Active Biotech acknowledged in an update on laquinimod, the oral small molecule being developed by Teva Pharmaceutical Industries to treat multiple sclerosis (MS) and Huntington’s disease (HD), that the U.S. Food and Drug Administration (FDA) has rescinded the special protocol assessment given to a Phase 3 study of the treatment in relapsing MS patients because of a dose change that — necessarily, the company said — was made without prior FDA approval.
Laquinimod, which Active and Teva are working together to develop, is being evaluated for safety, efficacy and tolerability in the CONCERTO study (NCT01707992), a double-blind and placebo-controlled trial that was investigating two oral doses of laquinimod — 0.6 mg/day or 1.2mg/day — in relapsing MS patients. But the Data Monitoring Committee (DMC) supervising this trial and a similar study in progressive MS patients recommended use of higher doses be discontinued immediately in January, after cardiovascular events were reported in eight patients (none fatal) — seven in the relapsing MS and one in the progressive MS studies.
According to an Active Biotech press release, “Teva submitted to the FDA an amendment to the SPA to account for this change [in February]. However, per FDA regulatory process, the SPA [special protocol assessment] was rescinded as all changes must be agreed to prior to implementation of the change. This requirement could not be fulfilled in the current case, since the DMC recommendation triggered an immediate action … in the interest of patient safety.”
Primary progressive MS patients are enrolled in the Phase 2 ARPEGGIO trial (NCT02284568), which had also been evaluating the treatment at two doses — 0.6 mg or 1.5 mg — against placebo. Only the lower dose is continuing in this study as well.
Development of laquinimod has been through some rough patches. In 2014, the European Union’s Committee for Medicinal Products for Human Use (CHMP) did not recommend the first marketed version of laquinimod (Nerventra) as a therapy for relapsing MS. It is also not approved by the FDA. Since the CHMP opinion, Active Biotech and Teva have worked to further develop the drug and invested in strengthening its studies.
In April, Teva presented three posters at the 68th Annual Meeting of the American Academy of Neurology (AAN), reporting on evaluations of the lower dose of laquinimod.
Teva plans to use data from the CONCERTO trial to support the filing of a new marketing approval application in the United States and Europe.