ARTICLE IN BRIEF
Experts compare the latest approval of an oral drug for relapsing-remitting multiple sclerosis with other oral drugs and injectables for safety, cost, and effectiveness.
Figure. THE FDA APPR...Image Tools
A new oral multiple sclerosis (MS) drug reported to be safer, more effective, and less expensive than most alternatives could emerge as a front-line agent for relapsing-remitting multiple sclerosis (MS), according to some neurologists and industry analysts.
The US Food and Drug Administration approved dimethyl fumarate, tested as BG-12 and marketed as Tecfidera, on Mar. 27. Developed by Biogen Idec, the agent will have a wholesale annual cost of about $54,900, according to the company — about 8 percent less than the Novartis agent, fingolimod (Gilenya), which sells for about $59,595 annually.
By not establishing a new price peak among the notoriously expensive MS drugs, dimethyl fumarate could emerge as a first-line agent instead of being held in reserve until less expensive drugs have failed, experts told Neurology Today.
In two phase 3 trials, both published in the Sept. 20, 2012 issue of the New England Journal of Medicine, BG-12 cut the number of relapses in half compared with placebo. In DEFINE (Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS), a two-year study involving more than 1,200 patients with relapsing-remitting MS, BG-12 reduced relapses by 53 percent among those taking the oral medication twice daily, and by 48 percent among those taking it three times daily (p<0.001 for the comparison of each BG-12 regimen with placebo). The study also showed a reduction in disability progression of 38 percent (hazard ratio, 0.62; 95% CI, 0.44 to 0.87; p=0.005) among those taking the pill twice a day, and 34 percent for among those taking three per day (hazard ratio, 0.66; 95% CI, 0.48 to 0.92; p=0.01).
The two-year CONFIRM (COmparator and aN oral Fumarate In Relapsing-remitting MS) study, which also involved more than 1,200 MS patients, compared BG-12 with glatiramer acetate (Copaxone) and a placebo, and found that BG-12 reduced relapses by 44 percent among those who took it twice a day (0.18-0.28, 95% CI, p<0.001), and by 51 percent among those taking it three times daily (0.16-0.25, 95% CI, p<0.001). However, the trial did not find evidence that the drug reduced disability progression. Glatiramer acetate, in contrast, reduced relapses by only 29 percent (0.23-0.35, 95% CI, p=0.01) compared with placebo, and did not slow the progression of disability.
The results, which have excited neurologists and MS patients alike, followed a lackluster phase 2 trial involving 257 patients, in which BG-12 reduced relapses by only 32 percent.
“The phase 2 trial that led to phase 3 was a lot smaller,” said Michael Kaufman, MD, director of the Multiple Sclerosis Center at the Carolinas Medical Center in Charlotte, NC. “You probably should believe the phase 3 trial results, because those trials were larger and longer, so chance played less of a role. But it's a little confusing why phase 2 wasn't as good as phase 3.”
Dimethyl fumarate, a methyl ester of fumaric acid, modulates the immune system and reduces neuroinflammation apparently by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway, which encodes proteins that increase antioxidant and detoxification enzymes, according to a 2011 article in Brain. The authors of that paper found evidence of Nrf2 upregulation in the spinal cord of autopsy specimens taken from MS patients and in mouse models of MS.
The active metabolite of dimethyl fumarate — monomethyl fumaric acid — is already licensed in Germany and sold under the trade name Fumaderm as an oral treatment for psoriasis. After two physicians noticed that two patients with MS stabilized after treatment with Fumaderm, a 2006 study was conducted and found that seven relapsing-remitting MS patients showed a reduction in the number and volume of lesions after 18 weeks of treatment with Fumaderm — results that encouraged Biogen to develop the drug.
Dimethyl fumarate, once used to combat moisture and mildew in couches, shoes, and other consumer products, was blamed for an outbreak of severe dermatitis among people exposed to the compound. After a Dutch researcher established the link in a 2008 paper, dimethyl fumarate was banned for such uses in Europe.
