Author Topic: Biotin in progressive MS: A new lead?  (Read 118 times)

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Offline agate

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Biotin in progressive MS: A new lead?
« on: November 04, 2016, 02:52:10 pm »
An editorial in Multiple Sclerosis Journal, November 4, 2016 (references omitted):

Quote
Biotin in progressive multiple sclerosis: A new lead?

Jeremy Chataway

Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London, UK
Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London, WC1B 5EH, UK. jeremy.chataway@uclh.nhs.uk

To reverse progressive multiple sclerosis (MS) would be an extraordinary claim. The current global effort, exemplified by the Progressive MS Alliance, would be delighted by news of any interventions that truly delay progression. Indeed, the dawn may finally be breaking, with chinks of light radiating from reports of ocrelizumab in primary progressive multiple sclerosis (PPMS) or siponimod in secondary progressive multiple sclerosis (SPMS). These drugs, given over 23 years, delayed the confirmed progression of MS by about 20%25%. These are in stark contrast to the long list of failed attempts over the last 25 years which have been so sadly archived.

Yet, the report in this edition of MSJ contains exactly that claim reversal of progression in progressive MS, by high dose biotin (300 mg/day). The readers would expect careful scrutiny.

So why biotin? It has acquired a number of names of the years: vitamin H, B7 and coenzyme R. Leafing through biochemistry books, it is water soluble and composed of a ureido (tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring (C10H16N2O3S1). Foods with relatively high biotin content include peanuts, leafy green vegetables and liver. It is a cofactor for four carboxylases: acetyl-CoA carboxylase, pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase. Deficiency symptoms include hair loss and dermatitis. Rare biotin-dependent genetic multiple carboxylase defects can occur, characterised by seizures and myoclonus accompanied by immune defects.

So why the role in MS? The authors postulate that biotin may be activating these carboxylases to enhance fatty acid synthesis and support myelin repair and/or enhancing neuronal energy production to protect against hypoxia-driven axonal degeneration.

 How did they come to find biotin? In an earlier open pilot study of 23 patients, treated for variable lengths of time, they report improvement, including reductions in the Expanded Disability Status Scale (EDSS). It seemed a plausible lead to follow.

The next step is to examine the trial structure in detail. A standard plan in progressive MS might be to assume a phase 2 magnetic resonance imaging (MRI) marker of disease progression, such as whole brain atrophy changing by 0.5%/year over 2 years; or in phase 3, clinical progression by 35%45% over 3 years. These constructs would yield two-arm trial cohort sizes of ca. 150 or 1000, respectively. In this trial (n = 154, in a 2:1 randomisation ratio), and on the basis of their original work, the authors inverted this and looked for proportions improved over 9 months, which are confirmed 3 months later.

What is an event? The definitions are as follows: improvement in EDSS of ⩾0.5 or ⩾1.0 depending on the base level (6.07.0 or 4.55.5) or a ⩾20% decrease in timed 25-foot walk (T25FW).

How is the trial powered? The assumption from initial work is that 40% of biotin patients will improve and 10% on placebo. The key patients contributing to the primary endpoint are listed in their Table 2. This is the meat of the paper, and it is worth spending some time analysing it in detail. There is some discontinuity, with only two patients being concordant with improvement both in EDSS and in T25FW; eight are solely due to EDSS improvement, leaving three with walking gains alone. All are on biotin, none are on placebo. In terms of the magnitude of the EDSS change in the high ranges, four patients required an entry score of 6.5 to improve to at least 6.0, which of course is a major step over a 9 + 3-month trial changing from walking 20 m with two sticks to 100 m with one stick. The readers might be concerned by the lack of third-party assessment. However, to move back from 6.5 to 6.0 would be extraordinary, though highly welcome, could this be a symptomatic effect? Figure 3 shows that the improvement tends to come early, at about 3 months, perhaps supporting this thesis.

Does the trial contain any possible confounders apart from the lack of independent assessors? By chance, the arms are not balanced in terms of the disability subgroups. In the lower range EDSS 4.55.5, potentially the easier to improve or the most fluctuant, the active:placebo ratio was 27%:14%. Or vice versa: 6.07.0, that is, the hardest to improve, the proportions were 73% versus 86%.

Finally, of course, we eagerly await the full MRI analysis. This report contains the T2 data which show new lesions in 23% of those on biotin versus 13% on placebo. Atrophy would be perhaps more interesting, though to see a slowdown at 12 months would in itself be demanding and more advanced (may be metabolic) parameters might be more insightful.

Therefore, in summary, the bar for slowing MS progression is high, to reverse it is higher still. We celebrate this report, but unfortunately know that it is work only half-done. To come must be a large and long phase 3 trial. If that confirms this finding, we, and especially our patients with progressive MS, will be truly celebrating.
 

Acknowledgments

J.C. acknowledges the UK National Institute for Health Research (NIHR) University College London Hospitals/University College London Biomedical Research Centres funding scheme.


Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

The editorial can be seen here.

The actual article contains only this  by way of explanation of the increased number of MRI lesions in those subjects taking biotin compared with placebo:

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More new or enlarging MRI lesions occurred in the MD1003 arm than in the placebo arm during the double-blind phase. Future trials should include careful assessment of MRI activity to rule out an unwanted pro-inflammatory effect of biotin. There are no published data on animal models concerning a potential pro-inflammatory effect of high-dose biotin. Of note, MRI was not used to assess efficacy because of the relatively short trial duration which was not powered to see an effect on brain volume.

The entire article can be seen here.
« Last Edit: November 04, 2016, 03:00:18 pm by agate »
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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Can biotin help treat MS?
« Reply #1 on: January 14, 2017, 02:34:27 pm »
More on biotin in Medical News Today, January 14, 2017:

"Can Biotin Help Treat Multiple Sclerosis?"
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

 

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