CNS Drugs (2018) 32:661–672 https://doi.org/10.1007/s40263-018-0528-2 OR IGINAL RESEARCH ARTIC L E 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 1,2 3 4,5 6 • • • ´ • Ayman Tourbah Olivier Gout Alain Vighetto Veronique Deburghgraeve 7,8 9 10 11 • • • • Jean Pelletier Caroline Papeix Christine Lebrun-Frenay Pierre Labauge 12 13 14,15 16 • • • • David Brassat Ahmed Toosy David-Axel Laplaud Olivier Outteryck 17 18 19 20 • • • • Thibault Moreau Marc Debouverie Pierre Clavelou Olivier Heinzlef 21 22 23 24 • • • ´ ˆ ` ´ ´ Jerome De Seze Gilles Defer Frederic Sedel Carl Arndt Published online: 28 May 2018 The Author(s) 2018 Abstract Objective The aim of this study was to evaluate whether Background Chronic visual loss is a disabling feature in MD1003 improves vision compared with placebo in MS patients with multiple sclerosis (MS). It was recently patients with chronic visual loss. shown that MD1003 (high-dose pharmaceutical-grade Methods The MS-ON was a 6-month, randomized, double- biotin or hdPB) may improve disability in patients with blind, placebo-controlled study with a 6-month open-label progressive MS. 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 Electronic supplementary material The online version of this worsening of VA within the past 3 years following either article (https://doi.org/10.1007/s40263-018-0528-2) contains supple- mentary material, which is available to authorized users. Department of Neurology, CHU de Montpellier, Montpellier, & Ayman Tourbah France firstname.lastname@example.org INSERM U1043, Centre de Resource et de Competence SEP, Department of Neurology, Faculty of Medicine, CHU de Hopital Pierre Paul Riquet, Universite ´ de Toulouse, Reims, URCA, Reims, France Toulouse, France LPN EA 2027, Universite ´ Paris 8, Saint-Denis, France Department of Neuroinﬂammation, UCL Institute of Neurology, Queen Square Multiple Sclerosis Centre, Department of Neurology, Fondation Ophtalmologique University College London, London, UK Adolphe de Rothschild, Paris, France UMR 1064, INSERM, Centre de Recherche en Lyon Neuroscience Research Center (CRNL), ImpAct, Transplantation et Immunologie, Universite ´ de Nantes, INSERM U1028, CNRS, UMR5292, Lyon 1 University, Nantes, France Lyon, France Service Neurologie, CHU Nantes, Nantes, France Department of Neurology, Hopital Neurologigue, Hospices Civils de Lyon, Bron, France Department of Neurology, CHU de Lille, University of Lille, Lille, France Department of Neurology, CHU de Rennes, Rennes, France Department of Neurology, University Hospital of Dijon, Department of Neurology, APHM, Hopital de la Timone, Dijon, France Marseille, France Department of Neurology, CHU de Nancy, Nancy, France UMR 7339, CRMBM, CNRS, Aix-Marseille Universite, Marseille, France Department of Neurology, CHU de Clermont-Ferrand, Clermont-Ferrand, France ´ ˆ ` Department of Neurology, GH Pitie Salpetriere, Paris, France Department of Neurology, Centre Hospitalier de Poissy, Department of Neurology Pasteur 2, Universite Nice Cote Saint Germain, France d’Azur, Nice, France 662 A. Tourbah et al. acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean Key Points change from baseline to month 6 in VA measured in log- arithm of the minimum angle of resolution (logMAR) at Assessment of optic nerve function is a readily 100% contrast of the selected eye. Visually evoked accessible target for evaluating MS therapies that potentials, visual ﬁeld, retinal nerve ﬁber layer (RNFL) aim to restore neurological function. This study thickness, and health outcomes were also assessed. evaluated whether high-dose pharmaceutical-grade Results Ninety-three patients received MD1003 (n = 65) biotin (hdPB; MD1003) could improve visual or placebo (n = 28). The study did not meet its primary function in patients with MS who had chronic optic endpoint, as the mean change in the primary endpoint was neuritis (ON) nonsigniﬁcantly larger (p = 0.66) with MD1003 (- 0.061 MD1003 did not improve visual function compared logMAR, ? 3.1 letters) than with placebo (- 0.036 log- with placebo in the subset of patients with ﬁxed MAR, ? 1.8 letters). Pre-planned subgroup analyses visual loss following an acute episode of ON; showed that 100% contrast VA improved by a mean of ? however, there were trends towards improvement in 2.8 letters (- 0.058 logMAR) with MD1003 and worsened a number of measures of visual function in patients by - 1.5 letters (? 