subgroup, defined based on masitinib's mechanism of action, had a significant significant benefit with a median overall survival of more than 22 months, or nearly two years; They noted that this was unlikely to be an artifact, as patients had access to the same treatment. Care.
Masitinib has published results over 48 weeks that are positive and merit careful consideration when appropriate methodology for treating missing data is applied.
Health Canada's third issue was changes to the study design late in the trial that were not adequately justified and compromised the reliability of the data. AB previously acknowledged that the protocol changes were not data-driven, but the company said this was typical for such large-scale clinical trials.
The company also said there was a near-significant change in the secondary outcome of the Composite Assessment of Functioning and Survival (CAFS), a composite measure of survival-based outcomes and ALSFRS-R decline. This occurred despite the fact that the study was not statically powered for this result.
Finally, progression-free survival from the start of the study to the earliest date of at least a 9-point reduction in ALSFRS-R points showed a significant improvement in favor of masitinib, according to AB Science.
