Two studies of a new pill for multiple sclerosis (MS) suggest it may reduce relapses and disability progression in people with the more common, relapsing-remitting form of the neurological condition, which accounts for around 85% of cases.
The studies report the results of two phase 3 clinical trials, DEFINE and CONFIRM, evaluating oral BG-12 (dimethyl fumarate) for the treatment of MS. They are published in the 19 September online issue of the New England Journal of Medicine, NEJM.
The dose used in the trials was 240 mg of dimethyl fumarate, administered twice daily, or three times a day.
The results show that at this dose, compared to placebo, the drug resulted in significant and clinically meaningful reductions in MS relapses and brain lesions in patients with relapsing-remitting MS, as well as some benefit in slowing disease progression.
Experts believe MS is an autoimmune disease, where the body’s immune system reacts to normally occurring antigens as if they were a threat. This damages the nerve fibers in the central nervous system, which includes the brain, spinal cord and optic nerves, leading to a range of symptoms such as numbness in the arms and legs, fatigue, problems with vision, coordination and balance, dysfunction of bowel and bladder, pain, and even paralysis.
About 85% of people with MS have the relapsing-remitting form (RRMS), which means there are times when the disease flares up and is very active, and at other times it quietens down or remits. During remission periods, the symptoms can almost disappear, and the disease barely progresses.
Both studies were funded by the drug’s manufacturer Biogen Idec, a global biotech company, whose senior medical director for Neurology Research and Development, and lead author of both studies, is Katherine Dawson.
“The publication of both dimethyl fumarate pivotal studies in NEJM is another achievement for this important investigational therapy,” says Dawson in a press statement released on Wednesday.
“The data from its clinical development program consistently indicate that dimethyl fumarate may provide tangible benefits and address existing treatment needs of people living with MS. We are working closely with regulatory authorities across the globe with the aim of making the review of dimethyl fumarate as quick as possible,” she adds.
The drug is currently being reviewed by regulatory authorities in the United States, European Union, Australia, Canada and Switzerland.
The two studies summarize the Phase 3 clinical data from the DEFINE and CONFIRM trials: the data sets form part of the application to regulators around the world.
DEFINE was a two-year global trial that evaluated the new drug dimethyl fumarate (250 mg, twice or three times a day) against placebo in people with RRMS (relapsing remitting MS). The trial enrolled 1,237 people with RRMS.
This showed that both doses significantly reduced the proportion of patients who relapsed by 49% and 50% respectively, at two years, compared to placebo.
Compared with placebo, both doses also “significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI“, write the authors.
Lead author Ralf Gold, professor and chair of the Department of Neurology at St. Josef-Hospital, Ruhr-University in Bochum, Germany, says:
“In DEFINE, dimethyl fumarate demonstrated efficacy, as well as positive safety and tolerability profiles, which is a very attractive combination for an MS treatment.”
“Because MS is a chronic disease, we look for treatment options that not only control relapses but also slow patients’ disease progression for as long as possible,” he explains.
Like DEFINE, CONFIRM was a two-year global clinical trial that investigated the same dosage of dimethyl fumarate against placebo in people with RRMS, except it also included active agent, glatiramer acetate, as a reference comparator against placebo. The trial enrolled 1,430 people with RRMS.
The results show that both doses of dimethyl fumarate significantly reduced annualized relapse rate by 44% and 51% respectively, versus placebo, at two years.
Lead author Robert J. Fox, medical director of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio, US, says:
“Results of the CONFIRM study were consistent with those of DEFINE, demonstrating that oral dimethyl fumarate significantly reduced MS disease activity compared to placebo and has a strong safety profile.”
“I believe that these findings support the potential of oral dimethyl fumarate in RRMS for both treatment-naïve patients and those not tolerating or sub-optimally responding to currently available therapies,” he adds.
Fox is a paid adviser to Biogen Idec, but not in relation to clinical development of dimethyl fumarate.
CONFIRM was not designed to test whether dimethyl fumarate was better or worse than glatiramer acetate, which is an injectable MS drug. But in the NEJM report, the researchers include the results of a “post-hoc” analysis comparing the two drugs that might be helpful for comparing how dimethyl fumarate performs against an approved therapy for MS.
The authors conclude:
“In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo.”
The safety profile for both doses of dimethyl fumarate were largely similar in the two trials.
The overall incidence of adverse events, serious adverse events and adverse events that led to participants leaving the trial were similar in the dimethyl fumarate and placebo groups in both trials.
The most common adverse events in the dimethyl fumarate group included flushing and gastrointestinal (GI) events such as diarrhea, nausea, and abdominal pain.
Flushing and GI events were more frequent in the first month, and subsequently waned.
The most frequently reported serious adverse event across all treatment groups in both trials was MS relapse.
There were no increases in serious infections or malignancies in the dimethyl fumarate groups compared to placebo in either trial, and lab results showed mean white blood cell counts (WBCs) and lymphocyte counts went down in the first year in the dimethyl fumarate groups, then levelled off, and stayed in the normal range for the rest of the trial period.
Dimethyl fumarate, which also goes by the experimental name BG-12, is an investigational oral therapy in late-stage clinical development for the treatment of relapsing-remitting multiple sclerosis (RRMS).
It is currently the only compound known to be under investigation for the treatment of RRMS that experiments have shown activates the Nrf-2 pathway. This pathway plays a key role in helping cells defend against oxidative stress, which is thought to be involved in the development of several neurodegenerative diseases, including MS.
The drug was originally developed to treat psoriasis, an autoimmune skin disease.
Written by Catharine Paddock PhD