Substantial data supporting both the effectiveness and safety of Mavenclad (cladribine tablets) is before the U.S. Food and Drug Administration (FDA), and may lead to its approval as a short-course oral treatment for people with relapsing-remitting multiple sclerosis (RRMS) some seven years after a first such request was made, an executive for Merck KGaA said.
“Now, we have nearly 12,000 patient years of experience … a considerable amount of new safety data … and new efficacy information” before the FDA, John Walsh, MD, vice president of neurology and immunology for US Medical Affairs, said in an interview with Multiple Sclerosis News Today at the 34th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held Oct. 10-12, in Berlin, Germany. Merck KGaA is known as EMD Serono in the U.S. and Canada.
An integrated analysis of data from three Phase 3 clinical trials — CLARITY (NCT00213135), CLARITY EXTENSION (NCT00641537), and ORACLE-MS (NCT00725985) — and an ongoing registry study (PREMIERE, NCT01013350) shows no new safety concerns in more than 2,700 patients involved, with some followed for up to 10 years.
“We feel data really builds about what’s already known about the safety and efficacy of the product, and it helps fill out a bit more of what we know already,” Walsh said, adding that it “shows consistency.”
Mavenclad demonstrated an ability to harness disease activity for up to four years in the CLARITY study, after a maximum of 20 treatment days over two years. It was approved in the European Union for RRMS patients with highly active disease in August 2017, and is now available in 41 countries to date, including Canada, Australia, and Israel.
The FDA rejected an initial request for approval in 2011, stating it thought findings supporting filing incomplete, but agreed to a new review in July.
Mavenclad can trigger side effects, including a reduction in white blood cells, leading to lymphopenia. But this depletion of white blood cells is part of the drug’s mechanism of action in MS. Studies show that Mavenclad lowers counts of both B-cells and, to a lesser extent, T-cells; immune system cells that are thought to contribute to relapsing MS.
But such depletion is transient, and new immune cells reappear, supporting suggestions that Mavenclad works by resetting the immune system.
“Cladribine tablets work by selectively targeting B and T lymphocytes,” Walsh said. “And the way it does that is to reduce the B and T lymphocytes for a short period of time, and allow them to reconstitute … and go on to allow some of the durable efficacy that we’ve seen.”
But no increased rates of infection due to a repressed immune system were seen when compared to placebo treatment, “except for a very small increase in herpes zoster, which has been mild and well-resolved, and that continues through the safety data that we’ve seen even post-marketing now, which is very reassuring,” Walsh added.
According to Gavin Giovannoni, professor at Barts and the London School of Medicine and Dentistry, who also presented data on Mavenclad at ECTRIMS, the therapy has a “high to very high efficacy range, targeting diverse MS subtypes, a very favorable safety profile, and low monitoring requirements, meaning low healthcare resources needed.”
Efficacy findings included evidence of no disease activity (NEDA) — meaning no relapses, no evidence of disease activity, and no new or active lesions seen on MRI (magnetic resonance imaging) scans — in about 47 percent of the overall patient population, Walsh said.
While the EU label limits Mavenclad to RRMS patients with highly active disease, Merck is hoping for a broader U.S. approval — one covering all with RRMS — when the FDA decision is announced in the first half of next year.
In Europe, Merck followed Mavenclad’s approval with post-marketing studies, including a two-year Phase 4 open-label trial (NCT03369665) that will evaluate health-related quality of life in patients taking Mavenclad daily. Similar studies are planned in the United States should the FDA approve Mavenclad to treat RRMS there as well, Walsh said.