Friday, 16 January 2015

ClinicSpeak: fampridine trial results

Does fampridine, a chemical that drives axonal conduction, speed up progressive MS? #ClinicSpeak #MSResearch #MSBlog

"The fampridine/dalfampridine extension study below has mixed messages. The good news is that responders still respond; if you are a responder and come off the drug you will still respond when you go back onto the drug; there were no new safety signals seen with fampridine. The bad news is that MSers still progress. The million, or 100 million, dollar question is does fampridine/dalfampridine increase the rate of disease progression?"

"Fampridine is the name for slow-release 4-aminopyridine. We think fampridine works by lowering the requirements for axons (the electrical cables of nerves) to conduct an electrical impulse. Fampridine blocks a specific group of proteins on their surface called voltage-gated potassium channels. This makes it more likely for an electrical impulse or action potential to be transmitted across a demyelinated segment of an axon. Although this will improve motor function, i.e. walking speed, the effect on sensory and other pathways may make some symptoms worse, for example exacerbation of pain and increase in the frequency and severity of MS-related positive symptoms (pins & needles, muscle spasms) and it can trigger seizures." 

"Aminopyridines will almost certainly increase the energy requirements of damaged, vulnerable, demyelinated axons as they will require more energy for repolarization the process by which they get ready to transmit another electrical signal. There is now good evidence that increasing the energy requirements of axons may result in further axonal injury and loss. Essentially this is the theory underlying the use of sodium channel blockers, such as phenytoin and oxcarbazepine, as neuroprotective compounds in MS. By reducing transmission you reduce the energy requirements and hence protect vulnerable axons. We have shown neuroprotective effects of sodium channel blockers in our animal model many times. For these reasons I am wary about the long-term use of Fampridine in MS-related motor fatigue. I am worried that Fampridine may speed up the rate of disability progression. I stand to be proved incorrect on this; the only way to find out is by doing clinical trials and following up patients with progressive MS on these medications for long periods of time using standardised methods." 

"Several years ago we proposed two studies to Biogen-Idec, who market the drug in Europe, to look into whether or not Fampridine increases the rate of MS progression; again our suggestions fell on deaf ears. The first study we proposed was to use Fampridine in our animal model; as the tablet can't work we proposed administering 4-aminopyridine using small pumps. The pumps would release low levels of the drug slowly. The idea was to compare 4-aminopyridine to placebo and to a sodium channel blocker. Why to a sodium channel blocker? At the time Biogen-Idec though that contrary to our hypothesis fampridine may be neuroprotective. The second study was to use spinal fluid neurofilament levels to test this hypothesis. If fampridine exacerbated, or sped-up, progressive disease it would increase spinal fluid neurofilament levels, compared to placebo, in MSers going onto the drug. Neurofilaments are the structural, or scaffolding, proteins of nerves and axons and are released when nerves are damaged. Levels of neurofilament in the spinal fluid are proportional to the amount of nerve damage and predict a poor outcome. May be we will be proved wrong and these studies will show that Fampridine is safe and does not speed up disease progression. But until we do these studies we simply won't know what Fampridine does to the rate of MS disease progression."

"The following are Hugh Bostock’s videos, from Queen Square, on conduction in a normal nerve and a demyelinated nerve. These illustrate how slow and difficult it is to transmit an electrical impulse down a demyelinated nerve. When you watch the videos please try and imagine how much more effort/energy is required for conduction in demyelinated axons; aminopyridines are the chemical whip that keeps these axons firing."


Normal conduction


Conduction in a chronically demyelinated axon

"The following are two MSers who are clearly responders to Fampridine; despite these dramatic results we are not allowed to offer fampridine under the NHS. MSers wanting a trial of Fampridine have to pay for it themselves via a private prescription."




"Interestingly, fampridine may not work in the way we think it does. We don't think levels of the drug are high enough in the brain to block enough potassium channels to affect the so called resting membrane potential of nerves. If this is the case we need to go back to the drawing board to find out how it works. We think we may have an answer to this." 


BACKGROUND: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS).

OBJECTIVES: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT).

METHODS: MSers received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW.

RESULTS: We had 269 MSers enter MS-F203EXT and 154 MSers complete it; for a maximum exposure of 5 years. We had 214 MSers enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders.