Dimethyl fumarate is the third FDA-approved oral drug for MS following fingolimod, which reduces relapses by about 54 percent, and teriflunomide (Aubagio), which reduces them by about 30 percent — the same as older injectable drugs.
However, dimethyl fumarate produces far milder side effects than other MS medications. Around 40 percent of patients experience some gastrointestinal distress and skin flushing, which usually disappear after a few weeks of treatment.
“I'd say we have 150 to 200 patients who have been waiting for this drug to come out,” said John Corboy, MD, professor and director of neurology faculty affairs at the University of Colorado School of Medicine, who also serves on the editorial advisory board for Neurology Today. “That's not due to promotion on our part — we generally tell people if you're doing well on a drug there's no reason to stop it — but there's a high level of expectation among patients for this medication, which was not the case when the first or second oral drug came on the market.”
BG-12 requires very little monitoring, unlike fingolimod, teriflunomide, and Biogen's natalizumab (Tysabri), which is administered through an IV drip.
“When I saw the package insert I was impressed by the brevity of it,” said Dr. Corboy. “We're used to black box warnings and long discussions of side effects and lab tests. This requires almost no monitoring, and there's no risk mitigation strategy.”
An oral drug is especially welcome to long-term MS patients who have been injecting themselves with an interferon for so long they have developed induration, and have trouble finding new injection sites. “This is a drug that will be potentially attractive for new starts too because it doesn't have any significant side effects,” said Bruce A. Cohen, MD, a professor in the Davee department of neurology and clinical neurosciences at Northwestern University's Feinberg School of Medicine in Chicago. “Of course, as with any new drug, we don't know what we don't know, and problems may emerge over time, so we'll have to be vigilant, but I would say that this drug offers excellent efficacy and with modest tolerability issues.”
How does the newest MS drug compared with other MS drugs approved by the FDA in the last few years? Although natalizumab reduces relapse rates by about 68 percent, and appears to produce a 50 percent reduction in the probability of sustained disability, the drug brings with it a 1 in 3,000 chance of causing progressive multifocal leukoencephalopathy (PML), which usually causes death or severe disability. The risk of PML is increased in people who carry antibodies for the common John Cunningham, or JC virus, which typically lies dormant in the gastrointestinal tract, but can cross the blood-brain barrier and infect oligodendrocytes and astrocytes.
“We stratify the MS world into two populations — those that are JC antibody negative and those that are JC antibody positive,” said Timothy L. Vollmer, MD, professor and director of clinical research in the University of Colorado School of Medicine's department of neurology. “In JC-negative patients, natalizumab remains a very attractive therapy, but in patients who are infected with the JC virus, the cumulative risk of PML approaches 1 in 400. If chemotherapy or immunosuppressants are involved, the risk approaches 1 in 80.”
Patients who take fingolimod face a small risk of serious side effects, including skin cancer, viral infections, and potentially fatal heart rhythm disturbances.
Teriflunomide can have negative effects on blood pressure, bone marrow, liver, kidneys, skin, peripheral nerves, among other areas.
“I don't see any reason to put patients on first-line injectables now that dimethyl fumarate and fingolimod are available,” said Dr. Vollmer. “I don't know if one is superior to the other — that's still an open question — but we do know that both are superior to the current first-line agents.”
Dimethyl fumarate is likely to take the largest bite out of the market for glatiramer acetate, according to Dr. Corboy. “The main attraction for glatiramer acetate has been safety, and it is a safe drug,” he said, “but if dimethyl fumarate is perceived to be equally safe and oral and better, why would anyone take glatiramer acetate?”
LINK UP FOR FURTHER READING:
•. Gold R, Kappos L, Dawson KT, et al.for DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098–1107.
•. Fox RJ, Miller DH, Dawson KT, et al.for CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087–1097.
•. Linker RA, Lee DH, Gold R, et al.Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134 (Pt. 3):678–692.
•. Rantanen T.The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer. Br J Dermatol 2008;159:218–21.
•. Schimrigk S, Brune N, Przuntek H, et al.Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 2006;13(6):604–10.