Thursday, 16 March 2017

#ClinicSpeak & #ResearchSpeak: half-dose fingolimod not good enough

How close are we to knowing the optimal dose of fingolimod? #ClinicSpeak #ResearchSpeak

When fingolimod was licensed by the FDA for relapsing MS the FDA made this conditional on the basis that Novartis do a trial to compare 0.5 mg with a lower 0.25 mg dose. The reason for this is that the FDA were not satisfied that the dose of fingolimod had been optimised. In other words could the benefit:risk profile of fingolimod be improved with a lower dose; i.e. similar efficacy with a lower dose, but fewer adverse events due to less immunosuppression. The particular study 'MS Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ClinicalTrials.gov Identifier: NCT01633112)' started in 2012 and will only finish in 2022. 
  • Enrollment: 1056
  • Actual Study Start Date:August 9, 2012
  • Estimated Study Completion Date:March 23, 2022
  • Estimated Primary Completion Date:March 23, 2022 
Why so long? It shows you how difficult it is to recruit for trials that are unlikely to benefit study subjects. Those randomised to either the low-dose fingolimod, or Copaxone, arms are likely to on average do worse than the full-dose fingolimod arm. Knowing this would you volunteer for this trial?  Sometimes clinical practice has to be driven by pragmatic considerations. 


Thing-1 (0.5 mg) vs. Thing-2 (0.25 mg)

The real-life study below may help. This is an analysis of the outcome of relapsing patients who were switched to every other day fingolimod, or half dose (average daily dose 0.25 mg), due to low lymphocyte counts and were compared to a group of patients on standard daily fingolimod 0.5 mg per day. It is clear that the patients receiving every other day fingolimod did worse than those taking daily fingolimod. 

Does this study make the randomised study above irrelevant? No. The study below was not randomised and therefore there the results could be explained by some other factors associated with the need to go onto a lower dose of fingolimod, but not the actual dose of fingolimod itself, or the subjects on the full dose arm could have been biased to include fingolimod responders. Therefore, we can't be sure if half-dose fingolimod is inferior to full-dose fingolimod.  

What is interesting however is that low body weight, being female and have a low baseline lymphocyte count were associated with need to switch to alternate day fingolimod. All these factors make sense. What this study shows is that 0.5 mg daily of fingolimod is likely to be the optimal dose and if possible we should try and avoid the alternate day dosing. 

In Europe the EMA have mandated lymphocyte monitoring and dose interruption when the lymphocyte counts drop below 200/mm3. In comparison, the FDA have not mandated lymphocyte monitoring. The FDA decision was based on data that showed no link between lymphocyte counts and fingolimod efficacy and adverse events. At Barts-MS we have taken a pragmatic approach and use a lymphocyte cut-off of 100/mm3; this is somewhere between the EMA and FDA guidance. This means we rarely have to reduce the dose of fingolimod and hence are not putting many patients at risk of breakthrough activity. 


Zecca et al. Half-dose fingolimod for treating relapsing-remitting multiple sclerosis: Observational study. Mult Scler. 2017 Feb 1:1352458517694089.

OBJECTIVES: To investigate the efficacy and safety of fingolimod (FTY) 0.5 mg administered every other day (FTY-EOD) compared to every day (FTY-ED) in multiple sclerosis patients.

METHODS: Multicentre retrospective observational study. Clinical, laboratory and neuroimaging data were consecutively collected from 60 FTY-EOD and 63 FTY-ED patients. Baseline characteristics were compared using logistic regression. Efficacy in preventing occurrence of relapses and demyelinating lesions was tested using propensity score-adjusted Cox and linear regressions.

RESULTS: Weight was inversely associated with risk of switch to FTY-EOD because of any reason (odds ratio (OR) = 0.94, 95% confidence interval (95% CI) = 0.89-0.99, p = 0.026), and female sex and lower baseline lymphocyte count were positively associated with switch because of lymphopenia. Compared to FTY-ED patients, FTY-EOD patients were at higher risk of developing relapses (hazard ratio (HR) = 2.98, 95% CI = 1.07-8.27, p  = 0.036) and either relapses or new magnetic resonance imaging (MRI) demyelinating lesions (combined outcome, HR = 2.07, 95% CI = 1.06-4.08, p  = 0.034). Within FTY-EOD, treatment with natalizumab before FTY and lower age were positively associated with risk of developing relapses and combined outcome, respectively (HR = 25.71, 95% CI = 3.03-217.57, p = 0.002 and HR = 0.85, 95% CI = 0.77-0.96, p  = 0.005). FTY-EOD was overall well tolerated.

CONCLUSION: Disease reactivation was observed in a significant proportion of patients treated with FTY-EOD. Neurologists should be cautious when reducing FTY administration to every other day, especially in younger patients and those previously treated with natalizumab.

14 comments:

  1. The costs of the studies become staggering also, but the regulators dont care about costs.

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  2. Lot of G user (especially with under0.2 lymphocytes count) took it every other day. So it's may not enough for patient with highly active MS.

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  3. This is a good one... After experience with Tecfidera(rashes, GI problems, having to take it with fatty food etc) it is easy to start tinkering with the fingo dose if for some reason one has to lower the dose (for example grave lyphopenia on full dose fingo). Fingolimod for me was easier to live with than all the previous medications.
    So good, the study shows: don't try to tinker with dose, look for other alternatives if fingo does not work. And luckily, new options keep coming.