0.029 logMAR) with placebo with progressive chronic optic neuropathy (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsigniﬁcant These results are consistent with recent data that improvement in logMAR at 5% contrast and in RNFL showed that MD1003 can decrease progression and thickness and health outcome scores when compared with improving walking disability in patients with placebo-treated patients. There was no superiority of progressive MS. The treatment was overall well MD1003 vs placebo in patients with AON. The safety tolerated proﬁle of MD1003 was similar to that of placebo. Conclusions MD1003 did not signiﬁcantly improve VA compared with placebo in patients with MS experiencing 1 Introduction chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Multiple sclerosis (MS) is a frequent and disabling neu- Treatment was overall well tolerated. rological disease characterized by multifocal myelin Trial registration EudraCT identiﬁer 2013-002112-27. destruction in the central nervous system. Most patients ClinicalTrials.gov Identiﬁer: NCT02220244 with MS experience an initial period of relapsing–remitting Funding MedDay Pharmaceuticals. disease (RRMS) followed later by a progressive disease course (secondary progressive MS; SPMS) . Approxi- mately 15% of patients experience progressive disease from onset (primary progressive MS; PPMS) [1, 2]. Pro- gressive MS, either SPMS or PPMS, can be further cate- gorized as active or non-active depending on the presence of superimposed inﬂammatory activity . There are cur- rently no disease-modifying therapies approved for the treatment of non-active progressive MS. Among the potential causes of progressive axonal degeneration in progressive MS are chronic demyelination and mitochondrial dysfunction, which both lead to a state of virtual hypoxia [4–6]. We recently reported the results of a randomized, double-blind, placebo-controlled study that showed that MD1003 (high-dose pharmaceutical-grade biotin [hdPB]) achieved sustained reversal of MS-related INSERM 1434, Department of Neurology, Clinical disability in patients with progressive MS without activity Investigation Center, CHU de Strasbourg, Strasbourg, France in the last 2 years before inclusion . Biotin is a cofactor Department of Neurology, CHU de Caen, Caen, France for acetyl-CoA carboxylase, the rate-limiting enzyme that generates malonyl-CoA, the two-carbon building block for MedDay Pharmaceuticals, Paris, France fatty acid synthesis, which is an essential component of Department of Ophthalmology, Faculty of Medicine, CHU de myelin [9, 10]. Biotin is also a cofactor for three enzymes Reims, URCA, Reims, France MD1003 in Multiple Sclerosis-Related Chronic Optic Neuropathy 663 that generate intermediates for the tricarboxylic acid cycle: extension phase during which all patients received pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase, MD1003 [Online Resources 1, see electronic supplemen- and propionyl-CoA carboxylase . Therefore, the tary material (ESM)]. The study was conducted between improvements in disability seen in patients with progres- October 2013 and September 2015 at 19 sites in France and sive MS treated with hdPB may be due to an increase in the one site in the United Kingdom. supply of precursors for fatty acid and myelin synthesis and/or replenishment of the pool of adenosine triphosphate 2.2 Participants (ATP) in hypoxic neurons [7, 8]. Acute optic neuritis (ON) is an inﬂammatory and Eligible patients were aged 18–75 years old with a diag- demyelinating disorder of the optic nerve that occurs in up nosis of MS fulﬁlling the 2010 McDonald criteria , uni- to 50% of patients with MS and is the ﬁrst symptom in up to or bilateral optic neuropathy with VA in the worst eye of B 20% [11, 12]. Optic neuritis leads to loss of vision and 5/10 (decimal scale; 20/40 in US customary units) con- typically presents as an acute monocular loss of vision, ﬁrmed at 6 months, and evidence of worsening VA during though it can affect both eyes either simultaneously or the last 3 years (deﬁned as a change in VA of C 1/10 points sequentially [13, 14]. Symptoms of ON include reduced or more than one line). In AON, VA had to remain stable at visual acuity (VA), periocular pain (especially during eye least in the 6 months prior to inclusion. In PON, progres- movements), reduced contrast sensitivity, dysfunction of sive visual loss had to have been noted at two different color vision, and visual ﬁeld defects [11, 12]. Vision loss visits in the previous 3 years. typically develops over a period of hours or days and peaks Key exclusion criteria included relapse of ON within 3 within 1 or 2 weeks . Most patients regain VA within 6 months before inclusion; other concomitant ocular condi- months, though visual contrast often remains impaired tions (glaucoma, cataract, retinopathy, anterior uveitis, [15, 16]. In a minority of cases, VA remains low more than myopia [ 7 dioptrics, intraocular pressure [ 20 mmHg, 6 months after an acute ON. This type of chronic visual loss amblyopia, retinal