ClinicSpeak: third PML case on Tecfidera

Will there be more PML cases on Tecfidera? #MSBlog #MSResearch #ClinicSpeak

“This is the 3rd case of PML in an MSer who had no other risk factors for developing PML apart from being treated with dimethyl fumarate (Tecfidera) and having a persistently low lymphocyte counts. I note that Biogen imply that the risk factor is lymphopaenia (<500/mm3) and not necessarily the DMF. We can’t be 100% sure of this and need to remain vigilant of opportunistic infections on DMF. An important risk factor for PML is duration of immunosuppression and as DMF has not be on the market that long we have to wait and see. These 3 cases may be the tail of the curve with more cases to follow.”

Lisa LaMotta. Biogen’s Tecfidera Dogged By PML. SCRIP Mon, 21 Sep 2015


A third case of a deadly brain disease has been confirmed for Biogen’s  blockbuster oral multiple sclerosis Tecfidera – analysts say it’s manageable – but sales are likely to slump.

Analysts confirmed that a third case of progressive multifocal leukoencephalopathy (PML), a deadly brain disease, has occurred in a patient taking only Tecfidera (dimethyl fumarate). Like the two previous cases, the disease occurred in patients with prolonged white blood cell suppression – a condition known as lymphocytopenia. It is believed that only patients with severe lymphocytopenia could develop PML. The drug’s label was revised to reflect the PML death. PML has been known to crop up in patients taking certain MS drugs long-term – Biogen’s Tysabri (natalizumab) has had a long-running problem with the issue – but drugmakers have learned to screen patients better for certain signs that could indicate whether they will develop the fatal brain condition. Tysabri, for example, has a companion diagnostic that tests patients for the presence of JVC antibodies – those that are negative are less likely to develop PML. The creation of the test has led to fewer cases of PML for Tysabri patients and has bolstered sales of the drug The oral multiple sclerosis drug had one of the best drug launches in history when it entered the market in 2013, but increasing competition to the oral MS market, as well as other advances in the field and safety concerns have slowed revenues.

The first case of PML in a Tecfidera patient popped up in October 2014 and sales of the drug have been on a downward slide ever since. Biogen insists that Tecfidera is safe and has said for the last year that the cases of PML are not affecting sales of the drug. The company says that sales of the drug have been waning due to cannibalization by Biogen’s other MS drugs, as well as the increased competition in the market.

Jefferies analyst Brian Abrahams wrote in a Sept. 18 note that he believes the risk of the disease can be easily mitigated by physicians if they closely monitor patients’ white blood cell counts. 

“However, we believe it will be important for BIIB to ensure physicians are properly educated not only about monitoring to prevent additional PML occurrence, but about the high likelihood that careful monitoring should virtually eliminate any risk of this side effect and they needn’t avoid using the drug,” he wrote.

CoI: multiple

10 thoughts on “ClinicSpeak: third PML case on Tecfidera”

  1. I've been reading about it on another websites. The patient began treatment with Tecfidera in March 2014, and had previously been treated with Rebif. In the latest PML case, the first report of prolonged lymphopenia was recorded six months after the start of treatment with Tecfidera, and yet the patient was continued on the drug. The patient is alive and stable.

  2. What exact value is meant as lymphopenia for patients on fingolimod? Is it their usual level 0.5, or lover level of 0.2 when its recommended to stop using it?

    1. Re: "What exact value is meant as lymphopenia for patients on fingolimod? Is it their usual level 0.5, or lover level of 0.2 when its recommended to stop using it?"Yes, the EMA recommend stopping, reducing or interrupting dosing fi the levels drop below 0.2. The FDA does not recommend testing monitoring. As a result of the latter I use 0.1 as my action line; this is simply a pragmatic solution to prevent too many patients having to stop or interrupt their fingolimod dosing. At Barts-MS we test at month 3, month 6 and then 6 monthly after that. Please not on fingolimod there has been no correlation between the level of lymphopaenia and opportunistic infections or efficacy. This makes fingolimod-induced lymphopaenia different to lymphopaenia on other drugs.

  3. Here's a digest of something I wrote for myself about PML risk on Tecfidera after the case report for the first case came out in the NEJM. Summary is the estimate for PML risk in JC+ tecfidera patients with chronic lymphopenia (less than 800 cells/uL = 0.8 in the units used in this post) is comparable to PML risk on Tysabri. Caveats are the estimate is based on very little data and you're reading it on the comments to a blog. The first PML case in a tecfidera recipient was reported in October 2014 and the case report was published in April. She was JC+ and so could get PML. She was also unusual in two ways: (1) she was part of the DEFINE clinical trial and so is one of only a few thousand MS'ers so far with more than 4 years on tecfidera, and (2) she was one of the 5%-ish of tecfidera users that develop chronic lymphopenia.The one case gives a very little bit of data to estimate the per person risk. First, the data point occurred in someone who had been on tecfidera for 4.5 years, after 3.5 years of chronic lymphopenia. We know from tysabri that the risk increases over the first 4 years.Let's say we're estimating the risk 4 years out. From the NEJM case report, 47 of the 2470 subjects (2% of subjects) in the DEFINE trial had Grade 3 lymphopenia. So, in that cohort, the risk estimate is 1 PML case for every 47 people (1 in 47) who have chronic lymphocyte counts below 500 cells/uL.1 in 47 is probably the absolute upper estimate of the risk because Grade 3 is a very low cutoff and implies that the risk exceeds the risk on tysabri which is unlikely. For a more realistic definition of the at-risk cohort, 6% of subjects had lymphocyte counts less than 800 cells/uL (Grade 2 and 3). Using that as the denominator for the risk estimate says that the PML risk for grade 2 or higher lymphopenia is 1 in 150 people. A risk stratification plan is in order. We can pool knowledge from PML risk with other conditions and we do not have to wait for enough patients to get it within tecfidera users to do so.

  4. Why not have the makers of Tecfedera pay for monitoring for lymphocyte counts and JC status? Since strict rules are in place for Tysabri it seems the prudent thing to do.

  5. Is there any information on what Biogen is doing to elucidate the PML risk associated with their fumarate products (Fumaderm as well as Tecfidera)? More cases seem to have been reported, and some even without pre-existing severe lymphopenia ( Are there any studies under way on the significance of lymphocyte subsets, for example? I realise the drug is reasonably new to the market, and inevitably there has to be a degree of "wait and see", but having chosen Tecfidera as a first-line therapy this year, recent developments have been unnerving to say the least. This poor person had only been on the drug for around a year and a half.

  6. Is this a new case of PML in MS, or does the report refer to the third person with PML (1 psoraisis, 2 MS) from earlier in the year?

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