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Tecfidera (Dimethyl Fumarate), a New Oral Therapy Approved by the FDA for the Treatment of Relapsing Forms of Multiple Sclerosis

Special Feature Fifth Annual Payers' Guide to New FDA Approvals March 2014 Volume 7 - Payers' Guide
Loretta Fala
Medical Writer
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Multiple sclerosis (MS) is a chronic, inflammatory, potentially debilitating disease of the central nervous system (CNS) that disrupts the communication between the brain, spinal cord, and other areas of the body.1 MS may also result in nerve deterioration, which is an irreversible condition. The symptoms of MS can vary widely, depending on which nerves are affected and on the extent of the nerve damage.1 The most common symptoms associated with MS include fatigue, numbness, spasticity, vision problems, and bowel and bladder problems.2

Women are twice as likely as men to be affected by MS.1 It most frequently affects individuals between the ages of 20 and 40 years and those who have a family history of the disease. Certain infections (eg, Epstein-Barr virus) and autoimmune diseases (eg, thyroid disease, type 1 diabetes, or inflammatory bowel disease) may predispose a person to MS. Caucasians whose families originated in northern Europe have the highest risk for developing MS. Moreover, MS is more common in Europe, southern Canada, northern United States, New Zealand, and southeastern Australia.1

There are 4 types of MS, including relapsing-remitting MS (RRMS), secondary progressive, primary progressive, and progressive relapsing.2 RRMS is the most common type, accounting for 85% of initial diagnoses of MS.2 RRMS is characterized by temporary periods of relapses or exacerbations of neurologic functioning, followed by periods of remission in which partial or complete recovery occurs.3

MS, particularly if untreated or in the advanced phase, is associated with multiple symptoms that can impose a substantial burden on the patient’s mobility, daily activities, cognitive function, physical well-being, and overall quality of life.4 Patients with MS are at risk for depression, osteoporosis, pressure sores, and other complications. MS also has a marked impact on caregivers and on society and the healthcare system.4

According to a systematic review of MS-related healthcare cost studies published between 2007 and 2012, total all-cause (direct and indirect) costs for MS ranged from $8528 to $54,244 per patient annually.5 Direct costs accounted for an average of 77% (range, 64%-91%) of the total costs, with prescription medications accounting for the majority of the direct costs. Indirect costs accounted for approximately 23% (9%-36%) of the total costs. In fact, the direct all-care healthcare costs for MS ranked second only to congestive heart failure compared with other chronic conditions in a recent analysis.5 This systematic review did not take into account some of the newer and more costly treatments or the costs associated with the impaired disability, early retirement, and diminished quality of life associated with MS.5

The early diagnosis and early treatment of MS are crucial, because permanent CNS damage may occur even before a person experiences symptoms.6 Although no cure is available for MS, effective treatment strategies can help to slow the progression of the disease, manage symptoms, and improve function.7

One of the most dramatic treatment advances in recent decades is the development of disease-modifying therapies for MS. The disease-modifying therapies have been shown to be effective at reducing disease activity and disease progression in many patients with relapsing forms of MS.7 Consequently, adherence to prescribed therapy is important to achieve optimal outcomes. Until recently, the disease-modifying therapies for MS included beta interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, natalizumab, mitoxantrone, and 2 oral therapies—fingolimod and teriflunomide.1 Corticosteroids may also be used to reduce inflammation during a relapse.1

Other strategies that may improve the symptoms of MS include physical therapy, muscle relaxants, medications to reduce fatigue and to improve walking, and medications that may be prescribed for depression, pain, and bladder or bowel control problems.1 Lifestyle and behavioral approaches, including rest, exercise, nutrition, and stress management, may also help to alleviate some of the symptoms of MS.1

Dimethyl Fumarate: A New First-Line Oral Option

In March 2013, the US Food and Drug Administration (FDA) approved dimethyl fumarate (Tecfidera; Biogen Idec), a nuclear factor (erythroid-derived 2)–like 2 (Nrf2) activator, for the first-line treatment of adults with relapsing forms of MS.8 Dimethyl fumarate is a methyl ester of fumaric acid available as a delayed-release oral therapy.8-10

According to Russell Katz, MD, Director, Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, “No drug provides a cure for multiple sclerosis so it is important to have a variety of treatment options available for patients.” He added, “Multiple sclerosis can impair movement, sensation, and thinking and have a profound impact on a person’s quality of life.”8

Mechanism of Action

The mechanism by which dimethyl fumarate exerts its therapeutic effect in MS is unknown. Dimethyl fumarate and the metabolite monomethyl fumarate have been shown to activate the Nrf2 pathway in vitro and in vivo in animals and in humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. Monomethyl fumarate has been identified as a nicotinic acid receptor agonist in vitro.10

Dosing

The starting dose for dimethyl fumarate is 120 mg twice daily orally for 7 days.10 After 7 days, the dose should be increased to the maintenance dose of 240 mg twice daily orally. Dimethyl fumarate should be swallowed whole and intact, and should not be crushed or chewed. The capsule contents of dimethyl fumarate should not be sprinkled on food. Dimethyl fumarate can be taken with or without food; administration with food may reduce the incidence of flushing.