CONCLUSIONS: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

CoI: multiple

17 comments:

  1. Thank you Prof G - what impeccable timing for this post! I was planning on talking about this drug at my next appointment with the neurologist in about a month's time, as my leg function, walking, and fatigue are my worst symptoms, and he mentioned it in passing at my last appointment. To people other than physios or neurologists my walking "looks" OK but just a bit slow, but it's only that way for a max of about 50 metres, and then things seriously become a lot harder. Standing up for more than 10 minutes is really difficult, and on occasions I have just had to kneel on the floor if there are no chairs available to sit on, as my legs sometime just won't hold me up any longer. It's just a pity there aren't any answers yet on whether this drug speeds up progression - that's a bit of a price to pay if it does speed up the rate of progression.......

    Questions:
    Is it known whether people who do respond to this drug get any benefits if the dose is lower? (i.e. at 5mg twice daily instead of 10mg twice daily)

    If you took the drug and did get a very positive response, would it be worth seeing if halving the dose still produced sufficient benefits? That is, a sort of hedging your bets against it increasing progression. (I don't need to turn into a Grand National race winner - but would like to be able to function a bit better as even a fairly small improvement would make a big difference to me.)

    A question not related to the drug - is there any correlation between the amount of hyper-reflexia in lower limbs and walking difficulties? (Sometimes when my leg is tapped above the knee my foot seems to have ambitions to join the space race to Mars!)

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    1. Is it known whether people who do respond to this drug get any benefits if the dose is lower? (i.e. at 5mg twice daily instead of 10mg twice daily)

      Studies show the 5mg twice daily isn't effective.
      I try to only take 1 10mg everyday. Usually around 11am, earlier if really needed or later if I'm feeling good.
      Here in NZ, fampyra price was lowered from $1200 to $300/month.
      I only take a half dose because I can't afford more.
      Effects are profound. I can stand up from a chair without using my hands. Everything is more stable, I can trust my legs more and fall less. I can do more of everything, and even get some kind of normal fatigue. Previously my body 'clamped up' from any kind of movement, so couldn't 'exercise' at all in the sense of tiring a muscle out.
      SPMS - 18 years. No DMTs. A bit of valium and cannabis sometimes.
      Baza.

      Delete
  2. Being a rollator-user - a study into the possible neurodegenerative potential of using Fampridine is a valid proposal (but largely academic, with all due respect). Right now I'd be more interested in the immediate benefits of the treatment, if I respond positively -but it probably won't work as well in PPMS. Who said Fampridine was a DMT, anyway?

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    1. Re: "Who said Fampridine was a DMT, anyway?"

      Nobody that I am aware of. We hypothesising that it may act as a negative DMT, by speeding up progression.

      Delete
  3. I have SPMS, and have been on Fampridine for 20 months. Before starting on it, my walking speed was deteriorating by 1% per month.

    The Good News:
    Fampridine took my EDSS score back 2 years in time. I stopped using a stick, and began walking unaided with confidence.
    I could walk upstairs, and carry a cup of coffee in each hand without spilling a drop.

    The bad news:
    After 18 months my walking speed with Fampridine was as slow as it was before I started taking it. To test things I came off Fampridine for a week.
    My walking was half the speed of 18 months ago, I could hardly stand, and there was a pronounced weakness in my left wrist that stopped me using a fork. The reduction in walking speed amounted to 5% per month. Luckily I went back to my previous speed when I re-started Fampridine, but the regression is continuing.

    Pro's and Con's:
    Would my natural rate of regression have increased to 5% per month if I had not been on Fampridine? Maybe Prof G. can elucidate !
    My Neuro suggested I stay on it, because walking is my only exercise, and by keeping walking I was helping myself better than any drugs currently on trial for SPMS seem to. However, it is costing approx £200 per month, and having read the article above, I would not have started it.

    I am sure everyone reacts differently, but for me the regression in walking ability was faster than it was before I started taking it.

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  4. Re "we are not allowed to offer fampridine under the NHS"
    I don't live in the UK, but from much of what is posted here it seems to me that the UK NHS has a very short-sighted view of the cost of some of the treatments available for MS and its symptoms/impacts (and not just fampridine). Seems that the guidelines are overly driven by short-term bottom line costs, with no consideration of longer term benefits - i.e. MSers being able to continue to working and paying taxes (and participate in worshiping the almighty god of Retail Spending) are likely to be less of a drain on the economy overall. And let us not forget about the positive benefits (mentally, physically, and financially) for individuals if they are still part of the rest of society and not stuck away at home and "hidden" from the rest of the world.

