Lessons to Learn About Tecfidera (dimethyl fumarate)

Tecfidera is a good treatment for relapsing MS; it is orally administered, tolerated well by most and significantly reduces relapses, new MRI lesions and residual disability; but it is not a risk free treatment and does require monitoring.  This point became more than a hypothetical concern this week when Biogen Idec (the maker of Tecfidera) reported the first case of PML in an MS patient participating in one of their Tecfidera clinical trials.

PML (Progressive Multifocal Leukoencephalopathy), of course, is a dreaded complication of Tysabri therapy, a remarkably effective MS treatment also manufactured by Biogen Idec. There had been prior cases of PML in patients receiving fumarate esters very similar to Tecfidera (these are available in Europe to treat psoriasis), but in each case Biogen Idec suggested there was another potential explanation.  It seems that the common thread tying all cases together is the continuation of treatment despite the development of persistently low lymphocyte counts. The most recent person with MS developed PML after 4 ½ years of low lymphocyte counts (ranging from 200 to 500).  More importantly, there were no other potential explanations for PML in the most recent case.

So what information do you need to remember going forward if you are taking or planning to take Tecfidera?

1. Mean lymphocyte counts will decrease in the first year of treatment with Tecfidera by 30 % and then stabilize. Most reductions are minimal with lymphocyte counts remaining above 1000 but 6 % of patients will experience lymphocyte counts less than 500. The drop in lymphocyte count may be larger in those people who also received prior immunosuppressant therapy and prior immunosuppressant therapy likely creates a higher risk of PML . If you experience a persistent drop in Lymphocyte count below 500 (lasting more than 6 months), especially if you previously received immunosuppressant therapy (cyclophosphamide, mitoxantrone, methotrexate, azathioprine, alemtuzamab, Rituximab, mycophenolate, long term chronic steroids), you should discuss the pros and cons of stopping Tecfidera with your MS specialist.

2. You should have a baseline complete blood count (CBC) before starting Tecfidera, which is repeated every 6 months. This is already recommended. If Lymphocyte counts drop below 900 you should be monitored more frequently, perhaps every 3 months.

3. Lymphocyte counts will increase quickly (over a month) after stopping Tecfidera but may not return to normal levels.

What information do we need to learn about Tecfidera to minimize the risk of PML and other potential complications related to a low lymphocyte count?

1. What lymphocyte subsets are affected? There are many different types of lymphocytes with different roles and responsibilities. A prior study suggested that Fumaric acid esters preferentially lower CD8 positive lymphocytes. This would be important since research in HIV patients suggests that a strong cytotoxic response driven by certain CD8 positive lymphocytes against the virus causing PML protects HIV patients against PML. I plan to start testing these lymphocyte subsets in my patients on Tecfidera to help in decision making going forward.

2. Are JC virus antibody test results helpful in determining risk of PML? So far there is no evidence that the JCV antibody results are useful as a risk factor in Tecfidera treated patients. Since many patients are known to harbor the harmless form of the JC virus despite negative JC virus antibody results, I have no intention of using this lab result to make treatment decisions on Tecfidera without further research.

3. How long does it take for PML to develop in patients on Tecfidera and how common is PML in patients on Tecfidera? The most recent case of PML was taking Tecfidera for 4.5 years and the prior European cases on fumaric acid esters were either on prolonged treatment or with prolonged lymphopenia (low lymphocyte counts). This is consistent with the experience in Tysabri treated patients where the risk of PML rises after 2 years of treatment, especially in those patients at risk. Based on the current world wide experience it is unlikely that the risk of PML in the first 2 years of treatment with Tecfidera will exceed 1 in 10,000 treated patients; a very rare risk. What is not known is whether the risk of PML increases over time in Tecfidera treated patients and assumes a higher risk profile with prolonged use.

4. Are there other potential complications of Tecfidera that are not apparent yet simply because not enough patients have been on the drug long enough. Biogen idec reports that there may be 70,000 to 100,000 patient-years of therapy at present (50,000 patients treated for 2 year each equals 100,000 patient-years of therapy), but the vast majority of patients have been on treatment for less than 24 months. Although patients with psoriasis have been treated with fumaric acid esters for decades, few of these patients stayed on long-term treatment. Therefore, we do not yet know the long-term risks of Tecfidera treatment and must remain vigilant in our monitoring over time. It is too early to tell if the incidence of serious adverse outcomes increases after more than 2 years of treatment.

The take home lesson is to learn and remember that there are potential risks with all treatments, both prescribed and homeopathic. It is the magnitude of the risk that is important and, so far, PML seems to be a rare outcome in people with MS on Tecfidera.

Blog written by Revere Kinkel MD and reviewed by A Scott Nielsen MD, Benjamin Greenberg MD and Deborah Backus PT PhD