It is recommended that a complete blood cell count be performed before the initiation of therapy with dimethyl fumarate to identify patients with preexisting low lymphocyte counts.

Dimethyl fumarate is available as a delayed-release capsule in 120-mg and 240-mg strengths.10

Clinical Studies

The safety and efficacy of dimethyl fumarate were demonstrated in 2 studies, Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS (DEFINE) and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM), which evaluated dimethyl fumarate taken 2 or 3 times daily in patients with RRMS.10-12 The starting dose for dimethyl fumarate was 120 mg 2 or 3 times daily for the first 7 days, followed by an increase to 240 mg twice or 3 times daily. Both studies included patients who had at least 1 relapse over the year preceding the trial or who had a brain magnetic resonance imaging (MRI) scan demonstrating at least 1 gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization.10

The Expanded Disability Status Scale (EDSS) score was also assessed; to be included in the trials, patients could have scores ranging from 0 to 5. Neurologic evaluations were performed at baseline, then every 3 months, and at the time of suspected relapse. MRI evaluations were conducted at baseline, at month 6, and at years 1 and 2 in a subset of patients (44% in the DEFINE trial and 48% in the CONFIRM trial).10

Study 1: The DEFINE Study
Study 1, the DEFINE study, was a 2-year randomized, double-blind, placebo-controlled trial of 1234 patients with RRMS.10,11 The primary end point was the proportion of relapsed patients at 2 years. Other end points at 2 years included the number of new or newly enlarging T2 hyperintense lesions, the number of new T1 hypointense lesions, the number of Gd+ lesions, annualized relapse rate, and the time to confirmed disability progression. The confirmed disability progression was defined as at least a 1-point increase from the baseline EDSS score (a 1.5-point increase for patients with a baseline EDSS score of 0) sustained for 12 weeks.

Patients in study 1 were randomized to receive dimethyl fumarate 240 mg twice daily (N = 410), dimethyl fumarate 240 mg 3 times daily (N = 416), or placebo (N = 408) for up to 2 years.10 The median age of the patients was 39 years, the median time since diagnosis was 4 years, and the median EDSS score at baseline was 2. The median time of using the study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks while taking the study drug per treatment group were 69% for those assigned to dimethyl fumarate 240 mg twice daily, 69% for those assigned to dimethyl fumarate 240 mg 3 times daily, and 65% for patients assigned to placebo.10

The clinical and MRI findings for study 1 are shown in Table 1. Dimethyl fumarate was shown to have a significant effect on all of the end points described above; the 240-mg 3-times-daily dose showed no additional benefit versus the 240-mg twice-daily dose.10



Study 2: The CONFIRM Study
Study 2, the CONFIRM study, was a 2-year randomized, double-blind, placebo-controlled trial in patients with RRMS that also included an open-label comparator arm. The primary end point was the annualized relapse rate at 2 years. Other end points at 2 years included the number of new or newly enlarging T2 hyperintense lesions, the number of T1 hypointense lesions, the number of Gd+ lesions, the proportion of patients with relapsed disease, and the time to confirmed disability progression as defined in study 1.

Patients in study 2 were randomized to receive dimethyl fumarate 240 mg twice daily (N = 359), dimethyl fumarate 240 mg 3 times daily (N = 345), an open-label comparator (N = 350), or placebo (N = 363) for up to 2 years.10 The median age of the patients was 37 years, the median time since diagnosis was 3 years, and the median EDSS score at baseline was 2.5. The median time using the study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks with the study drug per treatment group were 72% for patients assigned to dimethyl fumarate 240 mg twice daily, 70% for patients assigned to dimethyl fumarate 240 mg 3 times daily, and 64% for patients assigned to placebo.

The clinical and MRI results for study 2 are shown in Table 2. Dimethyl fumarate demonstrated a significant effect on the relapse and MRI end points described above. No significant effect was seen on disability progression. The dimethyl fumarate 240-mg 3-times-daily dose resulted in no additional benefit versus the dimethyl fumarate 240-mg twice-daily dose.10



Safety

In placebo-controlled and uncontrolled clinical trials, a total of 2513 patients received dimethyl fumarate and were followed for up to 4 years, with an overall exposure of 4603 person-years.10 Approximately 1162 patients received more than 2 years of treatment with dimethyl fumarate. The adverse reaction profile of dimethyl fumarate in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled studies.

