Enrollment in Phase 3 Masitinib Trial Expected to Soon Resume in France
AB Science’s proposed measures to ensure patient safety in clinical trials of its experimental oral therapy masitinib were deemed sufficient by the French National Agency for Medicines and Health Products Safety (ANSM), and patient enrollment in the country may resume.
The announcement comes less than two months after the company temporarily suspended recruitment and treatment in all masitinib trials, after a potential risk of ischemic heart disease — a condition of recurring chest pain or discomfort — associated with masitinib’s use was detected.
Affected trials included a Phase 3 study in amyotrophic lateral sclerosis (ALS) patients called Study AB19001 (NCT03127267), a Phase 3 trial in adults with mastocytosis, a rare immune disorder (NCT04333108), and a Phase 2 study in hospitalized patients with moderate-to-severe COVID-19 infection (NCT04622865).
“The safety of patients included in our studies is our primary concern,” Christian Fassotte, MD, AB Science’s chief medical officer, said in a press release.
“We are delighted that the safety analysis produced by AB Science and the measures proposed to strengthen patient safety will allow for the restart of our studies,” Fassotte added.
These measures include the exclusion of patients with a history of severe cardiovascular disease, and the reinforcement of tests to monitor heart health during these studies. Requests for advice from each trial’s data and safety monitoring board regarding trial conduct and cardiovascular risk will also be made, and a committee of independent experts will be established to assess major adverse cardiovascular events.
AB Science will now update each trial’s protocols with these proposed measures, and submit a request to ANSM for permission to resume patient recruitment in France. Similar requests to regulatory agencies in other countries involved in these studies, such as the U.S. and Germany, are expected to soon follow.
Masitinib is an orally available therapy designed to block the activity of several immune cells involved in inflammatory and neurodegenerative processes by suppressing the activity of specific enzymes called tyrosine kinases.
As such, masitinib is being evaluating as a potential treatment for neurodegenerative diseases that include ALS, multiple sclerosis, and Alzheimer’s, and as a possible treatment of severe asthma, COVID-19 infection, and some types of cancer.
The therapy was designated an orphan drug by the U.S. Food and Drug Administration in 2015 for its potential with ALS. This designation is meant to accelerate its development and regulatory review by providing regulatory support and financial incentives, most notably a seven-year period of market exclusivity if approved.
Study AB19001 is assessing whether a combination of masitinib and Rilutek, Sanofi’s approved ALS medication, is superior to Rilutek plus a placebo at slowing disease progression in up to 495 adults.
Eligible patients must have been diagnosed in the past two years, have mild disability — as assessed with the ALS functional rating scale-revised (ALSFRS-R) — and show normal to fast disease progression. Normal or fast ALS progression is defined as a 0.3 or greater monthly decline in ALSFRS-R scores.
Patients should also be on a stable dose of Rilutek for at least three months prior to the trial’s first visit.
Participants will be randomly assigned to one of two doses of oral masitinib (up to 4.5 or 6 mg/kg/day) plus Rilutek (50 mg), or to Rilutek and a placebo twice daily for 48 weeks (nearly one year).
The trial aims to confirm the findings of a previous 48-week Phase 2/3 study (NCT02588677), which evaluated the safety and effectiveness of a masitinib-Rilutek combination, against Rilutek plus a placebo, among 394 adults with ALS. Participants assigned to masitinib received the therapy at a daily dose of either 3 or 4.5 mg/kg.
Results from that earlier trial showed that masitinib’s 4.5 mg/kg dose, combined with Rilutek, significantly slowed patients’ disease progression by 27% and improved their quality of life and survival, compared with a Rilutek-placebo combo.
Notably, these benefits were only observed in patients whose disease prior to enrollment was progressing at a typical rate of fewer than 1.1 points per month on the ALSFRS-R scale. Those showing faster disease progression did not appear to significantly benefit from the addition of masitinib to their treatment plan.
A subsequent group analysis, however, suggested that masitinib significantly delayed disease progression in patients with fast-progressing disease who started treatment at less severe disease stages.