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    1. Yes you are correct I believe...the short term cost is the driving force

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  5. 420 euros per month for Fampyra. I went back to work after starting this drug, but only sadly earn half of this amount. I can stand up long enough to play for 20 minutes, or conduct a choir.
    I haven't noticed any progression. I can still do what I could before Fampyra. I'm also on Rebif and have responded well for 14 years.
    So, I am confused now. Will I progress? Will I make it onto a stage and do a big concert/recital before I lose my faculties?
    Who knows, but I'm working and happy and playing and singing quite big stuff (Rossini, Handel) and teaching Rock music to slightly confused Galicians. Solfeggio versus notation anyone? I manage to teach two pupils in one class. One who can sing really well but prefers lessons in Spanish and the other who can't sing well, who wants explanations in English. I don't think that anyone without MS could manage this without feeling wrung out afterwards.
    I think that the risk of progression is worth it right now. No one said life is easy.

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  6. I have SPMS. I have been taking Fampyra for a year now. It not only improved my walking but also the use of my arms. For over a year before starting it, my walking was almost non-existent, my husband had to help me a lot with meal preparation and I had not been able to do any knitting or sewing. Within a few days of starting Fampyra, I was walking better, back to doing my own cooking preparation and I started knitting and sewing again. I knitted two cardigans for myself during 2015!
    I know it will not stop progression of my MS, but how can I be sure the progression is any different to what it would have been had I not been taking Fampyra? All I know is that it has revolutionise my life for the last year, and I wouldn't have missed that! (I was even able to do a tandem skydive - unimaginable a year ago!)
    Is there any further research planned on fampridine? Those of us taking it seem to have been left "in the air", with only anecdotal evidence to help us.

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  7. I´ve been using Fampridine for a month. I´ve a PPMS and the sympthoms are worse. I´ve stop taken a week ago and I can´t walk more than 100 meters. My neurogists says that Fampridine has no guilt... but I feel that It has.
    Regards

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    1. May I ask, how far could you walk before starting.?

      Some symptoms getting worse...it is probably part of biology. It blocks potassium channels and these are sometimes use to quell nerve excitation.

      Delete
    2. Before starting I could walk 500/600 meters. Thanks for your response...

      Delete
    3. I think the drug has desensitised your system. Hopefully after stopping drug it will reset itself but you are not alone I have heard from other people that after stopping fampridine people have struggled.

      Desensitisation is common for drugs that affect ion channel action. In the beasties we had one drug that blocked the muscle relaxation potential within a week for another drug it was a day. Hopefully things will right themselves if not let us know.

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    4. I´ve stopped the intake on march 29th. I´m still very dizzy and the balance is worst...
      I´ve a new visit with my neurologist this friday.

      Delete
    5. I´m not taking Fampridine yet and my walk doesn´t go to the previous time of the intake. Now I can´t walk more than 200 meters.
      Neurologist says there´s no serious test that says that Fampridine may speed up progression.
      Do you have some so I can you her?
      Thanks

      Delete
  8. I know this is an old entry but it’s new to me lol.

    After reading it, I googled 'fampyra and increased ms progression' to see if there's been any information more recent then this entry that settles the progression matter. Didn't find any more recent info, but did find that that UK MS society is advising on its webpage that "Fampyra does not change the progression of MS but does improve..." https://www.mssociety.org.uk/what-is-ms/signs-and-symptoms/balance-and-dizziness/coping-with-balance-problems

    If I had MS and was told something does not impact my MS, when there was chatter and questions about whether it does, I'd be mighty peeved if it ultimately turns out that it does impact my MS.

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  9. Hi, I've been on Fampridine for 2 years and have PPMS. I was told (1) it probably won't work (2) it's expensive (3) it may make things worse. Being stubborn/determined/desperate and having spent 12 months just trying to get it, I took personal responsibility for it. My Consultant signed off on it my walking improved greatly. If I accidently miss a dose the results are horrendous. I don't care if my MS progresses faster, I could just as likely die from something else.

    ReplyDelete

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