Guest post: FUMADERM and PML – can we make conclusions for BG12?

#MSBlog: What does Prof. Gold, the PI on the BG12 programme, have to say about Fumaderm and PML?

"In response to the intense interest on the blog concerning Fumaderm and PML and its possible implications for BG12, we invited Professor Doctor Ralf Gold to contribute a guest post on this topic! I hope it answers some of your questions. It has mine!"


Recently two cases of PML unfolding under monotherapy of psoriasis with Fumaderm have been observed, and await publication in a major journal. Fumaderm is the old mixture of dimethylfumarate and three different salts of ethylhydrogenfumarate, licensed since 20 years in Germany with more than 170.000 patient years of experience.

The German case is very well known to me: a dermatologist had initiated fumarate treatment in 2007 in a 71 year old male, and since summer 2009 this patient had developed marked lymphopenia (low lymphocyte count; a type of whit blood cell) with relative values below 10% and absolute lymphocyte counts around 300-400/µl (normal levels are usually greater than 1500//µl). According to the SPC (Summary of Product Characteristics) of Fumaderm this should have resulted in immediate cessation of treatment, and subsequent dose reduction after normalization of lymphocyte values. Of note, after PML occurred Fumaderm was stopped immediately by the neurologists. Yet it took over 12 months until lymphocyte values of this patient came back into lower normal range. 

What does this tell us? Although dimethylfumarates (BG12) were completely safe in controlled MS studies, a minimum of blood controls every 4-6 weeks as detailed in the SPC for Fumaderm should also be considered in this monotherapy. If needed fumarate dose may be adjusted – there may be rare genetic variants where higher systemic fumarate levels are achieved in patients. There is no doubt from recent research data that fumarates impact the immune system, and persistent violation of prescription rules can cause problems as in any immunoactive therapy. In view of the high efficacy of BG12 in phase III trials I feel that a minimum of safety controls is justified and should be performed. 

Of course we now have to wait if the drug receives approval for MS therapy by regulatory authorities, and which specific measures will be implemented in the SPC.

Disclosures: Professor Gold have received speaker’s honoraria, consulting fees and scientific support from Baxter, BayerSchering, BiogenIdec, ChugaiPharma, Merckserono, Novartis, Roche, Sanofi-Aventis, TEVA and ZLB Behring.

Important BG-12 publications

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098-107. Erratum in: N Engl J Med. 2012 Dec 13;367(24):2362.

Kappos L, Gold R, Miller DH, MacManus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Eraksoy M, Meluzinova E, Dufek M, Yang M, Dawson K, O'Neill GN. Effect of BG-12 on contrast-enhanced lesions in patients with relapsing--remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler. 2012 Mar;18(3):314-21. doi: 10.1177/1352458511421054. 

MacManus DG, Miller DH, Kappos L, Gold R, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Eraksoy M, Meluzinova E, Dufek M, Yang M, O'Neill GN, Dawson K. BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis. J Neurol. 2011 Mar;258(3):449-56. doi: 10.1007/s00415-010-5777-z. Epub 2010 Oct 21.

Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN; BG-12 Phase IIb Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008 Oct 25;372(9648):1463-72. doi: 10.1016/S0140-6736(08)61619-0. 

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