FDA Approves Dimethyl Fumarate for Treatment of Relapsing Forms of Multiple Sclerosis

By: Andy Zhang, PharmD Candidate c/o 2015

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On March 28, 2013, the U.S. Food and Drug Administration announced the approval of Tecfidera™ (dimethyl fumarate) for the treatment of relapsing forms of multiple sclerosis (MS) in adults.¹ Tecfidera™ (dimethyl fumarate) will be the third oral drug used for the treatment of MS. The manufacturer Biogen Idec, a leader in multiple sclerosis drugs, has also produced other successful MS drugs in the past, such as Tysabri® (natalizumab) and Avonex® (Interferon β-1a).²

MS, the disease Tecfidera™(dimethyl fumarate) treats, is a chronic inflammatory disease that targets the myelin in the central nervous system. Demyelination of axons can lead to irreversible damage, which inhibits proper conduction of nerve impulses in the central nervous system (CNS). This produces neurologic symptoms that vary from patient to patient in both severity and type.⁴ The exact pathogenesis of the disease is still unknown; however, there is convincing evidence that the disease is an autoimmune process in which the patient’s own T-cells target the body’s myelin and oligodendrocytes, the cells that produce myelin in the CNS.³ The disease occurs two to three times more often in women than in men, especially between the age of 20 and 50; however, it can affect both young children and older adults. About 85% of the patients are initially diagnosed with relapsing-remitting, and 50% of these patients progress into secondary-progressive MS within ten years of initial diagnosis.⁴ MS has debilitating effects on patients’ quality of life.

Currently, there is no cure for MS. Treatments aim to break acute attacks and relapses, alleviate symptoms, and modify the course of the disease.³ Disease modifying agents can help reduce the disease activity and slow down the disease progression for patients with relapsing forms of MS. Examples of such agents include interferon-beta products such as glatiramer acetate (Copaxone®), natalizumab (Tysabri®), fingolimod (Gilenya®), and mitoxantrone (Mitoantrone injection®).⁴  The standard intervention for acute exacerbations is short term intravenous injection of high-dose corticosteroids.³ Tecfidera™(dimethyl fumarate) is an immunomodulator that has been approved for the treatment of relapsing MS.

Two global, randomized, multi-center, double-blind, placebo-controlled, dose comparison Phase III clinical trials (DEFINE and CONFIRM) were conducted to demonstrate the safety and efficacy of Tecfidera™(dimethyl fumarate) in treating MS.⁵ The doses used in the trials were 240mg twice a day and 240mg three times a day. The primary end point of the DEFINE trial was the proportion of patients who relapsed within two years, and that of the CONFIRM trial was the annualized relapse rate over a period of two years.^6,7 In the DEFINE trial, the percentage of patients who had at least one relapse of MS in two years was lower in both treatment groups compared to the placebo group (27% for twice daily, 26% for thrice daily, and 46% for placebo).⁶ Secondary endpoints also showed that patients in the both treatment groups took longer to relapse (87 and 91 weeks for twice daily and thrice daily, respectively, and 38 weeks for placebo group).⁶ Results from the CONFIRM trial showed that patients in both treatment groups had a lower frequency of relapse compared to the placebo (adjusted annualized relapse rate at two years of 0.22 and 0.22 for twice daily and thrice daily, respectively, and 0.4 for placebo).⁷

Tecfidera™(dimethyl fumarate) has an overall favorable efficacy and safety profile compared to the other two oral agents fingolimod (Gilenya®) and teriflunomide (Aubagio®).⁸ While there are no direct comparisons done between the three oral agents, it seems that dimethyl fumarate (Tecfidera™) might be equally efficacious to fingolimod (Gilenya®) and be slightly better than teriflunomide (Aubagio®) for reducing relapses.⁸ Dimethyl fumarate has been used to treat psoriasis in Germany, and observational studies over the past 14 years has not shown serious or permanent adverse events, supporting a long history of safe use.⁹

Tecfidera™(dimethyl fumarate) is available in120mg and 240mg capsules, and has a dosing regimen as follows: starting dose of 120mg twice a day orally for 7 days, followed by a maintenance dose of 240mg twice a day orally. The capsule should be swallowed whole, and should not be crushed, chewed, or sprinkled on food. Most common adverse events are flushing and gastrointestinal events. Tecfidera™(dimethyl fumarate) is Pregnancy Category C¹⁰and may decrease lymphocyte count, so a recent complete blood count is recommended before initiation of therapy to identify patients with pre-existing low lymphocyte count.¹⁰ No serious infections were observed during the clinical trials even with the decreased lymphocyte count, and the incidence of infections were the same between patients treated with Tecfidera™(dimethyl fumarate) and placebo.^6,7,10

With the introduction of Tecfidera™ (dimethyl fumarate), there is now an alternative oral treatment which seems to have a safety profile comparable to the two other oral agents–fingolimod (Gilenya®) and teriflunomide (Aubagio®)—for MS. Some physicians and pharmacists might be enticed to try dimethyl fumarate over the injectible drugs as first line agent for treatment of MS, but further studies needs to be done to directly compare the different treatments before it can be proven to be a better first-line agent.

SOURCES:

1. Yao, Stephanie. FDA Approves New Multiple Sclerosis Treatment: Tecfidera. U.S. Food and Drug Administration. Updated March 28, 2013. Accessed May 24, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345528.htm
2. Pollack, Andrew. 3^rd Oral Drug to Treat MS Is Approved by the F.D.A. The New York Times. http://www.nytimes.com/2013/03/28/business/3rd-oral-drug-to-treat-ms-is-approved-by-the-fda.html?_r=0. Accessed May 24, 2013.
3. Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC. Chapter 64. Multiple Sclerosis. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds.Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7984977. Accessed May 24, 2013.
4. What Is Multiple Sclerosis? National Multiple Sclerosis Society Web Site. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/what-is-ms/index.aspx. Accessed May 24, 2013.
5. Tecfidera (dimethyl fumarate) Clinical Development Background. Biogen Idec. http://www.biogenidec.com/Files/Filer/USA/pdfs/Clinical-Trial-Fact-Sheet-FINAL.pdf. Accessed May 24, 2013.
6. Gold, R., Kappos, L., Arnold, D. L, et al;(2012). Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. New England Journal of Medicine 2012, 367(12), 1098–1107. DOI:10.1056/NEJMoa1114287. Epub 2012, Sept 20. http://www.nejm.org/doi/full/10.1056/NEJMoa1114287#t=article. Accessed May 24, 2013.
7. Fox, R. J., Miller, D. H., Phillips, J. T, et al;(2012). Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis. New England Journal of Medicine 2012, 367(12), 1087–1097. DOI:10.1056/NEJMoa1206328. Epub 2012, Sept 20. http://www.nejm.org/doi/full/10.1056/NEJMoa1206328#t=article. Accessed May 24, 2013.
8. Hester, Stacy. New Drug: Tecfidera (Dimethyl Fumarate). Pharmacist’s Letter [Internet]. [cited May 24, 2013]; 29/-(5):290512. Available from: http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=STUDENT&s=PL&pt=6&fpt=56&dd=290512&pb=PL
9. Killestein J, Rudick RA, Polman CH. Oral treatment for multiple sclerosis. The Lancet Neurology. 2011;10(11):1026-34. http://search.proquest.com/docview/900472684?accountid=14068
10. Tecfidera [Package Insert]. Available at http://www.tecfidera.com/pdfs/full-prescribing-information.pdf. Accessed May 24, 2013.