Fingolimod Trial in Progressive MS Misses Endpoint

Susan Jeffrey

December 01, 2014

Topline results of a phase 3 trial examining the use of fingolimod (Gilenya, Novartis Pharmaceuticals) in patients with primary progressive multiple sclerosis (PPMS) show the trial missed the primary endpoint, a combination of disability measures, Novartis reports.

Results of the INFORMS trial showed no significant difference between patients treated with fingolimod or placebo on the primary endpoint, the risk for 3-month sustained disability progression based on a composite of the Expanded Disability Status Scale (EDSS), assessment of upper-limb function, and walking speed.

"We understand this news is very disappointing for those affected by PPMS and involved in its management," said Vasant Narasimhan, global head of development at Novartis Pharmaceuticals, in a statement released December 1. "While PPMS is a focus of the MS community, relatively little is known about the disease so finding effective treatments remains a challenge. We will actively work with the MS community to review and analyze the INFORMS results to help increase the understanding of this devastating disease."

Fingolimod is already approved in the United States and elsewhere for the treatment of relapsing MS and was the first oral agent approved for that indication. Safety results in INFORMS were "consistent with the well-characterized safety profile" in relapsing MS, the statement says.

Distinct Disease Form

PPMS is a disease form distinct from relapsing MS in terms of the disease process, with few acute relapses and less-active lesions on MRI, the Novartis statement notes. The central nervous system damage is thought to be caused via different pathways, with a continuous loss of function over time, and typically later diagnosis than seen with relapsing MS.

"Despite considerable research and academic focus, there are currently no approved treatments that have been shown to change the course of this debilitating disease and management focuses mainly on the treatment of symptoms," the release notes.

The aim of the INFORMS study was to see whether fingolimod might affect the disease process in PPMS. This randomized, double-blind, multicenter, placebo-controlled, parallel-group study included 970 patients, making it the largest trial to date in PPMS, the company statement says. Patients were enrolled from 148 sites across 18 countries.

Patients were randomly assigned to receive fingolimod (0.5 mg) or placebo and were treated for 3 years.

The primary endpoint was the risk for 3-month sustained disability progression based on a composite measure of the EDSS, assessment of upper-limb function by using the 9-Hole Peg Test, and walking speed on the 25-foot Timed Walk Test.

Fingolimod acts not only peripherally but centrally, entering the central nervous system, the Novartis statement notes. "It was hypothesized that this central effect, which is well understood in relapsing forms of MS, would also be relevant in PPMS. As opposed to the consistently strong efficacy seen in relapsing MS, the results of the INFORMS study seem to suggest that PPMS and relapsing forms of MS have different underlying mechanisms."

Phase 3 studies of fingolimod are ongoing in pediatric MS and chronic inflammatory demyelinating polyradiculoneuropathy, "where there is a high unmet need," the Novartis statement adds.

The company is also investigating BAF312, or siponimod, a second-generation selective S1P1 and 5 receptor modulator in the largest phase 3 trial in secondary progressive MS. "The IL-17 pathways is also being explored as a novel therapeutic target in MS," it notes.

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