Dimethyl Fumarate Shows Efficacy in Phase III Clinical Studies

The first peer-reviewed phase III clinical trials of an experimental oral drug for the most common form of multiple sclerosis met their expected benchmarks of efficacy and safety this week. The findings were widely previewed at meetings and in company press releases during the last year. Dimethyl fumarate (better known as BG-12, Biogen Idec) achieved key measures in two new studies with a combined population of about 2,600 people who have relapsing-remitting MS (RRMS).

The highlights include less frequent relapses on average, slower progression to disability, and fewer new and enlarging lesions by MRI measures—all compared to placebo—as well as a sustained safety profile. The details appeared on September 20 in the New England Journal of Medicine (Fox et al., 2012; Gold et al., 2012).

"It's an oral agent with a very good safety profile that seems to be generally well tolerated," says neurologist Aaron Miller of Mount Sinai School of Medicine in New York City, who was not involved in the studies. "If it gets approved, it will be the third oral drug for MS [in the United States].” Having multiple oral options is a huge boon to MS populations, he adds, because injectable drugs have been the mainstay of therapy.

"The efficacy is not overwhelming, but it will be a welcome addition, no question," says neurologist Guy Buckle of Brigham and Women's Hospital in Boston, who also was not affiliated with the new research. "A lot of people are waiting for BG-12." Despite a standard caution about potential long-term side effects of a new drug, Buckle predicts its safety profile will make dimethyl fumarate attractive as a first-line therapy. Compared to the close monitoring required with the other oral MS drugs, "there isn't a lot to worry about," he says.

The pair of phase III studies testing oral BG-12, known as the CONFIRM and DEFINE trials, each ran for 2 years. Compared to a placebo treatment, taking BG-12 twice a day reduced annualized relapse rates in the MS patients by 44% in the CONFIRM study and by 53% in the DEFINE study. BG-12 also curbed the risk of disability progression by 38% in DEFINE and 21% in CONFIRM, although the latter finding wasn’t statistically significant; MRI findings also showed significant decreases in disease activity (see “More Than Meets the Eye” for a discussion of MRI measures in MS clinical trials). The phase III findings are holding steady for remaining study participants, who all switched to twice-daily BG-12 at the end of the trials, says neurologist Ralf Gold of Ruhr-University Bochum in Germany, first author of the DEFINE paper. He will present follow-up data at the European Committee for Treatment and Research in Multiple Sclerosis Congress meeting next month.

Although its exact mechanism in humans is unknown, dimethyl fumarate exerts neuroprotective and immunosuppressive effects in mice through a cellular antioxidant defense system called the nuclear factor E2-related factor-2 (Nrf2) pathway.

The comfort level with BG-12’s safety arises from its history as an ingredient in a psoriasis drug prescribed off-label since 1959 and licensed in Germany in 1994. In the late 1990s, German neurologist Horst Przuntek noticed remission in two MS patients who were treated for severe psoriasis with a formulation that included dimethyl fumarate, Gold says. Although that observation was never published, a subsequent pilot study in MS by Przuntek's team appeared about the time Biogen Idec acquired the drug’s maker, Fumapharm, in 2006.

By then, scientists had isolated dimethyl fumarate from the psoriasis compound, where it lurks at half the dose tested in the newly published trials. The MS formulation seems to have the same flushing and gastrointestinal side effects as the psoriasis drug, although BG-12 is made with a coating to help protect against the GI symptoms. About 80% of participants completed the current trials, with mild to moderate diarrhea, nausea, upper abdominal pain, and flushing occurring in about one-third of patients on twice-daily BG-12.

"If patients can keep on the drug for several weeks, those short-term reactions disappear," says Gavin Giovannoni, a neurologist at the London School of Medicine and Dentistry in the United Kingdom, who was an investigator in the DEFINE trial (and is also an MSDF scientific adviser). "There's nothing new in the side effect profile. The psoriasis legacy is the biggest selling point."

The safety issue may become a deciding factor in choosing a first-line oral drug for a newly diagnosed person with RRMS or someone switching from an injectable, says Trevor Kilpatrick, a neurologist at the Melbourne Brain Centre in Australia. The two oral agents approved by the U.S. Food and Drug Administration (FDA) require close monitoring, which is a big hassle, he and others say. Although fingolimod (Gilenya, Novartis) reduced relapses by 54% compared to placebo in its phase III trial, its use requires a battery of initial and follow-up tests—including an ophthalmologic exam, electrocardiogram, and a 6-hour observation of patients after they receive their first dose to prevent fatal heart failure. Teriflunomide (Aubagio, Sanofi Aventis), approved by the FDA last week, reduced relapses by 31% but came with a warning of potential birth defects and fatal liver damage. "You can't have someone getting pregnant on teriflunomide," Buckle says, which he calls a major consideration in treating a disease that affects young women.

Although the new studies do not directly indicate how well BG-12 works compared with any other MS drug, their results seem to position dimethyl fumarate at midlevel effectiveness, say several neurologists consulted for this article. CONFIRM did include a glatiramer acetate (Copaxone, Teva) reference arm, primarily to satisfy European Union regulatory authorities, says Biogen Idec spokesperson Kate Niazi-Sai; the paper explicitly cautions that the study was not designed to test BG-12’s efficacy relative to glatiramer acetate. But the older drug—in its phase III trial (Johnson et al., 1995) as well as in CONFIRM—registered a 29% reduction in the annualized relapse rate.

The data from the phase III studies form the basis of Biogen’s New Drug Application for the twice-daily dose, submitted to the FDA on February 28. The company expects a decision in December or January, Niazi-Sai says. A full-page advertisement on the back cover of a recent issue of Neurology promises: "Coming soon from Biogen Idec/dimethyl fumarate." The company declined comment on the anticipated pricing of the oral agent.

Remarking on the new research in an accompanying editorial (Ropper, 2012), Allan Ropper, a neurologist at Brigham and Women's Hospital, cautions that long-term outcomes on BG-12 are still needed. Published trials for drug approvals "all make new drugs look favorable in the short run," he points out. "Even fumarate will need to prove that its efficacy is durable by reducing disability over the many decades that encompass the representative course of multiple sclerosis."

Key open questions

• Will the promising short-term effects of dimethyl fumarate hold up over the many decades of a typical MS disease course?
• Will the risk of serious opportunistic infections increase if combined or used serially with other drugs?
• What additional information does the glatiramer acetate arm give if it cannot provide evidence of superiority or noninferiority?
• How does dimethyl fumarate work in people?