PML Reported With Fumarates

Susan Jeffrey

April 24, 2013

New reports describe cases of progressive multifocal leukoencephalopathy (PML) in 2 patients with psoriasis who were treated with oral fumarate (Fumaderm, Biogen Idec) or a compounded version of fumaric acid esters (Psorinovo, compounding pharmacy Mierlo-Hout).

The cases give pause to the multiple sclerosis (MS) community in the wake of the recent approval by the US Food and Drug Administration (FDA) of dimethyl fumarate, also known as BG-12, for patients with relapsing MS (Tecfidera, Biogen Idec), which is expected to be a potential blockbuster because of its proven efficacy and perceived safety.

The case reports, in the form of letters to the editor with a reply from Biogen Idec, were published in the April 25 issue of the New England Journal of Medicine.

Case 1

In the first report, Ummehan Ermis, Joachim Weis, MD, and Jörg B. Schulz, MD, from the Rheinisch-Westfälische Technische Hochschule Aachen, in Aachen, Germany, describe the case of a 74-year-old man with psoriasis who was treated with oral fumaric acid for 3 years in doses of up to 120 mg dimethyl fumarate and 95 mg monoethyl fumarate, each taken twice daily.

In July 2010, the patient developed progressive sensory aphasia. Findings on magnetic resonance imaging, investigation of specimens obtained at brain biopsy, and the presence of JC virus in the cerebrospinal fluid and brain led to a diagnosis of PML.

The authors further report that a differential blood count showed the patient had grade 3 lymphocytopenia that, in retrospect, had developed as soon as 1 year after the start of treatment. "Although it was the manufacturer's recommendation to discontinue treatment of fumaric acid in patients with severe lymphocytopenia, treatment was continued in this patient until the diagnosis of PML was made 2 years later," the authors write.

By January 2011, the patient's condition improved, despite persistence of a "marked sensory aphasia syndrome," they write.

"Fumarate, unlike other immune-based therapies that may cause PML (e.g., rituximab, natalizumab, efalizumab, and infliximab), does not belong to the monoclonal antibody family," they conclude. "Although this patient may have been at higher risk for PML for other reasons, long-term treatment with fumarate was probably an important factor in its development, given the unrevealing evaluation for other causes of immune deficiency, the induction of an IRIS [immune reconstitution inflammatory syndrome] within 5 weeks after the withdrawal of fumarate, and the patient's clinical improvement and survival after a follow-up of more than 2 years. Similar to treatment with natalizumab, long-term treatment with fumaric acid and prior treatment with other immunosuppressants may have increased this patient's risk of PML."

Case 2

In the second report, researchers from the VU University Medical Center in Amsterdam, the Netherlands, with corresponding author Bob W. van Oosten, MD, PhD, describe the case of a 42-year-old woman who had complained of progressive right-sided hemiparesis for several months and was referred to them for a second opinion in 2012. She had been given a diagnosis of possible MS 2 months before and had been treated for it with intravenous methylprednisolone without effect.

She also had a history of psoriasis, for which she had been receiving enteric-coated, slow-release Psorinovo (compounding pharmacy, Mierlo-Hout), in which the active ingredient is dimethyl fumarate, which had contained an additive of copper gluconate until 2010. She had been taking it since 2007 at a dose of 420 mg per day, along with calcium ascorbate and fish oil capsules.

Magnetic resonance imaging showed lesions suggestive of PML, the patient's cerebrospinal fluid was positive for JC virus, and hematologic studies showed lymphopenia with a count of 200 lymphocytes/mL3 (vs a normal range of 600 - 2900 lymphocytes/mL3), the authors write. "We realized in retrospect that the lymphopenia had developed after the initiation of treatment with Psorinovo."

They made a diagnosis of PML, stopped treatment with Psorinovo, and started PML treatment with mefloquine and mirtazapine. The patient stabilized in early January 2013 and showed signs of recovery.

"We believe that treatment with Psorinovo contributed to the development of PML in our patient," the authors conclude. "First, lymphopenia developed during treatment with Psorinovo and is a well-known side effect. Second, our patient had used no immunosuppressive medication before the onset of PML, and she was seronegative for HIV. Finally, the occurrence of IRIS after the discontinuation of Psorinovo argues in favor of a causal link.

"We think this case report is of special relevance since preparations of fumaric acid esters, including dimethyl fumarate, are emerging drugs that may have a broader range of therapeutic indications in the near future," they conclude.

4 PML Cases in Total

In correspondence of their own, Biogen Idec responded to the case reports. Marianne T. Sweetser, MD, PhD, Katherine T. Dawson, MD, and Carmen Bozic, MD, all employees of the company, acknowledge that overall, there have actually been 4 reports of PML in patients with psoriasis treated with fumarates: 3 with Fumaderm (Biogen Idec) and 1 with compounded fumaric acid esters (FAEs), including the 2 published here.