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  4. Wonder what will happen with regulators and oral cladribine. There was clearly no dose-response with the dosing used, will they ask for a lower dose. At least in terms of efficacy but there was in relation to effects on some lymphocytes but no dose response on other lymphocytes can you guess which ones showed the same relation to efficacy T or B cells? 50% chance you are right, unless you have the bias of dogma:-)

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  5. I think the regulators will be positive to cladribine this time.

    But I intend to be provocative and ask you, MD, a very personal question:
    Suppose you got diagnosed with MS today. MR shows, say, 10 T2 lesions and 1 of them is Gd enhancing. You have some OCB in you CSF and your MS started with sensory symptoms ( say: optic neuritis). Fairly typical case, nobody has any doubts about what it is and that you need treatment. NICE is really nice to you and you get to choose freely. And for the sake of this exercise, let's assume that daclizumab, ocrelizumab and cladribine are already on your hospital's pharmacy shelf and you can start tomorrow.

    WHAT do you choose?

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    Replies
    1. Ocrelizumab! PIRT, generally safe and the most effective one.

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    2. The treatment that i think is the most active, which minimises my exposure to side effects.
      I would practise what i preach.

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    3. In terms of ocrelizumab and port besides our recent paper there is no published data that it is a PIRT. The phase ii extension study suggests it is what happened to the hundreds of people in that trial we are now four years on so that is 6 years on. Did they continue to need no drug or did people begin the fail and switch.

      I would like the answer for this. Maybe the regulators will ask for this. It is something that needs an answer.

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    4. You forgot to tell me about my JCV virus status

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    5. Good question.
      but do you test for that routinely? Nobody tested me before they started thinking: she should be on natalizumab.

      But, to keep all options open, let's say you are JCV negative today (which is no guarantee that you are not positive next time we test).

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    6. "The treatment that i think is the most active, which minimises my exposure to side effects."

      Isn't it a bit like saying: "I would like a Tesla Model X please but I do not want to pay for it." :-)?

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    7. JC virus testing I think that is our routine. I would want to know.

      Tesla model X I guess is a car?

      Not at all, If I have MS today, I want to start treatment today or tomorrow at the latest, So you have to work with what you have today.

      It will always be better just round the corner, so in your scenario ocrelizumab, oral cladribine aren't a possibility, fingolimod wouldnt be because it is second line, as is natalizumab which as I am JCV negative I could consider, but would my disease activity allow me to have it. Same for daclizumab. If I try and wait for ocrelizumab or cladribine, what could I do now and what is the issue of transitioning from one to the other? Will they be licenced first line, because their price will mean they go second line, I predict.

      So I am left with tec, teri, interferon or cop and alem (I have an active lesion). What's the most active? Am I willing to have the side effects, is there a way to reduce them?

      However, I then ask can I afford rituximab or HSCT (ablative v non ablative...Do I try a treatment first and see if I get NEDA). I am going to have a battle with my disease history to get HSCT and I'm not going to get rituximab on NHS england. Can I persuade my neuro to try off-label cladribine? or maybe the other idea I have up my sleeve. If I can get rituximab can I persuade them to use as a PIRT, would they monitor my disease in the way I want it to be monitored?

      I know you want me to name names but, that's not my job here.
      You know what I don't like and you may have fair ideas of what I like.

      At the end of the day it is about getting as much detail on each agent, deciding how good they look and what are the side effects and their convenience but you have to live with your own decisions and deal with the "what if".

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    8. Well said MD.

      This is also in the MS tunnel. That is to say, presuming MS is the only existing condition and other medications are not problematic.

      In my case for example, when I presented resulting in diagnosis I was hit with a plethora of symptoms. Face drop, urinary incontinence, numbness, anxiety, sleep problems, severe fatigue and depression.

      To this day unsure of which of the invisible symptoms were directly causal of plaques.

      All I wanted do was lay in bed and fade away.

      I did the steroids and got prescribed some mood altering meds. Helped a bit.

      Then one day surfing the web I ran across LDN information so I tried it. Bam. I am one of those people where for whatever the reason it worked miracles. Incontinence gone, mood changes, energy up, the face drop did not last long. Of course, have had exacerbations since. If I stop LDN, incontinence returns rapid, energy fades etc. If I take a wee bit too high dose, get some spasticity.

      So... You can imagine when DMT selection came about I was completely unwilling to come off LDN. High JCV positive put Tysabri off the options page. Copaxone, Interferon were options but back then I felt I was doing "ok."

      When the orals hit I was quite scared of the side effects. When finally convinced to get on something both Aubagio and Gilenya when my Neuro inquired about LDN said, "no." Biogen said, "Dont see a problem" so on Tecfidera I went.

      Baseline MRI done. I cant take the contrast dye, severe allergic reaction. This was also when I was told about that we bump on my vertebral artery. Get on the med. No significant side effects, runny nose. Then within 2 weeks ramping up to the full dose... BAM... Mind numbing headaches. Brutal. Left side of my head towards the back.

      Hospitalized twice it was so bad. Even Morphine had minimal relief. On Baclofen. Headaches stop. Months later, restart Tecfidera. Then get told after 6 months need take a new baseline MRI.

      Another 6 months passes, another MRI. The phone rings. Congratulations, you are NEDA! Yay! Throw roses! But, get your buttocks over to the neurosurgeon.

      Huh? What?

      You know the rest.

      What a CRAZY ride.

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  6. Excellent, the same question would many of us ask as well!

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