or optic head abnormalities); bilateral is referred to as ‘sequelae of an acute optic neuritis’ (AON). VA \ 1/20, visual impairment caused by ocular ﬂutter or In rare cases, visual loss becomes slowly progressive, so- nystagmus; or normal RNFL. Patients who were treated called ‘progressive optic neuropathy’ (PON) [17–19]. with fampridine initiated \ 1 month prior to inclusion or Patients with optic nerve injury represent a good target any other new medication for MS (immunomodulators and group to evaluate the efﬁcacy of drugs aimed at restoring immunosuppressive agents) initiated \ 3 months prior to neurological function in patients with MS, as the optic nerves inclusion were also excluded. Full eligibility criteria are are accessible to precise and quantitative measures. Visual shown in Online Resource 2 (see ESM). function can readily be assessed using ETDRS (Early Treatment Diabetic Retinopathy Study) logarithm of the 2.3 Intervention minimum angle of resolution (logMAR) charts at high and low contrast to determine VA  and automated perimetry In the placebo-controlled phase of the trial, patients were to examine visual ﬁeld defects . Optic nerve function can randomized 2:1 to either MD1003 (oral biotin 300 mg/day be assessed by recording visual evoked potentials (VEPs) administered as 100-mg capsules three times daily) or  and the pathological changes seen in the thickness of the placebo. Placebo capsules were identical to hdPB capsules retinal nerve ﬁber layer (RNFL) can be accurately quantiﬁed except for an additional 100 mg lactose excipient in place via optical coherence tomography (OCT). of hdPB. Randomization was performed with a computer- In the initial open-label study of MD1003 in patients with generated sequence provided by an independent contract progressive MS, four patients with a progressive visual loss research organization. Each participating hospital phar- caused by chronic ON (PON type) had an improvement in macy was provided with a block of six treatment units (four VA within 6 months of treatment with hdPB . The aim of active and two placebo treatments in random order). No the MS-ON study was to conﬁrm these initial observations in stratiﬁcation was performed. patients with either AON or PON. Patients and investigators were masked to the assigned treatment during the placebo-controlled phase and remained blinded during the extension phase as to which 2 Methods treatment was administered during the ﬁrst phase. The treating neurologist was different from the evaluating 2.1 Study Design ophthalmologist. All usual treatments were allowed during the study MS-ON was a 6-month double-blind, multi-center, ran- providing these were initiated as described in the exclusion domized, placebo-controlled study followed by a 6-month criteria. 664 A. Tourbah et al. 2.4 Assessments improvement at 5% contrast in at least one eye of C 0.3, C 0.2, or C 0.1 logMAR; and the mean change from baseline Impairment of the optic nerve was assessed by VA in each of the mean deviation in visual ﬁelds, RNFL thickness, eye separately using ETDRS logMAR charts presented temporal RNFL values, and macula volume. with standard illumination . Visual acuity was per- Safety was investigated by comparing the incidence of formed at 100 and 5% contrast at screening, baseline, and adverse events (AEs) and laboratory/electrocardiogram every 3 months. ﬁndings between study arms. In addition, VEPs, automated perimetry, and OCT including RNFL thickness was performed. Assessment of 2.6 Statistical Considerations VEPs was conducted at baseline and months 6 and 12 according to guidelines of the International Society for Sample size determination was based on limited data. In Clinical Electrophysiology of Vision . Improvement four patients with progressive ON treated with hdPB was deﬁned as (i) the reappearance of a P100 wave not 300 mg/day , a mean improvement of VA on treatment visible in a previous examination or (ii) improvement of of 0.423 logMAR (SD 0.29) was observed. VA in patients the P100 wave latency of at least 10 ms. Visual ﬁeld with ON after 6 months of chronic visual loss does not analyses were performed using standard automated typically improve spontaneously . Therefore, assuming perimetry at screening, baseline, and months 6 and 12. a conservative mean improvement of 0.3 logMAR for the Spectral domain OCT was conducted at baseline and patients in the MD1003 arm and a mean change with months 6 and 12 and RNFL thickness and macular volume placebo of 0.0 logMAR, and a common standard deviation were recorded at these time points. of 0.29, 70 patients in the MD1003 arm and 35 patients in Health outcome assessments consisted of the clinical the placebo arm (total sample size