Europe’s CHMP recommends against masitinib authorization
Developer AB Science says it will ask for re-examination
An advisory committee of the European Medicines Agency (EMA) has recommended against granting conditional marketing authorization to masitinib as an oral add-on treatment for amyotrophic lateral sclerosis (ALS).
The negative opinion by the Committee for Medicinal Products for Human Use (CHMP) confirms the committee’s view, announced last month, that there were a number of unresolved issues with trial protocol and data analyses, despite no concerns about safety.
Developer AB Science said it plans to ask for re-examination, though in a press release it highlighted “the difficulty of a conditional marketing authorization in ALS” and said it “cannot guarantee a positive outcome following this re-examination.”
Masitinib is a small molecule designed to potently inhibit tyrosine kinases, a type of enzyme that helps immune cells mount an inflammatory response. Inhibiting these enzymes is expected to reduce inflammation and protect nerve cells from damage in ALS, slowing disease progression.
The company’s application drew on data from AB10015 (NCT02588677), a Phase 2/3 clinical study that involved 394 adults with ALS. The trial tested two doses of masitinib — 3 or 4.5 mg/kg — against a placebo, given twice daily for nearly one year on top of the standard ALS medication Rilutek (riluzole).
Disease progression slowed
In a group of patients with normal disease progression, defined as an ALS Functional Rating Scale-Revised (ALSFRS-R) decline rate of less than 1.1 points per month, the 4.5 mg/kg dose of masitinib slowed disease progression by 27% versus a placebo, meeting the trial’s main goal.
The combination therapy also led to significantly slower declines in quality of life and lung function in patients progressing normally, but no changes were observed in fast-progressing patients.
When normal and fast-progressing patients were examined together, those with mild or moderate ALS benefited the most, living more than two years longer and progressing 42% slower with masitinib than with a placebo.
When reviewing the efficacy data, the CHMP identified issues with the way the study was run that could not be addressed. The company said concerns about good clinical practice were addressed by showing that deviations from standard procedures did not affect the results.
The CHMP also expressed concerns with the decision to exclude patients with fast-progressing disease from the primary analysis, but the company maintained that a more consistent population was needed to complete the study. Exclusion was done while the study was blinded, which eliminates any bias, AB Science said.
The advisory committee also objected to the analyses of mild or moderate ALS patients. The company said it was following EMA’s guidelines for post-hoc analyses (those conducted after the study is complete and all the data has been gathered) to identify a group with a convincing risk-benefit profile. The group also “showed extremely compelling results, including a significant 12 months survival benefit,” the company wrote.
The company also said it tackled issues with how missing data were handled, with different statistical analyses recommended by the CHMP showing consistently positive results.
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