Saturday, 14 December 2013

Clinic speak: 5-year fingolimod data

Fingolimod remains effective over 5 years with no new safety signals. #ClinicSpeak #MSBlog #MSResearch

"It is always reassuring to see long-term extension data published from clinical trials. The study below shows that in MSers who have received fingolimod for 5, or more years, the drug remains effective with MSers have a low relapse rate and low MRI activity and no new safety signals have emerged."

"This data mirrors the clinical experience of using fingolimod in the real-world. The main issue with fingolimod are the initial effects of the drug on the heart, or the so called first dose effect, which is the transient slowing of the heart rate when the drug is first started. This means that all MSers have to have a cardiac screen with an ECG, or EKG, to make sure there are no abnormalities of cardiac rhythm. In addition, MSers who are on cardiac drugs that may slow the heart and interact with fingolimod may not be able to start fingolimod. Providing your heart is normal you need to spend 6 hours in hospital for the first-dose observation. Rarely, in less than 0.5% of MSers, fingolimod may cause a transient block in the conduction of electricity in the heart, i.e. a heart block, which may need to be treated with a temporary pacemaker. The heart block, however, typically resolves spontaneously.If the heart rate remains low after 6 hours the observation period may need to be extended and very rarely the MSer may needed to be admitted for overnight observation. In our experience the heart monitoring is not cumbersome and MSers tolerate it well."

"As fingolimod is an a drug that suppresses your immune system you need to be vigilant about infections. As it is an immunosuppressant you are not allowed to have live vaccines whilst on the drug. This is why we test you to see if you have been infected in the past with the chickenpox virus, or varicella-zoster virus. If you don't have antibodies against the chickenpox virus we assume you have not been infected with the virus and we vaccinate you before starting fingolimod. In some parts of the world where TB, or tuberculosis, is common we may screen you for latent TB. If positive for latent TB we have to give you a short course of anti-TB drugs. In all the MSers I have started on fingolimod I have only needed to do this once. Please note as you are unable to have live vaccines on fingolimod you need to consider travelling to areas with exotic viruses, for example yellow fever, with care. The current yellow fever vaccine is a live vaccine and hence you can't be immunized against the virus before you travel. If you do decide to go to a yellow fever area, and you are on fingolimod, you need to take precautions and try and prevent yourself being bitten by mosquitoes; mosquitoes transmit yellow fever."

"What about ongoing monitoring? Once you on fingolimod we need to check your eyes, or retina, at about 3-4 months after starting to make sure you don't develop swelling of the retina or so called macular oedema. If this should occur, fingolimod needs to be stopped and the oedema clears spontaneously. You also have to have your liver function tests and blood counts monitored regularly. A small number of MSers develop abnormal liver tests and fingolimod may have to be stopped, and restarted. All MSers who start fingolimod develop a low lymphocyte count; this is how the drug works. Fingolimod traps the lymphocytes in lymph nodes; it does not kill them hence they are still in the body, but not in the blood. If fingolimod is stopped the lymphocyte counts return to normal within a period of 6 to 8 weeks. If the lymphocyte count drops below 200 per mL we are meant to stop the drug. However, as there are no adverse events reported in MSers with lymphocyte counts below 200 I tend to continue the drug. I may switch to alternate day dosing, i.e. every second day, if the MSer concerned becomes anxious or the counts go lower than 100. If you stop the drug for longer that 2 weeks you need to repeat the first dose monitoring."

"Overall our experience with fingolimod has been positive. MSers who start the drug are doing well. As it is one of the highly-effective drugs they should continue to do well. What I find quite amazing is that the NICE cost-effectiveness model that are used to assess whether or not DMTs are cost-effective and can be used in the NHS, the models assume that there is a waning of the therapeutic effect. I am not sure why? The data set below suggests the drug continues to work without a waning effect; well at least for 5 years. I can only speculate that the assumption that the therapeutic effects of the drug wanes over time helped the NHS get a further discount on the price. I am not sure if you are aware that the NHS does not pay the list price for fingolimod, but a discounted price. The discounted price is a secret; if it gets out it will allow other nations to drive a hard bargain and also demand a bigger discount."

"One of the interesting aspects of the biology of fingolimod is the fact that it not only works on the immune system, but may have positive effects on cells within the central nervous system. There are suggestions that it may promote remyelination and it may be neuroprotective. Fingolimod is one of the drugs that has a positive impact on brain atrophy or brain shrinkage; this effect is seen within the first 6 months and is significant across at least the first 2 years of treatment."