of 105) were required to global impression scale evaluated by the patient (SGI) and provide 99% power to detect a difference between arms, at by the clinician (CGI) at months 6 and 12 and the Multiple a 0.05 two-sided signiﬁcance level. Sclerosis Quality of Life-54 (MSQOL-54) questionnaire Quantitative data were summarized using descriptive and the National Eye Institute 25-Item Visual Function statistics and qualitative data using proportions. The intent- Questionnaire (NEIVFQ-25) assessed at baseline, month 6, to-treat population (ITT) was deﬁned as all randomized and month 12. patients who received at least one dose of study medication A detailed description of all the efﬁcacy and health and had at least one baseline VA score. All patients from outcome assessments used in this study is provided in the the ITT population who also had a VA score at month 6 Online Resources (Online Resources 3, see ESM). without any major protocol deviations comprised the per- protocol population (PP). The safety population was 2.5 Study Objectives deﬁned as all patients who received at least one dose of study drug. Baseline values were deﬁned as the last The primary endpoint of the study was the mean absolute available assessments before or at date of ﬁrst study drug change from baseline to month 6 of VA in the selected eye administration. as measured by best-corrected VA (logMAR) at 100% The primary endpoint was assessed in the ITT popula- contrast. The selected eye was the eye with the worst VA at tion and differences in the mean absolute change in VA at baseline and with evidence of worsening during the past 3 month 6 between arms were evaluated by an ANCOVA years. analysis with adjustment for baseline VA. A Welch t test Secondary endpoints were assessed at month 6 and and a Wilcoxon–Mann–Whitney test were performed on comprised the proportion of patients with improvement of the primary efﬁcacy endpoint in the ITT population as VA of the selected eye of C 0.3 logMAR at 100% contrast sensitivity analyses. The primary efﬁcacy analysis was also or improvement of binocular VA from\ 70 to C 70/100 at assessed at months 3 and 12 in the ITT population and in 100% contrast; the proportion of eyes with reappearance of the PP population. Pre-planned subgroup analyses were P100 waves or improvement of P100 latencies of C 10 ms; conducted in subgroups stratiﬁed according to PON or the mean change from baseline in selected P100 latencies AON; baseline binocular VA at 100% contrast \ 70 or C and amplitudes (all eyes); CGI and SGI; and the mean 70/100; and baseline RNFL thickness \ 75 or C 75 lM. change from baseline in NEIVFQ-25 composite score and Between the two groups, the differences in secondary MSQOL-54 composite score and sub-scores. endpoints were examined using Fisher’s exact test for Exploratory analyses assessed at month 6 consisted of proportions, Mann–Whitney’s U test for means, and a the mean change from baseline in logMAR at 100 and 5% logistic model using generalized estimating equations. All contrast in non-selected eyes, all eyes, and binocular vision statistical analyses were two-sided with a signiﬁcance level (at 100% contrast only); the proportion of patients with of p\0.05 and were conducted by the Biostatistics Unit of MD1003 in Multiple Sclerosis-Related Chronic Optic Neuropathy 665 BIOTRIAL using SAS software 9.3 (SAS Institute Inc., Treatment compliance was good during the placebo- Cary, NC, USA). The Last Observation Carried Forward controlled part with 67 (72.0%) patients overall achieving imputation method was used for missing data. compliance rates of C 90%. Mean duration of treatment in the safety population was 5.6 months in both arms. One patient was withdrawn from the study during the placebo- 3 Results controlled part because of an adverse event (AE)—retinal artery occlusion in the MD1003 arm considered to be Between October 2013 and January 2015, 117 patients possibly treatment related by the Investigator. The were screened, of which 93 met the inclusion criteria and remaining 92 patients entered the 6-month extension phase. were randomized to MD1003 (n = 65; 69.9%) or placebo Treatment compliance was lower during the extension (n = 28; 30.1%; Fig. 1). Baseline patient demographics phase with 55 (59.8%) patients overall achieving compli- and disease characteristics were balanced between study ance rates C 90%. The mean (SD) overall duration of arms (Table 1). Most patients (62; 66.7%) had AON; 31 treatment during the extension phase was 5.5 (0.6) months. (33.3%) patients had PON. Fifty-nine patients (63.4%) had Twelve (23.7%) patients had treatment withdrawal during RRMS, 14 (15.1%) had PPMS, and 20 (21.5%) had SPMS. the extension phase (Fig. 1). Patients