INFORMS Published: Fingolimod Fails in Primary Progressive MS

February 19, 2016

Full details of the INFORMS trial have confirmed that the multiple sclerosis (MS) drug fingolimod did not slow progression of disability or brain volume loss vs placebo in the primary progressive form of the disease.

The trial results have now been published online in The Lancet January 27, with lead author Fred Lublin, MD, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, New York. Top-line results were announced previously by Novartis.

In the Lancet paper, Professor Lublin and colleagues note that fingolimod did show an anti-inflammatory effect in the INFORMS trial, significantly reducing the numbers of gadolinium-enhancing and new T2 lesions on brain MRI. However, unlike the situation with fingolimod in relapsing-remitting MS, this had little effect on the process that leads to brain volume loss and disability progression in the primary-progressive MS population.

They conclude that: "The results of INFORMS suggest that anti-inflammatory strategies applied at present in relapse-onset multiple sclerosis are unlikely to be beneficial in primary progressive multiple sclerosis, and that novel approaches might be needed to treat patients with primary progressive multiple sclerosis."

The authors of an accompanying editorial reach a similar conclusion. Benjamin M. Segal, University of Michigan, Ann Arbor, and Olaf Stüve, VA North Texas Health Care System, Dallas, state: "Collectively, results of clinical trials in primary progressive multiple sclerosis suggest that neuroinflammation is relevant, but might differ spatially and qualitatively from that in relapse-onset multiple sclerosis.

"Future success in drug development will depend on the ability to decipher the distinctive and overlapping immune and neurodegenerative pathways engaged in individuals with this form of multiple sclerosis," they add.

For the INFORMS study, 970 patients with primary progressive MS were randomly assigned to fingolimod or placebo. Fingolimod was initially given at a dose of 1.25 mg per day, but the protocol was changed midstudy to 0.5 mg per day on the basis of results from studies in relapsing-remitting MS.

The study used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25-foot Timed-Walk Test, and Nine-Hole Peg Test to assess time to 3-month confirmed disability progression.

With use of these measures, Kaplan-Meier estimates of 3-month confirmed disability progression worked out as 77.2% of patients in the fingolimod group vs 80.3% of patients in the placebo group (risk reduction, 5.05%; hazard ratio, 0.95; 95% confidence interval, 0.80 - 1.12; P = .544).

The researchers point out that the composite endpoint was successful in increasing the number of progression events, and outcomes of all measures included were consistent, which supports the potential usefulness of this composite endpoint in future studies of primary progressive MS.

Two key secondary endpoints were disability progression, assessed by EDSS, and percentage brain volume change, but neither endpoint was met. The researchers report that brain volume loss occurred at roughly 0.5% per year in both groups, and most patients progressed in their disability status, irrespective of treatment.

They note that that despite inclusion of older patients and those with more advanced disability than in previous trials, safety and tolerability results for fingolimod in INFORMS were in line with those of studies in relapsing-remitting MS, including cardiac conduction issues at first dose and infections.

Anti-CD20 Monoclonal Antibodies Offer Some Hope

The editorialists note that no positive results of a disease-modifying therapy in primary progressive MS have been published so far.

However, there is some hope in the form of anti-CD20 B-cell–depleting antibodies. They note that a subgroup analysis of the OLYMPUS trial of rituximab (an anti-CD20 chimeric monoclonal antibody) suggested that patients aged 51 years or younger, or patients with gadolinium-enhancing lesions on baseline MRI receiving rituximab, had a delayed time to confirmed disability progression compared with matched controls.

More recently, a positive outcome was reported in the ORATORIO trial in patients with primary progressive MS taking ocrelizumab, a fully humanized anti-CD20 monoclonal antibody.

"Results of the OLYMPUS and ORATORIO trials suggest a pathogenic role of B cells in some patients in the early stages of primary progressive multiple sclerosis," they add.

Professor Lublin reports personal fees from Bayer Healthcare, Actelion, Acorda, Questcor/Mallinckrodt, Roche/Genentech, Medimmune, Osmotica, Xenoport, Receptos, Forward Pharma, BBB Technologies, Akros, TG Therapeutics, AbbVie, and EMD Serono; grants and personal fees from Novartis, Biogen Idec, Teva Neuroscience, Sanofi /Genzyme, and Celgene; and grants from Transparency Life Sciences. Dr Segal reports personal fees from Vitae Pharmaceuticals, Novartis, Best Doctors Inc, Bristol-Myers Squibb and grants from Biogen Idec. Dr Stüve reports grants from Teva, Opexa Therapeutics, and Medscape; personal fees from Genentech, Sanofi Aventis, Huron Life Sciences, and Navigant Consulting; and travel expenses from Pfizer, Sanofi-Aventis, JAMA Neurology, Multiple Sclerosis Journal, Therapeutic Advances in Neurological Disorders, and Novartis.

Lancet. Published online January 27, 2016. Abstract Editorial

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