"If any of you are on fingolimod it would be nice for other readers to hear about your experience. Thank you."


Epub: Izquierdo et al. Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis. Mult Scler. 2013 Nov 30.

Background: The investigators present here results at 60 months, from the extension component of a phase 2, randomized, placebo-controlled, double-blind, six-month study evaluating oral fingolimod (1.25 mg or 5 mg daily) in relapsing MS. 

Methods: Placebo treated MSers from the core study were re-randomized to fingolimod 1.25 mg or 5 mg in the extension. All MSers received 1.25 mg fingolimod after the month 24 visit. A total of 140/281 (49.8%) patients completed month 60. 

Results: Fingolimod treatment was associated with a low annualized relapse rate (0.2 relapses/ year), low MRI activity, and a modest rate of disability progression in those treated for five years. No new safety issues were reported.

Conclusions: Fingolimod has a durable effect, both clinically and on MRI, and no new safety signals have emerged after 5 years of treatment. 

CoI: multiple

8 comments:

  1. Hi,

    I already posted on here but it didn't publish. I'll try again..

    I am in the States and have been taking fingolimod for about 9 months now as part of a year long clinical drug study. The only side effects I have experienced so far were loss of appetite and some stomach upset during the first month of therapy. I spent 6 hours in my doctor's office for the first dose. Heart rate dropped a bit but was not a problem.

    I was just diagnosed last year (at age 58), and was treatment naive so I don't have any other drug therapy to compare. I haven't had any major relapses since been taking it though. My cognitive issues are somewhat stable. My lymphocytes were really low at last test so I am now on an every other day dosing schedule.

    My MS specialist says things should only get better the longer I can stay on this drug. I am hopeful that I can continue with fingolimod after the study ends in March. But that will depend on the decision of my insurance company and any assistance the drug company can give me.

    I hope this information is helpful to you.

    Sandra

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  2. I have PPMS, and am partaking in a double blind trial for fingolimod run by Dr Chataway. I have felt no ill effects whatsoever but obviously this could be because of placebo. My only worry is that if I am on placebo, I would have had no medical treatment whatsoever for 3 years. I sometimes think I am on the drug as I seem to get flu very easily and usually get hit hard by it, a consequence of the immunosuppressant effect? I have not had any flu vaccines and would very much like to travel to exotic locales, but overly worry in case I am on the drug.

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    1. I have PPMS and am on the same trial. The following is an abridged copy of a letter I wrote to MS Australia commenting on an article in their publication. We need to reform the approval process for drugs.

      Article – In Touch Autumn 2013 –

      Emerging Treatments Series – Part 3

      Exploring stem cells

      The assertion that these treatments have not been shown to have any effect is wrong. This arises from your confusing the idea of proving effectiveness with the concept quantifying effectiveness.

      The 2 points here are, firstly, that effectiveness is established in phase 2 of such trials and if there had been no observed effect it would not have even got to phase 1. Secondly, although it might sound appropriate that we use the highest standards when approving new drugs the mistake is that this is not relevant. What is needed is a sufficiently accurate assessment of effectiveness. The difference between an observed effect of 75% in an experiment and of an assessed effect of 74.75% in a phase 3 trial is irrelevant. Both figures are approximations at different scales and it is important to select the appropriate scale for your application.


      Our present system for approval of new treatments needs to be overhauled.
      There are treatments available in other countries that are not available here such as Sativex for spasticity which is approved in Canada, the UK and Spain.

      Drug companies are abusing the system to maximize profits by manipulating trials. I am on a phase 3 trial for Fingolimod for progressive MS. Phase 3 trials of this drug have been done for RRMS and it was approved early in 2011. Progressive MS was excluded from the earlier trials so that this smaller fraction of the ‘market’ could be trialed later and so a ‘new application’ for the product can be claimed so the patent can be extended. Prior to about 5 years ago all trials of treatments for MS included all forms of the disease. Since then most trials exclude progressive forms for trialing later. The argument is that results would be skewed but this is a Furphy. The trials can easily be divided into sections. This is ethically wrong and morally reprehensible.

