Friday, 18 November 2016

#ResearchSpeak: is it or is it not; that is the question?

Is high-dose biotin neuroprotective or is it not? #ResearchSpeak #MSBlog

MS is #1-disease-not-2-or-3-diseases #ResearchSpeak #MSBlog


Everyone who reads this blog regularly will be sensitised to high-dose biotin as a treatment for more advanced MS. Biotin is hypothesised to improve the energetics of axonal transport, by augmenting mitochondrial function and may increase myelination. In pwMS with more advanced non-relapsing MS (previously known as progressive MS) about 10-20% notice a sustained improvement in function. Please note this improvement occurs early, within the first 3 months, but not immediately with minutes or hours. The latter observation argues against it being a symptomatic treatment. Early recovery of function within months is compatible with axonal or remyelination effects. 

So should everyone be taking high-dose biotin? No. It is not available commercially and I have recently been told that some compounding pharmacies selling it online are lacing their tablets with 4-aminopyridine, the active compound in fampridine. If 4-aminopyridine is not formulated to be released slowly it is much more likely to cause peak-dose side effects, for example seizures. 

Where next? I really think we need a properly powered randomised placebo-controlled trial to see if the MD1003 works in a wider population. We also need biomakers studied to see how it is working. Is it neuroprotective, i.e. does it reduce brain atrophy and reduce CSF and plasma neurofilament levels? Is it a remyelinating agent; does it improve central conduction speeds of axons? The latter can be measured using evoked potentials. Is it increasing axonal sprouting (one axon taking over the function of an adjacent dead, or dying, axon) and/or is it promoting synaptogenesis? We have a panel of CSF biomarkers that will tell us this.

The graph below shows that pwMS treated with high-dose biotin (MD1003) stay stable over a 24 month period. In comparison, placebo-treated pwMS, initially improve (placebo-response) and then get worse over the first 12 months on treatment; they then stabilise over the next 12 months when they are put on active drug. On the same graph is the behaviour of so called 'progressive' pwMS from other clinical trials; it is clear that they do much worse on the EDSS over 2-years (red line) compared to MD1003-treated pwMS. 

Please note that we still have to use the awful term 'progressive' MS to describe historical cohorts. This term is wrong, wrong, wrong. Progressive means progress, an improvement, however, in the context of MS it implies worsening. From now on we will refer to it as worsening MS. Instead of progressive MS we will now call it advanced MS; which implies worsening disability. There is really very little scientific reason to split MS up into different sub-types, i.e. relapsing, vs. secondary and primary progressive disease. MS is one disease. As I have recently discovered making MS 2 or 3 diseases was a ploy by Pharma to get MS recognised as an orphan disease, which allowed them to get interferon-beta licensed on the data from one trial and to charge a higher, than expected, price for the drug. MS is 1-disease-not-2-or-3-diseases.




Tourbah et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016 Nov;22(13):1719-1731.

BACKGROUND: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study.


OBJECTIVE: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study.

METHODS: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits.

RESULTS: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo.

CONCLUSION: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.

CoI: multiple

20 comments:

  1. "Please note that we still have to use the awful term 'progressive' MS to describe historical cohorts. This term is wrong, wrong, wrong."

    A high-five on this; I have felt the same way as you for decades. I will help get the message out! Can you please get this post into print in a peer-reviewed journal. I am sure many of us in the field will adopt your proposal; it builds on the recent Lublin et al. publication. I also am supportive of the one-disease concept.

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  2. Few want the term MSer ProfG still using it.

    If there is a treatment will we care what it is called.

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  3. 'I have recently been told that some compounding pharmacies selling it online are lacing their tablets with 4-aminopyridine, the active compound in fampridine. If 4-aminopyridine is not formulated to be released slowly it is much more likely to cause peak-dose side effects, for example seizures.'

    I take fampridine and also 5000ug biotin by Solgar. While I know that this dose of biotin is far from high and nowhere near the suggested amount which may help MS, should I be worried about the use of 4-aminopyridine?

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    1. Different but related: I've used Ampyra for years, and experimented with Biotin. Is there a good reason NOT to mix them in one pill?

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  4. "Progressive means progress, an improvement, however, in the context of MS it implies worsening."

    I don't agree with you - I don't have an issue with the use of "progressive MS". It depends on your feeling for language, your 'Sprachgefühl'. I think "worsening MS" sounds clumsy.

    On the other hand, I don't really care what it's called - it is what it is.

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    1. I don't have an issue with the use of 'progressive MS' too.

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    2. the point, i think, is not so much in a name but the dogma associated with the name (3 diseases instead of one)

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    3. I'd rather say secondary progressive than secondary worsening. The difference for me is the disease is progressing in my CNS, but my health is worsening. I have issue with the term Relapsing Remitting it implies the disease has disappeared. I always described myself as having MS with severe exacerbations, a bit of a mouthful.

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  5. I attended the MS Life conference this year and the topic of high dose Biotin came up. The speakers seemed to be very sceptical about its use as neuroprotective and couldn't understand why and how it works.

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    1. it is anti-oxidant the company came and presented to us last week but i can't talk about the content until they publish

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    2. Well whatever it's doing..it's sure not very effective..12.6% ???

      RESULTS: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients

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    3. In those 13% there is an improvement, so it is reversing the deficit.

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  6. I am not sure I understand this study. 12.6% showed improvement of EDSS (reversal of deficit) but what percentage maintained or slowed the worsening of the EDSS of the remaining patients on Biotin 100 mg daily vs placebo?

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  7. Also confused. In the same (I believe) study, the longer term treatment showed a trend towards more patients improving. If I recall, it increased to 15+%. So, is this evidence of a dose dependent,sustained improvement? Also, doesn't the fact that the patients being treated remained stable (this needs better definition) for 24 months imply a disease modifying effect or neuroprotection? Was brain atrophy looked at? I have been on a compound formulary biotin 100mg prescribed by my neurologist by a reputable pharmacy for 3 months and have noticed no difference at all. Even if there is no improvement in EDSS, I would be thrilled if it slowed or stopped progression

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    1. The dose used in the study is 1000mg and as you say the data indicate that it does not do something for everyone. The team came to present at our lab meeting as we may become a trial site. So unfortunately I can't say more than what's in the public domain

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    2. The MedDay trials for Biotin and MS were 100mg capsules, 3 times per day.
      Where do you come up with this 1000mg dose that you are stating ?

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  8. Complex B vitamins seem to have all antioxidant roles, at least that's what I've read so far. I've read something about B3 being able to act by controlling the immune system. Now it remains to know if they are neuroprotective. I use B1 and B12 and at least seem to have positive effects ...

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  9. I have been taking Biotin 300 mg for a year and stopped wearing my glasses, seem to have improved my vision. Take Tisabry 125 of infusion yesterday, and stable no new lesion.😊

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  10. In USA, purebulk,has biotin, a high quality scale, and neurologist to watch over. FDA is requiring all new study to be done using 100mg Biotin Three times per day. They have not started to recruit, but ucdavis is one site. Neurologist was glad I could obtain Biotin, and scale, and will be anxiously watching me, or side effects.

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