Wednesday, 28 August 2013

Fingolimod and infections

Fingolimod is not associated with an increased rate of infections. #MSBlog #MSResearch

"Because fingolimod causes a low lymphocyte count, and there have been a few deaths due to viral infections in people with MS on the drug, it is assumed that fingolimod is a potent immunosuppressive agent. The study below challenges this assumption. You also have to remember that the number of deaths due to infections is very small relative to the number of MSers treated; 3 herpesviral infection related deaths with over 70,000 treated MSers and two of these deaths occurred on a higher dose of fingolimod that subsequently was not licensed, i.e. the 1.25mg dose. The 0.5mg dose is the one that has been licensed."

"There is little doubt that fingolimod reduces the peripheral lymphocyte counts. However, you need to know about what type of lymphocytes are affected and what happens to those lymphocytes? Firstly, fingolimod is not a depleting agent; it simply traps lymphocytes in peripheral lymph nodes by removing one of the signals that lymphocytes use to migrate from lymph nodes. If you stop fingolimod and wait for it to wash-out of the system the vast majority of MSers will see their lymphocyte counts return to normal. This is reassuring. In addition, fingolimod does not affect all lymphocytes in the same way; it does not trap the so called effector cells. These cells are primed and ready for action when being exposed to an infection the immune system has already seen. This is good news if you get exposed to infectious agents you have seen in the past. What is not good news is if you come into contact with a new virus or infection, or so called exotic infections, that your immune system has not encountered in the past. Animals and people on fingolimod have a blunted response to new infections. Please note this is a blunted response, which means they can still respond to the agent but not as quickly, or briskly, as someone not on fingolimod."

"What about opportunistic infections? Opportunistic infections are defined as infections that rarely occur in humans unless they are immunocompromised. For example people with HIV or AIDs, with cancer, with malnutrition, or on immunosuppressive drugs to prevent transplant rejection tend to get opportunistic infections. Examples include fungal infections and infections related to tuberculosis. The study below reassuringly shows that fingolimod is not associated with opportunistic infections. This is very good news and indicates that fingolimod is not a potent immunosuppressive agent."

"Can the manufacturers therefore claim that fingolimod is not immunosuppressive, but rather an immunomodulatory agent? Immunomodulatory in this context implies that it modulates the immune system without causing immunosuppression. I say no. Why? Well it is known that fingolimod reduces your lymphocyte count, it also blunts, but not abolishes, your response to vaccines and it blunts the immune response to novel, or new not previously seen, infections. Fingolimod was also tested as an anti-rejection agent in people having kidney or renal transplants and it worked reasonably well. All this points to fingolimod being immunosuppressive. Fingolimod must  therefore be, at least, mildly immunosuppressive to have these effects."

"You will note from reading the study below that fingolimod was not associated with an increase in infections in the studies analysed. So that take home message is that fingolimod is mildly immunosuppressive and is not associated with an increased rate of infections nor rate of opportunistic infections. MSers who choose to go onto fingolimod will find this very reassuring. However, they must stay vigilant to infections and if they get infections they should seek medical attention to have them treated promptly; why take a chance if you don't need to. The other thing is MSers will not be able to have live vaccines whilst on fingolimod."

"It is a great pity that the EMA has given fingolimod a second-line license in Europe, when it is used first-line in many other countries, for example Switzerland, USA and Australia. Fingolimod is one of the highly-effective agents, is an oral tablet, and MSers in Europe are being forced to wait until they have failed one of the so called 1st-line treatments to access the drug. Hopefully, now that the EMA has recommended Alemtuzumab for active MS they will change their stance on fingolimod, and for that matter natalizumab in JCV-seronegative MSers. Time is brain and the sooner MSers have a choice to go onto highly-effective treatments the better. I personally don't think regulators should be making the these decisions for MSers. What do you think?"


Epub: Francis et al. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler. 2013 Aug 15.

BACKGROUND: Reduction in peripheral blood lymphocytes is an expected pharmacodynamic outcome of fingolimod therapy.

OBJECTIVE: The objective of this article is to evaluate lymphocyte dynamics during and after fingolimod therapy and assess the relationship between lymphocyte counts and infections.

METHODS: Lymphocyte counts and their relationship with infections were evaluated in three multiple sclerosis (MS) populations: (Group A) FREEDOMS phase 3 core study group (n = 1272); (Group B) All Studies group (one phase 2 and two phase 3 studies, plus their extensions; n = 2315); and (Group C) Follow-up group (after fingolimod discontinuation; n = 538).

RESULTS: Administration of fingolimod 0.5 mg led to reductions in lymphocyte counts to a steady-state of 24%-30% of baseline values within two weeks, which remained stable while on therapy. Following fingolimod discontinuation, average counts exceeded the lower limit of normal range within six to eight weeks, and were 80% of baseline values by three months. In Group A, infection rates per patient-year were 1.4 with placebo and 1.0 in fingolimod-treated patients who had the lowest lymphocyte counts (< 0.2 × 109/l). No evidence was seen for an increase in serious or opportunistic infections.

CONCLUSIONS: Fingolimod induces a rapid and reversible reduction in lymphocyte counts without an increase in infections relative to placebo. Because fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a MSer.



CoI: multiple

3 comments:

  1. I can only agree with you, Prof G regarding Fingolimod - had a row with my neuro because I wanted it and in my country it is second-line only (I have a rather agressive form of MS but obviously not agresssive enough for my doc!). The second point - yes lobby us as decision-makers not the regulators - it is OUR brains that degenerate fast. Maybe this could be brought up at ECTIMS? Too many neuros are still too hesitant and listeniny blindly to the EMA ( like in the 'Little Britain' sketch: 'computer says no so no meds'. However, if our docs march with us then EMA will think again.

    Best as always

    Anna

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  2. I just wondered what you think about the fact that my lymphocytes have been 0.3-0.4 pretty much the whole time I have been on Fingilimod but this month they have risen to 1.6. Very odd and I havent missed any tablets at all. Is it a bad sign.

    Jo

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