Only weeks following the exciting news that Tecfidera (oral dimethyl fumarate), also known as BG-12, has been approved by the FDA for the treatment of relapsing forms of multiple sclerosis, the headlines have turned to focus on PML, or progressive multifocal leukoencephalopathy.
In the April 25, 2013 issue of the New England Journal of Medicine (NEJM),1 two separate case studies are reported involving patients in Europe diagnosed with psoriasis who developed PML while taking different forms of dimethyl fumarate. The patient cases are described in Letters to the Editor with a response provided by Biogen Idec, maker of Fumaderm® (fumaric acid esters) tablets and Tecfidera™ (dimethyl fumarate) delayed release capsules.
PML is a serious brain infection caused by the reactivation of the JC Virus in patients who are immunosuppressed due to drug treatment or disease. Signs of PML include neurological symptoms which can be mistaken as MS symptoms. Risk factors for PML include presence of JC virus antibodies in the blood or cerebrospinal fluid and immunosuppression (often by use of certain medications).
In Germany, a 74-year-old man diagnosed with psoriasis received treatment with Fumaderm®2 (fumaric acid esters) tablets for 3 years (2007-2010) in twice daily doses of dimethyl fumarate (up to 120 mg) and monoethyl fumarate (95 mg). He had previously taken acitretin (2005-2006) and methotrexate (2006-2007). Within a year of starting treatment with Fumaderm®, he had developed lymphocytopenia, or very low white blood cell counts, which is a risk factor for PML. He continued treatment with Fumaderm® for two years until PML diagnosis in August 2010, which presented with sensory aphasia that affects a person’s ability to communicate, and began treatment with mefloquine and mirtazapine for PML.
In the Netherlands, a 42-year-old-woman diagnosed with psoriasis received treatment with Psorinovo3, a compounded preparation of dimethyl fumarate (which used copper gluconate as an additive until 2010) in daily doses of 420 mg since 2007. She also took supplements of calcium ascorbate and EPA-1000 fish oil capsules. In restrospect, she had developed lymphocytopenia after beginning treatment with Psorinovo.
Bob W. van Oosten, M.D., Ph.D. and colleagues at the VU University Medical Center in Amsterdam report that the patient was diagnosed with possible MS in September 2012 after having developing progressive right-sided hemipharesis since May. She was unsuccessfully treated for MS relapse with 3-days IV methylprednisolone in September. In November 2012, she was diagnosed with PML, stopped taking Psorinovo, and started treatment for PML with mefloquine and mirtazapine.
Both patients developed immune reconstitution inflammatory syndrome (IRIS) within 4 to 5 weeks after initiating PML treatment. Follow-up treatment with IV methylprednisolone was successful.
Marianne T. Sweetser, M.D., Ph.D. and colleagues from Biogen Idec comment that PML is rarely associated with fumaric acid esters4 based on “more than 180,000 patient-years of experience with Fumaderm” and that treatment with Fumaderm or compounded fumaric acid esters “may have contributed to the development of severe and prolonged lymphopenia.” They emphasize that severe lymphopenia which is a risk factor for PML can be mitigated through periodic monitoring of lymphocytes.
Biogen Idec shares that there have been two additional reports of PML in patients with psoriasis who were treated with Fumaderm and had significant confounding factors for PML. One patient with a history of sarcoidosis that was treated with methotrexate and steroids was diagnosed with PML after 1 month of exposure to Fumaderm. The other patient had been treated with Raptiva® (efalizumab) and received a diagnosis of cancer before beginning treatment with Fumaderm for psoriasis. Raptiva was withdrawn from the market in 2009 due to its association with PML.
In the MS placebo controlled trials of Tecfidera, more than 2600 patients with multiple sclerosis have been treated for periods of up to 4 years or more, with a median follow-up of approximately 2 years. Tecfidera is associated with a reduction in lymphocyte counts of approximately 30% during the first year of treatment. In trials, four weeks after stopping Tecfidera, mean lymphocyte counts increased but did not return to baseline. The FDA recommends that complete blood counts be checked before starting treatment and monitored annually, thereafter.
Sweetser and colleagues conclude, “Overall, fumarates are distinct products with different active ingredients, metabolites, and formulations, and they are used in different populations with varying coexisting conditions. These factors may lead to important differences in the safety profiles among the various products.”