were severely impaired as illustrated by low VA and neuro-ophthalmologic measures. Most (61/89; 68.5%) 3.1 Primary Efﬁcacy Analysis patients did not have identiﬁable P100 waves as assessed by VEP and the majority (74/81; 84.1%) had a thin At month 6, the mean (SEM) change in logMAR VA at (\ 75 lm) RNFL. The distribution of disease-modifying 100% contrast for the selected eye was - 0.061 (0.026) in concomitant medications was similar between arms during the MD1003 arm and - 0.036 (0.035) in the placebo arm the placebo-controlled part of the study except for (Fig. 2), indicating an improvement in VA in both arms methylprednisolone and natalizumab (Table 1). corresponding to an additional 3.1 letters and 1.8 letters, Fig. 1 CONSORT diagram— Enrollment Assessed for eligibility (n=117) screening, enrolment, randomization and follow-up of Excluded (n=24) study patients Randomized (n=93) Allocation MD1003 (biotin 300 mg/day) Placebo Allocated to intervention (n=65) Allocated to intervention (n=28) � Received allocated intervention (n=65) � Received allocated intervention (n=28) Follow-up Lost to follow-up (n=0) Lost to follow-up (n=0) Discontinued intervention (n=1) Discontinued intervention (n=0) • Adverse event (n=1) Analysis Analyzed (n=64) Analyzed (n=28) Excluded from analysis (n=0) Excluded from analysis (n=0) 6-month extension phase MD1003 (biotin 300 mg/day) Allocated to intervention (n=92) Discontinued (n=12) � Consent withdrawn (n=2) � Major protocol deviation (n=1) � Adverse event (n=2) � Lack of efficacy (n=2) � Other (n=5) Ongoing extension phase at month 12 MD1003 (biotin 300 mg/day) n=80 666 A. Tourbah et al. Table 1 Baseline MD1003 (n = 65) Placebo (n = 28) p value demographics and disease characteristics (ITT population) Female, n (%) 35 (53.8) 15 (53.6) 1 Age, years, mean (SD) 41.6 (10.5) 41.1 (10.6) 0.795** Duration of MS (SD), years 12.6 (9.4) 11.3 (8.1) 0.705** Relapsing–remitting MS, n (%) 45 (69.2) 14 (50.0) 0.101 Progressive MS, n (%) 20 (30.8) 14 (50.0) 0.101 AON, n (%) 41 (63.1) 21 (75.0) 0.340 PON, n (%) 24 (36.9) 7 (25.0) 0.340 Mean VA in logMar (SD) 0.82 (0.38) 0.77 (0.45) 0.196** b,c Binocular VA, n (%) \ 70 21 (39.6) 7 (30.4) 0.623 C 70–100 32 (60.4) 16 (69.6) 0.506 P100 waves, n (%) Absent 42 (66.7) 19 (73.1) 0.815 Present 21 (33.3) 7 (26.9) 0.623 RNFL, n (%) \ 75 lM 51 (83.6) 23 (85.2) 0.784 C 75 lM 10 (16.4) 4 (14.8) 1 Concomitant DMT (%) 46 (70.7) 16 (57.1) 0.234 Fampridine 6 (9.2) 2 (7.1) 1 Fingolimod 10 (15.4) 7 (25.0) 0.380 Interferon b-1A or b-1B 10 (15.4) 3 (10.7) 0.747 Natalizumab 9 (13.8) 1 (3.6) 0.272 Cyclophosphamide 0 (0.0) 1 (3.6) 0.301 Methylprednisolone 12 (18.5) 1 (3.6) 0.099 Glatiramer acetate 9 (13.8) 4 (14.3) 1 Methotrexate 1 (1.5) 2 (7.1) 0.214 Azathioprine 2 (3.1) 1 (3.6) 1 Mycophenolate mofetil 7 (10.8) 1 (3.6) 0.427 AON acute optic neuritis, DMT disease-modifying therapy, ITT intention-to-treat, ON optic neuritis, MS multiple sclerosis, PON progressive optic neuropathy, RNFL retinal nerve ﬁber layer, SD standard devi- ation, VA visual acuity p values were calculated using Fisher exact test or Mann–Whitney test (**) Time between ﬁrst appearance of MS and ﬁrst treatment b c At 100% contrast; data were missing for: 12 patients in the MD1003 group and ﬁve patients in the placebo d e group, two patients in each group, four patients in the MD1003 group and one patient in the placebo group The progressive and relapsing phenotypes relate to the overall patient status whereas the AON/PON classiﬁcation relates to the optic neuropathy type. The two classiﬁcations do not necessarily correlate respectively, on the ETDRS chart. This difference between C 75 lM RNFL thickness at baseline. All results were arms was not signiﬁcant (mean treatment difference similar when analyzed in the PP population (n = 86). - 0.01983; 95% CI - 0.1085 to 0.0689; p = 0.66). At the end of the extension phase (month 12), the mean change in 3.1.1 Subgroup Analyses in Acute Optic Neuritis (AON) logMAR VA at 100% contrast for the selected eye corre- and Progressive Optic Neuropathy (PON) sponded to ? 4.3 letters in the MD1003 [ MD1003 arm and ? 4.0 letters in the placebo [ MD1003 arm. In patients with PON, the mean (SD) change from baseline There was no difference between treatment arms in pre- in logMAR values at 100% contrast in the selected eye at planned subgroup analyses according to fampridine treat- month 6 was - 0.058 (0.185) in the MD1003 group and ? ment and in patients with\ 70 or C 70/100 binocular VA 0.029 (0.176) in the placebo group. This equated to an at 100% contrast at baseline, or in patients with \ 75 or improvement of ? 