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