The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea.10

The prescribing information for dimethyl fumarate does not include any boxed warnings. In addition, there are no contraindications for dimethyl fumarate in the FDA-approved labeling.

Warnings and Precautions

Lymphopenia. Dimethyl fumarate may decrease lymphocyte counts. Low lymphocyte counts can increase the risk of infection; however, in clinical trials, no significant increase in infections was seen in patients taking dimethyl fumarate.8 Before initiating treatment with dimethyl fumarate, a recent complete blood count (ie, within 6 months) should be available.10 A complete blood count is recommended annually and as clinically indicated. Withholding treatment in patients with serious infections should be considered.10

Flushing. Dimethyl fumarate may cause flushing (eg, warmth, redness, itching, and/or a burning sensation). In clinical trials, 40% of patients receiving dimethyl fumarate experienced flushing. Symptoms of flushing generally began soon after initiating treatment and usually improved or resolved over time.10

Drug Interactions

No potential drug interactions with dimethyl fumarate or with monomethyl fumarate were identified in the in vitro cytochrome P inhibition and induction studies, or in P-glycoprotein studies.10

Use in Specific Populations

Pregnancy. There are no adequate and well-controlled studies in pregnant women. Dimethyl fumarate should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.10

Nursing mothers. It is not known whether dimethyl fumarate is excreted in human milk. Caution should be exercised when dimethyl fumarate is administered to a nursing woman.10

Pediatric use. The safety and effectiveness of dimethyl fumarate in pediatric patients have not been established.10

Geriatric use. Clinical studies of dimethyl fumarate did not include sufficient numbers of patients aged ≥65 years to determine whether they respond different from younger patients.10

Conclusion

With the FDA approval of dimethyl fumarate in 2013, a new, disease-modifying first-line oral treatment option became available for patients with relapsing forms of MS.

Based on findings from 2 key clinical trials in this patient population, patients treated with dimethyl fumarate had significantly fewer MS relapses compared with patients who received placebo. In one of these trials, treatment with dimethyl fumarate was also associated with a
significant reduction in the rate of disability progression associated with MS compared with placebo.

The most frequently reported adverse reactions associated with dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea.

References

  1. Mayo Clinic staff. Diseases and conditions: multiple sclerosis. December 15, 2012. www.mayoclinic.org/diseases-conditions/multiple-sclerosis/basics/definition/CON-20026689. Accessed January 23, 2014.
  2. National Multiple Sclerosis Society. How relapsing-remitting MS (RRMS) differs from progressive courses of MS. www.nationalmssociety.org/about-multiple-sclerosis/relapsing-ms/relapsing-remitting-ms-rrms/how-rrms-differs-from-progressive-courses-of-ms/index.aspx. Accessed January 23, 2014.
  3. National Multiple Sclerosis Society. What we know about relapsing-remitting MS (RRMS). www.nationalmssociety.org/about-multiple-sclerosis/relapsing-ms/relapsing- remitting-ms-rrms/index.aspx. Accessed January 23, 2014.
  4. National Multiple Sclerosis Society. Living with advanced MS. www.nationalms society.org/about-multiple-sclerosis/living-with-advanced-ms/index.aspx. Accessed January 27, 2014.
  5. Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16:639-647.
  6. National Multiple Sclerosis Society. Adherence: starting a disease-modifying therapy and sticking with it. www.nationalmssociety.org/about-multiple-sclerosis/what-we-know- about-ms/treatments/adherence/index.aspx. Accessed January 27, 2014.
  7. National Multiple Sclerosis Society. Treatments. www.nationalmssociety.org/about- multiple-sclerosis/what-we-know-about-ms/treatments/index.aspx. Accessed January 27, 2014.
  8. US Food and Drug Administration. FDA approves new multiple sclerosis treatment: Tecfidera. Press release. March 27, 2013. Updated March 28, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345528.htm. Accessed January 22, 2014.
  9. MedlinePlus. Dimethyl fumarate. Revised July 15, 2013. www.nlm.nih.gov/medline plus/druginfo/meds/a613028.html. Accessed January 22, 2014.
  10. Tecfidera (dimethyl fumarate) delayed-release capsules [prescribing information]. Cambridge, MA: Biogen Idec Inc; March 2013.
  11. Gold R, Kappos L, Arnold DL, et al; for the DEFINE Study Investigators. Placebo-­controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-1107. Erratum in: N Engl J Med. 2012;367:2362.
  12. Fox RJ, Miller DH, Phillips JT, et al; for the 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. Erratum in: N Engl J Med. 2012;367:1673.
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