Brain Volume Declines May Represent Remyelination With MD1003 for Progressive MS


MD1003 led to a pseudo-atrophy phenomenon that was likely related to remyelination.

Dr Douglas L. Arnold

Douglas L. Arnold, MD, from McGill University Health Centre

Douglas L. Arnold, MD

Treatment with MD1003, a high-dose version of biotin, was associated with improvements in expanded disability status scale (EDSS) and time to walk 25 feet (TW25) compared with placebo but led to a pseudo-atrophy phenomenon that was likely related to remyelination for patients with progressive, non-clinically active multiple sclerosis (MS), according to a sub-study of the phase 2b/3 MS-SPI study presented at the 2017 MS Paris Meeting.1

Overall, in the MRI-based study, there were decreases in whole brain volume (WBV) and gray matter volume (GMV) associated with MD1003. These declines in WBV and GMV were linked with a decrease in brain water volume and astrocytic edema, likely due to increased energy metabolism in the brain. Furthermore, the magnetization transfer ratio (MTR) was higher in the MD1003 arm versus the placebo group across all measures, suggesting possible remyelination, said lead investigator Douglas L. Arnold, MD. Additionally, for diffusion tensor imaging (DTI), there were improvements in fractional anisotropy (FA) with MD1003 versus placebo.

"In an MRI sub-study, MD1003 was associated with a decrease in whole brain volume and gray matter volume. The effects of MD1003 on volumetric measures may be due to a pseudo-atrophy phenomenon consistent with a decrease in virtual hypoxia," said Arnold, from the Montreal Neurological Institute and Hospital, McGill University Health Centre, Montreal, QC, Canada. “Results from MTR and DTI analyses suggest possible remyelination.”

Biotin is a coenzyme in the B vitamin family, with many dependent carboxylases. MD1003, which is high-dose pharmaceutical grade biotin, is thought to target neuron and oligodendrocyte metabolism. Biotin supports increased ATP production and could lead to enzyme-driven increases in fatty acids that may support myelin production.

In the full MS-SPI study, 154 patients were randomized in a 2:1 ratio to receive MD1003 (n = 103) or placebo (n = 51). MD1003 was given at 100 g three times a day. The initial study was blinded for 12 months followed by an open-label expansion phase, wherein patients in the placebo group crossed over to receive MD1003 at 100 g three times per day. At entry, 47% of patients were receiving fampridine and 40% were on concomitant disease-modifying therapy.

Overall, 12.6% of patients treated with MD1003 experienced reversed progression compared with 0% in the placebo group (P = .005).2 In an extension phase that went beyond 12 months, there was a 13.2% improvement with MD1003 at month 18 and a 15.4% improvement at month 24. Even those switching to MD1003 at 12 months experienced a subsequent response of 7.1% at month 18 and 11.9% at month 24.

There was a mean decline in EDSS of -0.03 with MD1003 compared with an increase of +0.13 with placebo. For those in the MD1003 group, EDSS was -0.03 and +0.04 at 18 and 24 months, respectively. In the placebo group, MD1003 slowed progression, with an EDSS of +0.13 and +0.15 at months 12 and 24, respectively.

There were 74 patients available for the sub-study MRI analysis presented at the MS Paris Meeting. Of these, 49 had received MD1003 in the randomized and extension stages of the trial and 25 received placebo followed by MD1003. Normalized volumes of the WBV, white matter (WMV), and GMV at baseline were analyzed using SIENAX in 66 patients and the remaining were examined using SIENA and paired Jacobian integration.

At 12 months, by NeuroRx there was a -0.3% decrease in WBV in the MD1003 group versus a +0.1% increase in the placebo arm (P = .046). For GMV, there was a -0.6% decrease with MD1003 and no change in the placebo group (P = .0435). Changes in WMV were not statistically significant, at -0.3% with MD1003 and +0.2% in the placebo group (P =.107). Similar findings were seen in those examined using INSERM.

At month 24, by NeruoRX there was a -0.5% decline in WBV in the MD1003 group and a decline of -0.6% in those initially treated with placebo who crossed over to the biotin group (P = .502). For GMV, there were declines of -0.5% and -0.8% in the initial MD1003 group and the placebo/MD1003 groups, respectively (P = .606). WMV declined by -0.4% and -0.5%, in the MD1003 and placebo/MD1003 groups, respectively (P = .874).

For normal appearing white matter, the MD1003 group had a 0.7% increase from baseline in MTR at 24 months compared with a decline of -0.6% in the placebo group. For MS lesions both groups had MTR declines, although there were greater drops in the placebo group (-0.6% vs -1.2%). For gray matter, 0.6% had an MTR increase with MD1003 versus a decline of -0.04% with placebo. For DTI, there was a 2.4% increase in FA with MD1003 versus a -1.5% decline for the placebo group.

A phase 3 study, known as SPI2, is currently enrolling participants to compare MD1003 with placebo for patients with progressive MS. The primary endpoint of the study is EDSS and TW25. The trial has a target enrollment goal of 600 patients and an estimated primary completion date of September 2019 (NCT02936037).


  1. Arnold D, Ranjeva J-P, Pelletier J, et al. MD1003 in progressive multiple sclerosis: 24-month brain MRI results of the MS-SPI trial. Presented at: 7th Joint ECTRIMS - ACTRIMS Meeting; October 25-28, 2017, Paris, France. Abstract 130.
  2. Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016; 22(13):1719-1731.
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