MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study

Ayman Tourbah, Christine Lebrun-Frenay, Gilles Edan, Michel Clanet, Caroline Papeix, Sandra Vukusic, Jerome De Sèze, Marc Debouverie, Olivier Gout, Pierre Clavelou, Gilles Defer, David-Axel Laplaud, Thibault Moreau, Pierre Labauge, Bruno Brochet, Frédéric Sedel, Jean Pelletier, MS-SPI study group, Ayman Tourbah, Christine Lebrun-Frenay, Gilles Edan, Michel Clanet, Caroline Papeix, Sandra Vukusic, Jerome De Sèze, Marc Debouverie, Olivier Gout, Pierre Clavelou, Gilles Defer, David-Axel Laplaud, Thibault Moreau, Pierre Labauge, Bruno Brochet, Frédéric Sedel, Jean Pelletier, MS-SPI study group

Abstract

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.

Keywords: MD1003; Multiple sclerosis; clinical trial; disability progression; high-dose biotin; primary progressive multiple sclerosis; secondary progressive multiple sclerosis.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Prof. Ayman Tourbah has received consulting fees, travel grants and reports institutional financial compensation for patient visits during the trial from MedDay Pharmaceuticals and consulting and lecturing fees, travel grants and research support from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva Pharmaceuticals and Roche. Prof. Gilles Edan reports personal fees from Biogen Idec and Novartis and grants and personal fees from Merck Serono, Teva, Sanofi and Bayer, outside the submitted work. Prof. Sandra Vukusic reports clinical trial support from MedDay Pharmaceuticals, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals and Genzyme; advisory or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharmaceuticals; and invited congress support from Biogen Idec, Merck Serono, Novartis and Genzyme. Prof. Jérôme De Sèze reports clinical trial support from MedDay Pharmaceuticals, Biogen Idec, Merck Serono, Bayer, LFB, UCB, AB Sciences, Sanofi-Aventis, Teva Pharmaceuticals and Genzyme; advisory or consultancy fees from Biogen Idec, Merck Serono, Bayer, LFB, Sanofi-Aventis, Teva Pharmaceuticals, Almirall and Allergan; and invited congress support from Biogen Idec, Merck Serono, Bayer, LFB, Sanofi-Aventis, Teva Pharmaceuticals, Genzyme and Allergan. Dr Olivier Gout reports personal fees and non-financial support from Biogen Idec, Teva Pharmaceuticals, Genzyme and Novartis and personal fees from Merck, outside the submitted work. Prof. Gilles Defer reports personal fees from Biogen Idec, Novartis, Sanofi-Aventis, Genzyme and Teva Pharmaceuticals; grants from Novartis, Merck Serono and Teva Pharmaceuticals; and funding for travel from Merck Serono, Biogen Idec, Guerbet, Sanofi-Aventis, Novartis, Genzyme and Teva Pharmaceuticals, outside the submitted work. Prof. David-Axel Laplaud reports personal fees from Biogen and Teva Pharmaceuticals and grants and personal fees from Novartis and Genzyme, outside the submitted work. Prof. Thibault Moreau reports personal fees and non-financial support from Biogen, Novartis, Sanofi-Genzyme, Bayer, Merck, Teva Pharmaceuticals and Almirall, outside the submitted work. Prof. Bruno Brochet received grants from MedDay Pharmaceuticals during the conduct of the study; personal fees and non-financial support from Biogen Idec, Novartis and Genzyme; grants from Merck Serono; grants, personal fees and non-financial support from Teva Pharmaceuticals; and grants and non-financial support from Bayer, outside the submitted work. Dr Frédéric Sedel is CEO and a shareholder at MedDay Pharmaceuticals (the study sponsor). Prof. Jean Pelletier has received consulting and lecturing fees, travel grants and unconditional research support from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono and Teva Pharmaceuticals. Dr Christine Lebrun-Frenay, Prof. Michel Clanet, Dr Caroline Papeix, Prof. Marc Debouverie, Prof. Pierre Clavelou and Prof. Pierre Labauge have nothing to disclose.

© The Author(s), 2016.

