MD1003 (High-Dose Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study

Ayman Tourbah, Olivier Gout, Alain Vighetto, Véronique Deburghgraeve, Jean Pelletier, Caroline Papeix, Christine Lebrun-Frenay, Pierre Labauge, David Brassat, Ahmed Toosy, David-Axel Laplaud, Olivier Outteryck, Thibault Moreau, Marc Debouverie, Pierre Clavelou, Olivier Heinzlef, Jérôme De Sèze, Gilles Defer, Frédéric Sedel, Carl Arndt, Ayman Tourbah, Olivier Gout, Alain Vighetto, Véronique Deburghgraeve, Jean Pelletier, Caroline Papeix, Christine Lebrun-Frenay, Pierre Labauge, David Brassat, Ahmed Toosy, David-Axel Laplaud, Olivier Outteryck, Thibault Moreau, Marc Debouverie, Pierre Clavelou, Olivier Heinzlef, Jérôme De Sèze, Gilles Defer, Frédéric Sedel, Carl Arndt

Abstract

Background: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS.

Objective: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss.

Methods: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed.

Results: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo.

Conclusions: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated.

Trial registration: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals.

Conflict of interest statement

Funding

This study, and editorial support for the preparation of this manuscript as well as open access fee, was funded by MedDay Pharmaceuticals.

Conflict of interest

Ayman Tourbah received consulting and review activities fees and support for travel to meetings from MedDay Pharmaceuticals. Ahmed Toosy received speaker honoraria from Biomedia, Serono Symposia International Foundation, and Bayer, and meeting expenses from Biogen Idec. He is the local principal investigator for clinical trials in multiple sclerosis funded by MedDay Pharmaceuticals. Oliver Gout received personal compensation for scientific advisory boards and funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Sanofi-Genzyme, Merck-Serono, MedDay, and Teva. David-Axel Laplaud received grants, consultancy fees or honoraria, and payment for lectures including service on speaker’s bureaus from Merck, Biogen, Sanofi-Genzyme, Roche, and Novartis. Alain Vighetto, Christine Lebrun-Frenay, Jérôme De Sèze, and Carl Arndt received consultancy fees or honoraria from MedDay Pharmaceuticals. Jean Pelletier received unconditional research grants from Merck, Novartis, and Roche; consulting fees or honorarium from Biogen, Genzyme, MedDay Pharmaceuticals, Merck, Novartis, Roche, and Teva; and support for travel to meetings for the study, manuscript preparation or other purposes from Biogen, Genzyme, MedDay Pharmaceuticals, Merck, Novartis, Roche, and Teva. Pierre Clavelou received consulting fees or honoraria from Biogen, Roche Merck, Teva, Novartis, and Genzyme. Frédéric Sedel is Chief Executive Officer and Co-Founder of MedDay Pharmaceuticals. Giles Defer received personal compensation for scientific advisory boards and funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Sanofi-Genzyme, Merck-Serono, and Teva; and institutional research grants from Merck-Serono, Biogen Idec, Sanofi-Genzyme, and Novartis. Véronique Deburghgraeve, Caroline Papeix, Pierre Labauge, David Brassat, Olivier Outteryck, Thibault Moreau, Marc Debouverie, and Olivier Heinzlef have nothing to declare.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. The conduct of the study was overseen by an independent data safety monitoring board.

Informed consent

All subjects gave their written informed consent prior to their inclusion in the study.

Figures

Fig. 1
Fig. 1
CONSORT diagram—screening, enrolment, randomization and follow-up of study patients
Fig. 2
Fig. 2
Primary endpoint: mean (± SEM) change from baseline in logMAR at 100% contrast (selected eye) at month 6 (n = 93). ITT population. The figure also shows the results of the primary efficacy analysis during the extension phase (month 12; n = 92). ITT intention-to-treat, SEM standard error of the mean
Fig. 3
Fig. 3
Pre-planned subgroup analysis of the primary efficacy analysis in patients with a progressive optic neuropathy (n = 31) and b sequelae of an acute optic neuritis (n = 62). ITT population. ITT intention-to-treat, SEM standard error of the mean
Fig. 4
Fig. 4
Mean (± SEM) change from baseline to month 6 in a logMAR at 5% contrast (all eyes), b mean RNFL thickness (all eyes), and c NEIVFQ-25 composite score, in patients with progressive optic neuropathy (n = 31). ITT population. ITT intention-to-treat, NEIVFQ-25 National Eye Institute 25-Item Visual Function Questionnaire, RNFL retinal nerve fiber layer, SEM standard error of the mean

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