PML in MSer on Fingolimod – no report of prior immunosuppression or Natalizumab treatment

#MSResearch PML case with Gilenya

“Novartis confirms that it has received a report of a PML (progressive multifocal leukoencephalopathy) case. The patient had been receiving Gilenya® (fingolimod) for the treatment of relapsing MS (RMS) for more than 4 years. The diagnosis was made based on MRI findings and additional tests for JC (John Cunningham) virus. The patient is currently doing well. The case has been reported to Health Authorities. Patient safety is of paramount importance to Novartis, and we continue to monitor all aspects of patient safety on an ongoing basis. The positive benefit-risk profile of Gilenya in relapsing MS is based on experience with 114,000 patients treated with Gilenya and more than 195,000 patient years and accumulation of real-world efficacy and safety data.”

It is important to put this into perspective. This is so far a rare occurrence based on experience with 114,000 patients treated with fingolimod, more than 195,000 patient years as well as related real-world efficacy and safety data. 

The logic of fingolimod was a step down from Tysabri that traps cells in the blood, so they can’t get in the brain and so do not protect against the virus in the brain…when fingolimod traps most cells in the lymph glands so they can’t get in the blood, so they don’t get in the brain to protect against the virus. One may suspect that there will be leucopaenia, but we we will have to wait for further details. There was no indication on the website that this person had had natalizumab/immunosuppression

Novartis will claim that Gilenya does not affect the anti-viral arm, but one of the side effects of the drug can be poorly controlled viral infections. Nevertheless, the risks of Tysabri and Gilenya are clearly not the same. There is a thought that Tysabri is part of the problem that causes release of JC virus from the bone marrow.

This is another day of concern for people with MS, however it shows that if you persistently suppress the immune system PML is going to be an ongoing risk; this is one of the reasons why induction therapies have merit: after the initial period of immune suppression the immune system is drug free to fight viral attacks.

CoI: multiple

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  • It's a bit spooky cos I've been thinking about a possible PML on Gilenya today and well ……..didn't need long to wait.

    So, my prediction is that as long as you have drugs which severely drive down the immune system indiscriminately we'll hear about PMLs or other opportunistic viruses. It's quite common sensical – if your anti-viral defense is non-existent how is the body to fight viruses/infections/bacteria etc?

    And then again all the anti-infammatories don't stop progression so if one doesn't have grave relapses what is the point in taking them and risking a potentially lethal infection on top of that?

  • Why is it so hard to fight JC virus? If HIV can be controlled, can Biogen and Novartis develop an anti-viral that controls JCV? This may be harder for Tysabri, fut it's apparently a problem of controlling JC virus in the blood for gilenia and tecfdera.

  • This is to be expected, unfortunately, with all the drugs that in some way suppress immune response. The risk og Gilenya causing PML looks low at this point, but let us not forget that the 195,000 patient years of experience are "the first patient years" since fingolimod has been on the market for a relatively short time ( and the risk of PML rises with time as the virus has to mutate to get to CNS). There have also been multiple cases of PML on Gilenya earlier, those were interpreted as a "carry-on" effect of natalizumab.
    I am on Gilenya and this piece of news does not change anything for me at this point, other than I am more aware of the PML possibility.

    • Seems right. If I read the map correctly, they should have something around 30-40K patients who were treated with G for more than 2 years. If this is the accepted cutoff for risk of PML, then 1 in 30-40K is still different from 3-13 in 1000…

  • I don't get it, there has already been one previously reported case of PML in Gilenya (with no prior Tysabri use) in 2013 – Refer to the FDA web article
    PML is not new to Gilenya and on top of these 2 PML cases there have also been multiple reports of PML in prior use with Tysabri so why does this drug keep getting considered as 'safe' and 'a once off thing'. Its a dangerous drug that can and has caused PML.

  • I am away on a break with the family and this passed me by. We need to keep our thinking caps on and not over-interpret this. Almost every immunosuppressive drug has been linked to PML. Therefore it come as no surprise to me that a de novo case of PML has occurred after prolonged fingolimod use. The other case that occurred that was not carry-over PML from natalizumab may have had PML before fingolimod was started. What is important is that the incidence of PML on fingolimod is probably in the order of that which occurs with other immunosuppressive agents (> 1 in 10,000-20,000) and as a result this should not change our practice. The exception to this are JCV+ve MSers previously treated with natalizumab. The PML clock is not reset to zero when natalizumab is stopped and hence the risk of PML in these MSers may be higher than this.

  • Despite an apparently low risk here I expect the regulators may yet have an opinion about this and imagine JCV testing will become increasingly standard in pwMS not only on Natalizumab, but also for those on DMF and Fingolimod.

  • I have tested positive for the JC Virus, and have just changed my RRMS medication from Copaxone, (first the 20mg once per day, then the 40mg 3 times per week) and I am currently taking DMF (Dimethyl Fumarate) aka Tecifidera. I want to know what the REAL risks are if I am JC Virus positive and taking Tecfidera? I would like a clear explanation in laymans terms, for example, does the longer I am on Tecfidera increase my risk factor of PML? What are my risk of having Lymphopaenia? Would I be asked to discontinue Tefidera until my lymphocyte numbers increase? Is there ongoing research for PML treatment and a possible cure? I'm sure you understand the reasons for my concern. Thank you for your consideration in answering my questions.

  • Thank you for the update Professor Giovannoni. I am currently considering a switch to an oral, and with your latest update i have decided to go with Tecfidera – given that it has a lower chance of PML and no risk to the heart and eye.

  • I came across this article today when searching for info. regarding my extremely low WBC count on my most recent blood test (T4 – 8.6, B Cell – 1.5). I was on Tysabri for 2 1/2 years, but then tested pos. for the JC virus, and so switched to Gilenya in May of last year. This is the first that I have heard of the danger of PML while on Gilenya, and I am the exception that Professor Giovannoni speaks of. Should I be discontinuing the Gilenya, or maybe decreasing my dose to every other day as I have heard some mention? I would even consider stopping treatment altogether due to my almost non-existant symptoms, but my neurologist recommended it, due to my MRIs indicating a large number of lesions.

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