Figures

Figure 1.
Figure 1.
Screening, enrolment, randomisation and follow-up of study patients. The ITT population was defined as all patients who were assigned to a treatment arm. The per-protocol population was defined as all patients of the ITT population with assessments of EDSS or TW25 at screening, baseline, month 9 and month 12 without major protocol deviations. EDSS: Expanded Disability Status Scale; ITT: intention to treat; TW25: timed 25-foot walk.
Figure 2.
Figure 2.
Proportion of patients with reversal of MS-related disability. Reversal of disability was defined as improvement of EDSS or TW25 values confirmed at the next visit (except for month 24 where no subsequent visit was available) compared with best respective values recorded at either the screening or the randomisation visits. EDSS: Expanded Disability Status Scale; TW25: timed 25-foot walk.
Figure 3.
Figure 3.
Mean change from baseline in EDSS during the 12-month double-blind placebo-controlled phase and 12-month extension phase. This figure also shows the mean change from baseline in EDSS (represented as the mean of means) as reported in other published placebo-controlled studies of pharmacological agents in PPMS or SPMS (>6000 patients in total).,,– EDSS: Expanded Disability Status Scale; DR 2/4 (+ or −): human leukocyte antigen haplotype (positive or negative); GA: glatiramer acetate; IFNb: interferon beta; PPMS: primary progressive multiple sclerosis; SEM: standard error of the mean; SPMS: secondary progressive multiple sclerosis; TW25: timed 25-foot walk.

References

    1. Browne P, Chandraratna D, Angood C, et al. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology 2014; 83: 1022–1024.
    1. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014; 83: 278–286.
    1. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol 2014; 72: 1–5.
    1. Levin MC, Douglas JN, Meyers L, et al. Neurodegeneration in multiple sclerosis involves multiple pathogenic mechanisms. Degener Neurol Neuromuscul Dis 2014; 4: 49–63.
    1. Stys PK, Zamponi GW, van MJ, et al. Will the real multiple sclerosis please stand up? Nat Rev Neurosci 2012; 13: 507–514.
    1. Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009; 8: 280–291.
    1. Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66: 460–471.
    1. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360: 2018–2025.
    1. European Study Group on interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: 1491–1497.
    1. Wingerchuk DM, Carter JL. Multiple sclerosis: Current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014; 89: 225–240.
    1. Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: A pilot study. Mult Scler Relat Disord 2015; 4: 159–169.
    1. Sedel F, Bernard D, Mock DM, et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. Epub ahead of print 5 September 2015, DOI: 10.1016/j.neuropharm.2015.08.028.
    1. Confavreux C, Vukusic S, Moreau T, et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000; 343: 1430–1438.
    1. Andersen O, Elovaara I, Farkkila M, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2004; 75: 706–710.
    1. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): A randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–2221.
    1. Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002; 59: 679–687.
    1. Freedman MS, Bar-Or A, Oger J, et al. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology 2011; 77: 1551–1560.
    1. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: A randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 2010; 9: 681–688.
    1. Panitch H, Miller A, Paty D, et al. Interferon beta-1b in secondary progressive MS: Results from a 3-year controlled study. Neurology 2004; 63: 1788–1795.
    1. Rice GP, Filippi M, Comi G, et al. Cladribine and progressive MS: Clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000; 54: 1145–1155.
    1. Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007; 61: 14–24.
    1. Hommes OR, Sorensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: Randomised placebo-controlled trial. Lancet 2004; 364: 1149–1156.
    1. Wijeratne NG, Doery JC, Lu ZX. Positive and negative interference in immunoassays following biotin ingestion: A pharmacokinetic study. Pathology 2012; 44: 674–675.
    1. Hobart J, Blight AR, Goodman A, et al. Timed 25-foot walk: Direct evidence that improving 20% or greater is clinically meaningful in MS. Neurology 2013; 80: 1509–1517.
    1. Manouchehrinia A, Tanasescu R, Tench CR, et al. Mortality in multiple sclerosis: Meta-analysis of standardised mortality ratios. J Neurol Neurosurg Psychiatry 2015; 87: 324–331.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere