AB Science expects negative opinion on masitinib application in Europe
CHMP is expected to adopt formal decision in June
An advisory committee of the European Medicines Agency (EMA) is leaning against recommending the conditional approval of AB Science’s masitinib as an oral add-on treatment for amyotrophic lateral sclerosis (ALS), the company has announced in a press release.
The Committee for Medicinal Products for Human Use (CHMP) is expected to adopt a formal decision when it meets in late June. AB Science said it will work with CHMP to find the best path forward, including possibly requesting a re-examination.
The decision was pushed back earlier this year for the second time due to unresolved issues. The committee asked for written responses to questions instead of oral explanations, which delayed the evaluation process.
In a live webinar on May 30, AB Science said CHMP determined masitinib was safe, but “was not able to conclude on a favorable benefit.”
Masitinib is a small molecule that inhibits tyrosine kinase, a type of enzyme involved in the proliferation and activation of certain immune cells that drive ALS inflammation. By inhibiting the enzyme, masitinib should reduce inflammation and damage to slow the disease’s progression and ease symptoms.
AB Science’s application was based on data from the Phase 2/3 clinical study AB10015 (NCT02588677) wherein 394 adults with ALS tested two daily doses of masitinib (3 or 4.5 mg/kg) against a placebo given on top of Rilutek (riluzole), an approved ALS treatment.
The higher masitinib dose significantly outperformed the placebo at slowing disease progression in people with so-called normal progression, or a decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores of less than 1.1 points a month. In these patients, 4.5 mg/kg of masitinib resulted in a 27% lower decline in ALSFRS-R scores after nearly a year, but no changes were observed in patients progressing faster than normal.
Regardless of the initial rate of disease progression, a group of patients who had mild or moderate ALS saw the most benefit, as indicated by up to 42% less reduction in ALSFRS-R scores compared with the placebo.
Issues with masitinib for CHMP
The issues noted by CHMP after a recent oral explanation of the data included deviations from good clinical practice (GCP) that are standard for designing, recording, and reporting clinical studies.
While the deviations “cannot be corrected retrospectively,” the company said the drug’s risk-benefit can still be evaluated, as ALSFRS-R scores are reliable and continue to show benefit upon re-analysis.
CHMP is also concerned AB Science has excluded patients with fast-progressing disease from the primary analysis, but the company maintains there’s “a necessity in ALS drug development to use a more homogenous [consistent] population with greater chance [to reach the proposed follow-up time] and minimize missing data.”
Another issue relates to handling of missing data. According to CHMP, “jump to reference,” whereby the outcomes of a patient who has dropped out of the study are assumed to “jump” to those of the placebo group should be applied to all cases of discontinuation.
AB Science said the reasons for dropping out were recorded and “jump to reference” was applied to discontinuations due to side effects, lack of efficacy, and traveling. The results of two alternative methods, both recommended by CHMP, were consistently positive.
Lastly, determining if an analysis of mild or moderate ALS patients is justified involves assessing whether the group skews the results or provides a clearer understanding about how well masitinib works.
To justify the decision, AB Science cites EMA’s guidelines, according to which it’s “of interest to identify post hoc [after the study is conducted] a subgroup, where efficacy and risk-benefit is convincing,” regardless of whether the subgroup is identified by the company itself. AB Science notes that benefits in that group were observed in a variety of clinical endpoints, including a “12 months survival benefit [that] cannot be disregarded.”
AB Science also presented the issues on the basis of Health Canada’s rejection of masitinib for ALS, which were slightly different from the ones raised by EMA’s committee, the company said in a summary of the live webcast. Health Canada agreed in April to reconsider the application.
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