2.8 letters in the MD1003 group and a MD1003 in Multiple Sclerosis-Related Chronic Optic Neuropathy 667 0.04 MD1003 (n=65) worsening of - 1.5 letters in the placebo group (p = 0.45) P = 0.66 P = 0.95 Placebo (n=28) (Fig. 3a). At month 12, the mean change in logMAR values 0.02 (MD1003 after month 6) from baseline corresponded to ? 4.6 letters in the MD1003 group and – 1.2 letters in the placebo group at month 12 -0.02 +1.8 (p = 0.26). In contrast, there was no difference between letters treatment groups in patients with AON (Fig 3b). -0.04 +3.1 -0.06 letters 3.2 Secondary and Exploratory Endpoints +4.0 letters -0.08 +4.3 letters Overall, there were no signiﬁcant differences between -0.10 treatment arms for the secondary and exploratory endpoints -0.12 (Online Resource 4, see ESM). Post hoc analyses according -0.14 to PON and AON subgroups revealed trends in several 036 912 Time (months) secondary endpoints favoring MD1003 over placebo in patients with PON (Fig. 4), which was not the case in Fig. 2 Primary endpoint: mean (± SEM) change from baseline in patients with AON. In the PON subgroup, the mean change logMAR at 100% contrast (selected eye) at month 6 (n = 93). ITT population. The ﬁgure also shows the results of the primary efﬁcacy from baseline to month 6 in logMAR at 5% contrast for all analysis during the extension phase (month 12; n = 92). ITT eyes improved in the MD1003 group (? 3.7 letters) but intention-to-treat, SEM standard error of the mean Fig. 3 Pre-planned subgroup a Progressive optic neuropathy (n=31) analysis of the primary efﬁcacy analysis in patients with P = 0.45 P = 0.26 0.10 a progressive optic neuropathy MD1003 (n=24) (n = 31) and b sequelae of an -1.5 Placebo (n=7) acute optic neuritis (n = 62). letters (MD1003 after month 6) -1.2 ITT population. ITT intention- letters to-treat, SEM standard error of the mean +2.8 letters +4.6 -0.10 letters -0.20 036 912 Time (months) b Sequelae of an acute optic neuritis (n=62) 0.10 MD1003 (n=41) Placebo (n=21) (MD1003 after month 6) P = 0.75 P = 0.73 +2.9 letters +4.1 letters +3.2 -0.10 letters +5.7 letters -0.20 036 912 Time (months) Mean (± SEM) change from baseline in logMAR at 100% contrast (selected eye) Improving Worsening Mean (± SEM) change from baseline in Mean (± SEM) change from baseline in logMAR at 100% contrast (selected eye) logMAR at 100% contrast (selected eye) Improving Improving Worsening Worsening 668 A. Tourbah et al. the trend towards improvement in vision-associated daily a VA at 5% contrast (all eyes) life activities compared with placebo, as assessed by the -0.7 letters 0.10 P = 0.5 0.013 NEIVFQ-25 questionnaire (Fig. 4c). It should be noted that, because of the low number of patients in the placebo 0.05 group (n = 7), these positive trends are merely indicative Worsening of MD1003 effect. 0 No change There were no notable changes between study arms in Improving the PON subgroup in visual ﬁeld assessments or VEPs. -0.05 -0.10 3.3 Safety -0.074 -0.15 +3.7 letters Treatment in both arms was well tolerated. During the placebo-controlled part of the study, a similar proportion of MD1003 Placebo (n=24) (n=7) patients experienced an AE in both arms (49 [75.4%] in the MD1003 arm and 22 [78.6%] patients in the placebo arm; b RNFL thickness of all eyes Table 2). Most AEs were mild to moderate in severity P = 0.53 0.08 (95.4% of patients in the MD1003 arm; 92.9% of patients 0.0 in the placebo arm). Severe AEs were recorded in three 0.04 Improving (4.6%) patients in the MD1003 arm (single cases of 0 No change apparent hyperthyroidism due to the known biotin–thyroid -0.04 Worsening assay interaction, retinal artery occlusion, and back pain) -0.08 and two (7.1%) patients in the placebo arm (fatigue and -0.4 gastroenteritis). The only serious AEs to occur in more than -0.12 one patient were MS-related: MS relapse (symptoms con- -0.16 ﬁrmed to be associated with evolution of the disease) -0.20 occurred in nine (13.8%) MD1003-treated patients and one MD1003 Placebo (n=24) (n=7) (3.6%) placebo-treated patient, and MS symptoms (possi- bly but not necessarily associated with MS) occurred in c NEIVFQ-25 composite score two MD1003-treated patients. During the extension phase, P = 0.16 32 patients (50.0%) in the MD1003[ MD1003 arm and 12 4.15 patients (42.9%) in the placebo [ MD1003 arm experi- enced AEs. Again, the only serious adverse events (SAEs) Improving reported in more than one patient were MS-related: MS No change relapse was recorded in three (4.7%) patients in the MD1003 [ MD1003 group and three (10.7%) patients in Worsening -4 the placebo [ MD1003 group. No deaths occurred during the study. -8 -5.74 -12 MD1003 Placebo 4 Discussion (n=24) (n=7) Fig. 4 Mean (± SEM) change from baseline to month 6 in We evaluated the efﬁcacy of MD1003 in MS patients with a logMAR at 5% contrast (all eyes), b mean RNFL