Remyelination Therapy Promising in Multiple Sclerosis

Megan Brooks

September 08, 2014

An experimental monoclonal antibody for multiple sclerosis (MS) that enhances remyelination has shown promise in phase 1 studies.

The emerging safety, tolerability and pharmacokinetics data for BIIB033 (Biogen Idec), "support advancing the drug into phase 2 clinical development as a potential treatment for CNS [central nervous system] demyelination disorders," the investigators say.

"This was the first MS drug candidate to enter clinical development with the aim of remyelinating/repairing the myelin," senior author Diego Cadavid, MD, from Biogen Idec and member of the American Academy of Neurology, told Medscape Medical News.

"This is a unique drug candidate as all currently available MS treatments are anti-inflammatory or treat symptoms, but none of them are reparative treatments," he noted.

The phase 1 data on BIIB033 were published online August 27 in Neurology, Neuroimmunology and Neuroinflammation, a new online-only journal from the American Academy of Neurology.

Phase 1 Studies

BIIB033 selectively blocks leucine-rich repeat and immunoglobulin domain–containing neurite outgrowth inhibitor Nogo receptor-interacting protein-1 (LINGO-1), a protein expressed in neurons and oligodendrocytes that naturally inhibits oligodendrocyte differentiation and myelination. In animal studies, blocking LINGO-1 results in remyelination of CNS demyelination.

Two separate randomized, placebo-controlled, phase 1 studies of BIIB033 were conducted. In 1 study, 72 healthy volunteers received single ascending doses (0.1 to 100 mg/kg) of BIIB033 or placebo via intravenous infusion or subcutaneous injection. In the other, 47 patients with relapsing-remitting or secondary progressive MS received multiple ascending doses (0.3 to 100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo via intravenous infusion.

BIIB033 infusions were well tolerated, the researchers report, with a similar frequency of adverse events in BIIB033 and placebo recipients. No serious adverse events or deaths occurred.

The pharmacokinetics of BIIB033 was similar between healthy volunteers and patients with MS.

Of note, the researchers say BIIB03 doses of 10 mg/kg or greater resulted in concentrations of the drug similar to or higher than the concentration associated with 90% of the maximum remyelination effect seen in rat remyelination studies.

Transient development of antidrug antibodies following BIIB033 administration was seen in only 1 patient, and it had no detectable effect on pharmacokinetic levels or adverse events, the researchers report.

"With these results we have been able to start phase 2 studies to see whether this drug can actually repair the lost myelin in humans and have any effect on restoring physical and cognitive function and improving disability," Dr. Cadavid said in a statement.

"Two phase 2 trials are in progress: one in acute optic neuritis (RENEW trial) and the other in relapsing forms of MS (SYNERGY trial)," he told Medscape Medical News. "Both are fully enrolled."

Topline results from the RENEW trial are expected in January 2015, with full data to be presented at a medical congress in 2015, Dr. Cadavid said. The SYNERGY data are expected in 2016.

Biggest Challenge

Pedro Brugarolas, PhD, and Brian Popko, PhD, from the Department of Neurology, University of Chicago, Illinois, comment on the phase 1 data on BIIB033 in an accompanying editorial.

They say that while the low rate of antibodies against BIIB033 is "encouraging," the patients received only 1 or 2 doses of the drug, "which is not representative of the therapeutic paradigm in the long-term. Unfortunately, they also found antibodies against BIIB033 in one placebo-treated individual (false-positive), which indicates that a better assay may be needed."

"Perhaps the biggest challenge for bringing myelin repair therapies to the clinic is how to monitor efficacy," Dr. Brugarolas and Dr. Popko point out. Accurate methods to assess remyelination are "critical, and to date there are no fully validated tools to quantify this reparative process," they note.

In the near future, it's likely that many trials will test drugs that have been shown to enhance remyelination in murine models, the editorial writers say.

"Soon we should know whether this approach will provide benefit to patients with MS, which would be the first evidence that enhancing myelin repair may alter the course of this disease. Although the jury is still out on the phase II trial, the phase I verdict is promising," they conclude.

The study was supported by Biogen Idec. Five of the authors are employees of the company. A complete list of author disclosures appears with the original article and editorial.

Neurol Neuroimmunol Neuroinflammation. Published online August 27, 2014. Abstract Editorial

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