Tecfidera found to be effective in RRMS patients with highly active disease but may cause transient neurologic worsening in MS patients with progressive disease

Clinical trials for MS medications have traditionally evaluated relapse rates, brain lesions, and disability progression.   The results of these measurements are typically analyzed independently.  But increasingly, researchers are analyzing data from clinical trials to measure “freedom from measured disease activity” or absence of overall disease activity.  This composite analysis combines the absence of clinical disease activity (no relapses and no EDSS progression) with the absence of neuroradiologic activity (no new/enlarging T2 and no Gd-enhancing lesions).

At the American Academy of Neurology (AAN) meeting in Philadelphia, several abstracts were presented by researchers who analyzed integrated data from the Phase 3 DEFINE and CONFIRM studies in which patients were randomized and received treatment with placebo (n=771), delayed-release dimethyl fumarate (DMF; brand: Tecfidera) 240mg twice daily (BID; n=769) or three times daily (TID; n=761), or glatiramer acetate (GA; reference comparator; CONFIRM only; n=350), for up to 96 weeks.  At two years, the proportion of patients with no measured clinical disease activity were 69% (DMF-BID group), 71% (DMF-TID group), and 53% (placebo), and the proportions with no MRI-measured disease activity were 34%, 35%, and 20%, respectively.  The proportion of patients with no measured overall disease activity were 23%, 23%, and 11%, respectively, at two years.  This was a decrease from the proportions at 6 months which were 40%, 40%, 23%, and at 1 year which were 34%, 31%, and 18%, respectively [P3.159].

Disease activity can range from mild to very severe among patients with MS.  In another post-hoc, integrated analysis of data from the DEFINE/CONFIRM studies, delayed-release dimethyl fumarate (240 mg twice daily) was found to be effective after two years in RRMS patients with highly active disease at baseline.  Patients with highly active disease were defined as those who experienced two or more relapses in the year prior to entering DEFINE/CONFIRM and had one or more gadolinium-enhancing lesion at baseline (n=136), including 48, 45, and 43 randomized to the placebo and delayed-release DMF BID and TID groups, respectively.  Results show that in this group of patients, the twice daily dose of Tecfidera significantly reduced annualized relapse rate (AAR) by 60% and the proportion of patients who relapsed by 63%.  The three-times daily dose reduced AAR by 40% and the proportion of patients who relapsed by only 30%.  There was no significant effect of delayed-release DMF on 12-week confirmed disability progression [P3.189].

Tecfidera has been shown to be safe and effective for patients with relapsing forms of MS, but it has not been approved for patients with progressive MS but may be prescribed off-label.  A retrospective chart review study at a single MS center in New York looked at 259 patients with progressive MS who had not been on other disease-modifying therapy and consented to take Tecfidera.  Researchers found that 5% (n=14; 78% female; mean age 52 years; EDSS ranging from 3.5 to 8.5) of patients with progressive forms of MS had developed acute neurologic worsening after starting Tecfidera.  Ten of the 14 patients had secondary progressive MS and 4 had primary progressive.  The duration of treatment with Tecfidera before the onset of worsening neurologic symptoms was variable (1-42 days).  The most common neurologic complaint was increased motor weakness.  All patients returned to baseline neurologic status after discontinuation of Tecfidera, generally within a few days, leading the researchers to suggest that it is caused by a conduction block.  The transient worsening of neurologic function appears to be unrelated to the type of progressive disease and is not related to the known adverse effects associated with Tecfidera [P2.228].

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View References
  1. Biogen Idec. New Data Reinforce Efficacy of Tecfidera® (dimethyl fumarate) in MS Patients with High Disease Activity [Press release]. Published April 30, 2014. Retrieved from http://www.biogenidec.com/press_release_details.aspx?ID=14712&Action=1&NewsId=2320&M=NewsV2&PID=61997
  2. Havrdova E, Gold R, et al. [P3.159] Effect of Delayed-Release Dimethyl Fumarate on Freedom from Measured Clinical and Neuroradiological Disease Activity in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients: An Integrated Analysis of DEFINE and CONFIRM [Abstract].  Poster session presented at 66th annual meeting of the American Academy of Neurology; 2014 April 26-May 3; Philadelphia, PA. Retrieved from http://www.abstracts2view.com/aan/view.php?nu=AAN14L1_P3.159
  3. Hutchinson M, Zhang A, et al. [P3.189] Clinical Efficacy of Delayed-Release Dimethyl Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients with Highly Active Disease: An Integrated Analysis of the Phase 3 DEFINE and CONFIRM Studies [Abstract].  Poster session presented at 66th annual meeting of the American Academy of Neurology; 2014 April 26-May 3; Philadelphia, PA. Retrieved from http://www.abstracts2view.com/aan/view.php?nu=AAN14L1_P3.189
  4. Stark J, Chirls S, Sadiq S.  [P2.228] Transient Neurologic Worsening after Initiation of Dimethyl Fumarate Therapy in Progressive Multiple Sclerosis Patients [Abstract].  Poster session presented at 66th annual meeting of the American Academy of Neurology; 2014 April 26-May 3; Philadelphia, PA. Retrieved from http://www.abstracts2view.com/aan/view.php?nu=AAN14L1_P2.228