thickness (all chronic visual loss in a randomized, double-blind, placebo- eyes), and c NEIVFQ-25 composite score, in patients with progres- controlled, 6-month study involving 93 patients, followed sive optic neuropathy (n = 31). ITT population. ITT intention-to- by a 6-month, open-label extension during which all treat, NEIVFQ-25 National Eye Institute 25-Item Visual Function Questionnaire, RNFL retinal nerve ﬁber layer, SEM standard error of patients received MD1003. Inclusion of both AON and the mean PON allowed us to evaluate whether MD1003 would have efﬁcacy in driving recovery after a relapse (AON) or would worsened in the placebo group (- 0.7 letters; Fig. 4a). more speciﬁcally demonstrate efﬁcacy in the progressive MD1003 also appeared to halt the thinning of the RNFL in disease state (PON). the PON subgroup during the 6-month placebo-controlled Overall, the primary objective of study MS-ON was not phase (Fig. 4b). The positive effect of MD1003 on vision reached: the improvement in the number of letters read on in the subgroup of patients with PON was also reﬂected in the ETDRS chart at month 6 was larger with MD1003 (? Mean (±SEM) change from baseline Mean (±SEM) change from Mean (± SEM) change from baseline in in composite NEIFVQ-25 score baseline in RNFL thickness logMAR at 5% contrast (all eyes) MD1003 in Multiple Sclerosis-Related Chronic Optic Neuropathy 669 Table 2 Adverse events reported during the study (safety population) Trial phase Trial arm 1 Trial arm 2 p value Double-blind, placebo-controlled phase MD1003 (n = 65) Placebo (n = 28) Any AE, n (%) 49 (75.4) 22 (78.6) 0.797 AEs occurring in C 5% of patients in either group MS relapse 9 (13.8) 1 (3.6) 0.272 Nasopharyngitis 8 (12.3) 1 (3.6) 0.269 Urinary tract infection 4 (6.2) 1 (3.6) 1 Headache 3 (4.6) 3 (10.7) 0.360 Asthenia 2 (3.1) 2 (7.1) 0.581 Gastroenteritis 1 (1.5) 3 (10.7) 0.079 Dizziness 2 (7.1) Depression 2 (7.1) Anxiety 2 (7.1) Any severe AE , n (%) 3 (4.6) 2 (7.1) 0.635 Severe AEs occurring in C 1 patient in either group None Any SAE, n (%) 9 (13.8) 3 (10.7) 1 SAEs occurring in C1 patient in either group MS relapse 9 (13.8) 1 (3.6) 0.272 Extension phase MD1003 [ MD1003 (n = 64) Placebo [ MD1003 (n = 28) Any AE, n (%) 32 (50.0) 12 (42.9) 0.651 AEs occurring in C 5% of patients in either group Headache 1 (1.6) 3 (10.7) 0.082 MS relapse 3 (4.7) 3 (10.7) 0.363 Edema peripheral 2 (7.1) Oropharyngeal pain 2 (7.1) Any severe AE , n (%) 1 (1.6) 2 (7.1) 0.218 Severe AEs occurring in C1 patient in either group None Any SAE, n (%) 6 (9.4) 4 (14.3) 0.485 SAEs occurring in C1 patient in either group MS relapse 3 (4.7) 3 (10.7) 0.363 p values were calculated using Fisher exact test AE adverse event, MS multiple sclerosis, SAE serious adverse event Severe AEs during the placebo-controlled phase were single cases of hyperthyroidism, retinal artery occlusion, back pain, and MS relapse in the MD1003 group and single cases of fatigue and gastroenteritis in the placebo group Severe AEs during the extension phase were a single case of joint dislocation in the MD1003[ MD1003 group and single cases of headache and MS relapse in the MD1003 [ placebo group 3.1 letters) than with placebo (? 1.8 letters), but this dif- types of ON (AON and PON). The fact that, as an average, ference was not statistically signiﬁcant (p = 0.66). There placebo-treated patients with AON spontaneously improved were no signiﬁcant overall differences between study arms during the course of the trial, led to potential underesti- in the secondary endpoints. These results might reﬂect in mation of MD1003 therapeutic effect. In addition, the trial part the main limitations of our study. As mentioned earlier, lasted only 6 months, which might have been too short to sample size determination was based on limited data and the observe the full extent of MD1003 therapeutic potential. number of patients randomized was low, especially in the Interestingly, the pre-planned subgroup analyses in placebo group (n = 28). This small sample size limitation patients with AON or PON revealed two important ﬁnd- was further accentuated by the heterogeneity of the popu- ings. There was clearly no effect of MD1003 in the sub- lation, which included subsets of patients with two distinct groups of patients with AON for all measures related to 670 A. Tourbah et al. optic nerve involvement. This suggests that MD1003 does treatment with natalizumab had to be introduced at least 6 not trigger or re-initiate recovery after a relapse in this months prior to the MS-ON trial. Fingolimod, which is also population and time frame. In contrast, a consistent trend thought to induce remyelination , could have had an suggesting treatment efﬁcacy was observed in the PON opposite