AAN 2015: my take on the biotin the story

Is biotin a symptomatic therapy? #AAN2015 #MSBlog #MSResearch

"One of the MS highlights of the AAN 2015 meeting was the high-dose Biotin results in progressive MS trial. The following data sketch on the proportion of MSers in the trial with EDSS improvement confirmed at 2 study visits, sums up the results of the trial."

"The change in EDSS appears to occur very early in the course of the treatment, i.e. within the first 3 months. This strongly suggests that this is a symptomatic response and not a disease-modifying response. In addition, the changes are being driven by a very small number of responders (~10%), which means the majority of MSers in the trial did not have a confirmed improvement in disability as measure with the EDSS. The putative mode of action of Biotin is that it stimulates a large number of enzymes that increase the production of ATP or axonal energy. This local energy boost is what is hypothesised to overcome the energy deficits in vulnerable axons and presumably restore axonal conduction."
"The one proviso is that the early treatment response could be due to remyelination; from a biological perspective remyelination could occur early within the first 3 months of treatment. To sort this out the company will need to do a controlled withdrawal to see if the gains are reversible. If the gains persist (irreversible) it would support remyelination, however, if the gains are lost (reversible) it would suggest it is via an energy mechanism and hence a symptomatic therapy."

"I had informal talks with several pharma representatives at the meeting and it appears that several Big Pharma companies are doing due diligence on the product. If I worked for a Pharma company I would strongly recommend more work is done to sort out the symptomatic vs. remyelination issue. This could be done in animal models, for example Mouse Doc's chronic EAE model, in MSers using metabolic imaging (NMR spectroscopy, PET, SPECT), biomarkers (CSF studies), detailed conductions studies (evoked potentials and central motor conduction times) and a controlled withdrawal study in responders. Why is this important? The pricing model for symptomatic vs. disease-modifying therapies is very different; essentially symptomatic therapies are relatively cheap compared to disease-modifying therapies that are very expensive. A big pharma company will pay an order of magnitude more for the license of a putative disease-modifying therapy compared to a symptomatic therapy."

"On balance I think these results have been over-hyped by the media, and social media. The results are positive, but only weakly so, and it looks as if only a minority of MSers will be responders. The question about putative disease-modification remains open. Sorry to disappoint, but I don't want to set unrealistic expectations. I would, however, like to congratulate the academic team who have taken this product this far. Academic drug development is very, very difficult; well done. This study also places energy and metabolism centre stage when it comes to progressive MS."

Tourbah et al. Effect of MD1003 (High Doses of Biotin) in Progressive Multiple Sclerosis: Results of a Pivotal Phase III Randomized Double Blind Placebo Controlled Study. AAN 2015 PL2.002. 

OBJECTIVE: To evaluate the efficacy of Biotin 300 mg/day over placebo in patients with progressive multiple sclerosis (PMS).

BACKGROUND: Biotin is a water-soluble vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially key-enzyme in myelin synthesis. In one previous open-label pilot study involving 23 patients, it was found that high doses of biotin (100 to 600 mg/day) resulted in progressive and sustained improvement of disability in primary and secondary PMS patients.

DESIGN/METHODS: This is a randomized, double-blind, multicenter, placebo-controlled (2:1) trial of oral biotin 300 mg / day in patients with secondary or primary PMS with EDSS between 4.5 and 7 and evidence of EDSS progression within the past two years. Treatment duration was 48 weeks. The primary endpoint was the proportion of patients who improved at M9 and confirmed at M12, defined as decreased EDSS (by at least 1 point for EDSS ≤5.5 and .5 point for EDSS ≥6) or improved TW25 of at least 20%. Other endpoints included MSWS, CGI, % patients with stable or worsened EDSS, SF36, FIS, 9HPT.

RESULTS: The last patient is scheduled to complete the study January 2015. Baseline characteristics: 154 subjects from 16 sites across France were randomized; mean age 51.4; mean disease duration 16.6 years; 41% had PPMS and 59% had SPMS. The mean EDSS score was 6.1. The database will be locked by March 2015. Detailed results from primary and other outcomes will be presented.

CONCLUSIONS: This trial will evaluate the efficacy of Biotin 300 mg/d in a randomized, placebo-controlled trial. Effects of treatment with high doses of biotin in patients with PMS will be discussed in the context of future development of high doses of biotin as a novel potential treatment in PMS. 

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