      Approximately 1000 people world wide are being given a 50% chance of getting Fingolimod. The rest of the people with progressive MS have no option to access it. If instead of a sample of 1000 that is divided in half so that half get the drug and half are controls all the sample are given the drug then the size of the trial is doubled. The control is all of the clinical history of the disease world wide to date. The placebo control is irrelevant as there will always be a percentage of any group treated who will experience it. The assessment bias is very well controlled using standard tests. Doubling the size of the trial also eliminates some of variability due to effects that being double blinded controls for

      My final point re: scientific evidence is that a lack of evidence is not the same as evidence against and no scientific evidence will be discovered if no-one does the experiments.

      People who have MS deserve to have their rights considered and to be given the respect they deserve. I am disappointed that MS Australia would endorse such a stance at the expense of MS sufferers. I can only conclude that the drug companies have some financial input into MS Australia and Sense About Science and that both have, unethically, failed to disclose their conflict of interest.

      I also strongly resent the implication that, as I have PPMS, I should simply wait to progress to the stage where I am curled up in a hospital bed with some-one else feeding me and wiping my backside. I should not try an experimental treatment because it has not been proven to be safe. I feel sure that the flawed logic would be apparent to most reasonable people. The argument that such an experiment will deprive the scientific community of the chance to obtain information from controlled trials is another Furphy.

      I would also point out that no system is perfect. Thalidomide was approved.

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    2. Whilst I agree there could be an argument made for an overhaul of the drug licensing system and if a drug is very very effective and stops the condition then maybe you could argue for using historical data but in all likeliness one may see a change in the slope but it will not flat line then how do you get a sense there is any real difference.

      If you go on historical data there is a problem that it may not be reflective of modern data, as life styles change, even over a few years. If you look at the relapse rates of trials of yesteryear the drug effectiveness is now at a level where placebo is now and drug effectiveness is much better still, so if you compare apples with oranges you have a problem. However this will be a problem for RR MS as in my mind it is not longer ethical to put people on placebo when there are active drugs. However, look at the mess we are in with Alemtuzumab, there was no placebo control and they are suffering the consequences. Once one of the more highly effective drugs gets established as a first line treatment it will make it very difficult for a new kid to enter the block. Would you go on a trial with the risk of a drug failure when you know there is something for you out there.

      You could argue once you show efficacy in phase II allow people to access the drug and then have a rigourous monitoring process. However when you start lumping every thing together it makes it more difficult to see the trees from the wood.

      There are 1000 people with a 50% chance of getting drug and doing better, but the converse could be there are a 1000 people with a 50% chance of doing worse. This is a risk that people in trials take


      In Phase I (often not in MSers but health controls) safety is examined not effectiveness
      In Phase II safety is examined with the hope of showing some effectiveness
      in Phase III effectiveness is examined whilst showing safety.

      That a phase I is passed gives no message of whether a treatment will be effective.
      Stem cell research is full of promise but the reality in MS is, that it still has some way to go for that promise to be realised

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  3. I've been on fingolimod for 2.5 ears, and I am doing reasonably well on it. I can't compare it to other therapies - I was diagnosed during an unexpected, severe, debilitating relapse, and my other choice was Tysabri (but I am JCV-positive). During the first year on fingolimod, I had a couple of relatively minor relapses (probably as an aftermath of my major attack), which were treated with 3-day courses of IV steroids. I did not need steroids for the last year and a half. Fatigue has been the only notable side effect - but it's hard to tell whether it's MS-related or medication-related (and it's been more or less successfully managed with ADD medications lately). I would like to stay on fingolimod for as long as it continues to be effective. I would seriously consider combining it with other DMDs, but my neurologist is against this idea (apparently the only available data are on fingolimod as a monotherapy).

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    1. DMT + Another DMT increases the risks of generalised immunosuppresion.

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  4. This comment has been removed by the author.

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  5. I started Gilenya as my first MS treatment 9 months ago. I'm in my mid 40's and my MS symptoms had been ignored or misunderstood for 15 or so years. I had a bad flare 15 months ago that led to diagnosis, and another within two weeks of starting Gilenya. Nothing since and no MRI changes.

    Can't tell whether my new cognitive issues are from the Gilenya or from the relapse on starting Gilenya. Otherwise an ok experience. A few more chest colds. I'm not planning to take this drug into old age but for now I'm healthy enough to stand a few extra infections in exchange for real benefit. Hoping it's not too late in terms of my age and progression.

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