ARTICLE IN BRIEF
In response to several reports of progressive multifocal leukoencephalopathy in patients taking fumarates, experts in multiple sclerosis (MS) urge caution — and vigilance — about prescribing the newly approved oral MS drug, dimethyl fumarate.
A total of four European patients with psoriasis developed progressive multifocal leukoencephalopathy (PML), a rare infection of the brain's white matter, after taking oral fumarate preparations containing the active ingredient in the newly approved multiple sclerosis (MS) oral medication dimethyl fumarate, also known as BG-12 and marketed as Tecfidera, by Biogen Idec.
Each of the patients developed lymphocytopenia, in some instances for several years, prior to being diagnosed with PML. They were also seropositive for the JC polyomavirus, which causes PML, and had other medical conditions and/or had taken medications that can increase PML risk. All of them recovered after being taken off fumarates.
Lymphocytopenia is a well-recognized risk factor for PML in patients taking fumarates, and patients who develop the condition are advised to discontinue treatment.
It's estimated that at least 50 percent of adults carry the JC polyomavirus without any symptoms, but it can become a potentially deadly infection or cause lasting neurocognitive problems in individuals with compromised immune systems.
The US Food and Drug Administration (FDA) approved dimethyl fumarate for relapsing-remitting multiple sclerosis (RR-MS) in late March after Biogen Idec provided positive results from two phase 3 clinical trials involving more than 2,600 patients. An ongoing extension study has tracked some patients for more than four years, with no cases of PML.
Two case reports of PML were published in the April 25 issue of the New England Journal of Medicine, together with a response by Biogen, which also markets fumaric acid (Fumaderm), the product taken by one of the patients. The other had taken fumaric acid esters from a compounding company.
In its response, the company said it was aware of two additional patients who took fumaric acid and developed PML, but in all four cases the patients either had severe lymphopenia for prolonged periods and/or other health or medication-related factors known to increase PML risk.
While levels of lymphocytes can fall by as much as 30 percent in patients taking fumarates, severe lymphopenia occurs in only about 3 percent and prolonged severe lymphopenia occurs even less often. Periodic lymphocyte monitoring can mitigate this risk, according to the company.
Nonetheless, Neurology Today was told the cases are reminiscent of early reports of PML in a small number of patients who took another promising drug for relapsing-remitting MS, natalizumab (Tysabri), which was approved by the FDA in 2004 but temporarily removed from the market in 2005 after several deaths. The FDA reintroduced natalizumab as a monotherapy in 2006 after a safety review and the initiation of an intensive global risk-management program by Biogen Idec. The FDA has since alerted clinicians to three risk factors for PML in people taking natalizumab — the presence of anti-JCV antibodies; longer duration of treatment, especially beyond two years; and prior treatment with immunosuppressants (for example, mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil). Patients with all three known risk factors have an estimated risk of PML of 11/1,000 users, according to the FDA.
At press time, 349 cases of PML had been reported out of some 112,000 MS patients taking natalizumab, and there have been 79 deaths. The FDA estimates the risk of PML in natalizumab patients is 1 in 1,000.
The first European case involved a 74-year-old man who had taken dimethyl fumarate for around three years, two of which followed a diagnosis of grade 3 lymphocytopenia, according to Jörg B. Schulz, MD, and colleagues, at the Rheinisch-Westfälische Technische Hochschule Aachen, in Aachen, Germany.
“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,” they wrote. The patient had been treated with the cancer drug methotrexate, but no other causes of immune deficiency were discovered, and immune reconstitution inflammatory syndrome occurred within five weeks after fumarate was halted, with clinical improvement and survival at two-year follow-up.
The second case involved a 42-year-old woman from the Netherlands who took fumaric acid esters, which include dimethyl fumarate, from a compounding pharmacy. She developed lymphocytopenia five years before she was diagnosed with PML.
Bob W. van Oosten, MD, PhD, and his colleagues at the VU University Medical Center in Amsterdam, the Netherlands, reported the case. The woman had also been diagnosed with possible MS two months earlier and had been treated unsuccessfully with intravenous methylprednisolone.
The authors said that, in hindsight, her lymphopenia had developed after she began taking the fumarate compound and they halted treatment and switched to treating her PML. She stabilized in January.
“We believe that treatment with [fumaric compound] contributed to the development of PML,” the authors said.
QUESTIONS ABOUT THE REPORT
Mark S. Freedman, MD, professor of neurology and director of the Multiple Sclerosis Research Unit at University of Ottawa Hospital, expressed concern over the reports of PML, saying it was reminiscent of early cases in patients taking natalizumab and the psoriasis drug efalizumab, which was withdrawn from the market in 2009.
“I don't think that there's 100 percent agreement about what caused PML in these European cases, and I am not convinced that either of the patients had been seriously immunocompromised due to any of the factors reported,” he told Neurology Today.
“From what I am hearing, I think the common element is fumarate. We have to keep an open mind, but given past issues with PML I find these reports troubling. Remember, the PML problems with natalizumab started with sporadic case reports, and some of us are now thinking, ‘Oh no, here we go again.’”
However, the reports at this stage are cautionary and should not be grounds for not treating MS patients, he added.
“Neurologists and patients are hyped up about trying dimethyl fumarate. These reports do not mean not treating MS patients, but they should cause some hesitancy. Patients should certainly be tested for JC virus antibodies before treatment and monitored for lymphocytopenia and consider halting it if levels are low.”
NEED FOR POST-MARKET SURVEILLANCE
“I tell my MS patients going on dimethyl fumarate that there are three main side effects or risks — gastrointestinal, skin flushing, and the things we don't know about yet,” said Robert J. Fox, MD, staff neurologist and medical director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic Foundation in Ohio.
“Because dimethyl fumarate is the main active ingredient in both of the psoriasis medications, I think it is reasonable to assume that the lessons these patients teach us regarding lymphopenia probably apply to [dimethyl fumarate]. Lymphopenia was seen in the MS trials with dimethyl fumarate so I do think these new cases are relevant for MS patients taking dimethyl fumarate,” he told Neurology Today.
He noted that the two European psoriasis patients had extremely low levels of lymphocytes, a well-known risk factor for PML, and said MS patients taking the drug should be carefully monitored for low white blood cell counts, including lymphocytes, too.
“Because their lymphocyte levels were so much lower than those generally seen in the MS trials with dimethyl fumarate, I think it is likely that this could be a biomarker for possible infection. The low lymphocyte counts in these patients suggest they may have had significantly altered immune systems, so lymphocyte levels should be checked as the FDA advises.”
Despite the large number of patients involved in the MS clinical trials, dimethyl fumarate may have to be on the market for some time before risk factors are fully realized, he added.
“It's very important to recognize that, although the drug has been approved for MS, we are just at the beginning of understanding all of the potential risks. Patients in clinical trials typically do not have the breadth of comorbid health issues that we see in the general MS population, and as we extend treatment into this larger group we will understand more about its potential complications,” he explained.
“We do know quite a bit about Fumaderm because it has been on the market in Germany for a long time. We also know that our current level of experience with dimethyl fumarate is very different from natalizumab. Natalizumab was originally approved on the basis of just one-year efficacy in a clinical trial plus all safety data to date, and in not nearly as many patients as those taking either Fumaderm or dimethyl fumarate. We have had thousands of patients taking different fumaric acid preparations. At this point, I don't have significant hesitancy about putting MS patients on dimethyl fumarate, but we still need to be cautious.”