The 2 additional patients, they write, "had significant confounding factors for PML." In 1 patient with a history of sarcoidosis treatment with methotrexate and steroids, PML was diagnosed after 1 month of exposure to Fumaderm. "The other patient had been treated with efalizumab and received a diagnosis of cancer. Efalizumab was stopped, and the patient subsequently began treatment with Fumaderm for psoriasis," the authors note. "Sarcoidosis, cancer, and efalizumab are known risk factors for PML," they point out.

In one of these new cases, the patient was treated with a compounded version, they add. "Compounded FAEs and other compounded products are not approved by regulatory authorities and may be associated with risks." The compounded product Psorinovo contains dimethyl fumarate and may also contain other ingredients, such as copper monoethyl fumarate, they write.

Fumaderm, used in the other case, "an approved, fixed-combination product, contains four active ingredients: dimethyl fumarate and three monoethyl hydrogen fumarates (calcium, magnesium, and zinc salts)." Its safety profile has been assessed in 19 years of postmarketing surveillance and physician experience since its approval in Germany, as well as a large follow-up study, the authors add.

"In the two case reports, both patients had severe lymphopenia for prolonged periods — 2 and 5 years, respectively — before receiving a diagnosis of PML," they write. Although decreased lymphocytes are common with Fumaderm treatment, severe lymphopenia occurs in only 3% of patients, they note, "and it is likely prolonged and severe lymphopenia occurs even less frequently." Severe lymphopenia is also a known risk factor for PML, they add, "and can be mitigated through the periodic monitoring of lymphocytes."

As for BG-12, recently approved as Tecfidera for relapsing MS, the only active ingredient is dimethyl fumarate, they note.

"In the clinical program for BG-12, 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," Dr. Sweetser and colleagues write. "BG-12 is associated with a reduction in mean lymphocyte counts of approximately 30% from baseline. Among patients treated with BG-12 to date, there has been no evidence of an increased risk of serious or opportunistic infections, and no reports of PML.

"Overall, fumarates are distinct products with different active ingredients, metabolites, and formulations, and they are used in different populations with varying coexisting conditions," they conclude. "These factors may lead to important differences in the safety profiles among the various products."

Cases "Of Great Interest" to MS Community

The recent FDA approval of BG-12 was based on findings from the Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS (DEFINE) trial, and the Comparator and an Oral Fumarate in RRMS (CONFIRM) trial, published in the September 20, 2012, issue of the New England Journal of Medicine. Both trials were funded by Biogen Idec.

Principal investigator of the CONFIRM trial was Robert J. Fox, MD, neurologist and medical director of the Mellen Center for MS at the Cleveland Clinic in Ohio. Asked for his thoughts on these cases, he told Medscape Medical News that he had heard of these cases but was eager to see the details published.

"These cases are of great interest to the community as we learn more about the risk profile and the safety profile of fumaric acid therapies," Dr. Fox said.

He emphasized that there have been no cases of PML reported to date with Tecfidera, the BG-12 preparation that was just approved in the United States and in Europe for MS.

Whenever a drug arrives on the market, we're at the very beginning of understanding its risk profile. Dr. Robert J. Fox

"However, seeing these 2 cases with 2 different preparations, a second and a third preparation of fumaric acid, does suggest to us that there may be an elevated risk, but also that monitoring lymphocyte counts, which are part of the FDA label for monitoring white blood cell counts, may be helpful in identifying people at elevated risk for PML."

Both reported cases had markedly decreased lymphocyte counts that were confirmed over a long period of time, he noted.

"Whenever a drug arrives on the market, we're at the very beginning of understanding its risk profile," Dr. Fox concluded. "As we get greater and greater experience with therapies in a larger array of patients with different risk factors, we learn more and more about the therapy. I suspect we'll learn even more about this drug over the coming years; more nuances regarding its safety and risk profile."

Analysts have reported remarkable uptake of Tecfidera in the first month of its approval — faster certainly than that seen with the other approved oral agents, fingolimod (Gilenya, Novartis), which was approved first in September 2010, and teriflunomide (Aubagio, Genzyme/Sanofi), approved earlier this year.

Dr. Fox reports receiving consulting fees from Avanir Pharmaceuticals, Biogen Idec, EMD Serono, Novartis and Questcor. The other authors have disclosed various relevant financial relationships, which can be viewed on the journal Web site.

N Engl J Med. 2013;368:1657-1658, 1658-1659, 1659-1661. Ermis et al full text, van Oosten et al full text, Sweetser et al full text


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