inﬂuence to that of natalizumab, since the subgroup. This trend favoring MD1003 in patients with MD1003 group had a lower proportion of patients on ﬁn- PON was observed for VA at 100% contrast, VA at 5% golimod (15.4%) than had the placebo group (25%). contrast, RNFL, and NEIVFQ-25. We observed no changes This study also conﬁrmed the good safety and tolera- in VEPs or visual ﬁeld in the subgroup of patients with bility proﬁle of MD1003. The safety proﬁle of MD1003 PON. It should be noted that patients recruited to the study was similar to that of placebo and consistent with data from had considerable neurodegenerative damage of the optic the MS-SPI study  and the open-label pilot study . nerve at baseline as evidenced by the absence of measur- The incidence of MS relapse was higher in the MD1003 able P100 waves in approximately 70% of patients. group (9 of 65 patients; 13.8%) than in the placebo group Patients also had severe impairment of their visual ﬁeld at (1 of 28 patients; 3.6%) during the double-blind phase of baseline. This degree of baseline disability may have pre- the study, and was also higher in the patients newly treated cluded any meaningful improvement in these measures of with MD1003 in the extension phase (3 of 28 patients; optic nerve function. 10.7%) than in the placebo group in the double-blind phase The high proportion of patients with AON recruited to (1 of 28 patients; 3.6%). Others have reported an increase the study (63.4% of the overall population) may explain the in MS relapse in patients treated with high-dose biotin failure of the study to reach the primary endpoint. In fact, [29, 30]; however, these studies used a different source and only a relatively small number of patients with PON dosage of biotin than our study, which does not allow any (n = 31) were recruited, reﬂecting the relative rarity of generalization . Branger et al.  reported an occur- patients with this condition. rence of relapse in ﬁve patients with progressive MS after Since MD1003 is believed to target the underlying 3–7 months of treatment with hdPB, and recommended progressive aspect of MS , patients with PON provide an close monitoring of lesions by MRI. In a post hoc analysis appropriate model for the assessment of efﬁcacy of from the MS-SPI study in patients with progressive MS, MD1003. The trend of efﬁcacy observed in patients with the annualized MS relapse rate up to 36 months did not PON is consistent with observations from a pilot open-label appear to be inﬂuenced by exposure to MD1003 . We study in which VA improved after treatment with hdPB in believe that in the present study, the number of patients four patients with PON . This trend is also in line with with relapse is too low to allow us to draw reliable con- the ﬁndings of study MS-SPI, which demonstrated that clusions. It should be further noted that the incidence of MS relapse decreased in patients who continued to receive MD1003 signiﬁcantly improved MS-related disability in patients with a progressive spinal form of MS . Toge- MD1003 during the 6-month extension phase (4.7%) ther, these data are consistent with the proposed mecha- (Table 2). Additional safety data from an ongoing clinical nism of action for MD1003 in targeting mechanisms to trial on MD1003 (SPI2 study) may help clarify this issue. improve neuronal metabolism in context of virtual hypoxia, consistent with the pathophysiology of progressive MS. The absence of superiority vs placebo in patients with 5 Conclusion AON suggests that MD1003 does not accelerate sponta- neous recovery after an acute optic neuritis in a relatively While the efﬁcacy endpoints of study MS-ON were not short (6 months) time frame. This ﬁnding suggests that met, signs of efﬁcacy were apparent in the subgroup of MD1003 has some selective efﬁcacy when progression is patients with progressive disease. These data provide fur- ongoing. Further to this, it should be noted that the fre- ther evidence that the most appropriate target group for quency of patients with progressive MS was higher in the MD1003 is patients with progressive forms of MS, a placebo (50%) than in the MD1003 group (31%), which population that represents a signiﬁcant unmet medical might have negatively inﬂuenced the results of our study. need. Our study could also provide useful insights on the The MD1003 group had a higher proportion of patients on limitations associated with the assessment of any thera- natalizumab or methylprednisolone than had the placebo peutic agent in patients with MS-associated chronic optic group. Since it is thought to promote remyelination , neuropathy. we cannot exclude a potential inﬂuence of natalizumab on the results of our study. However, that inﬂuence would 5.1 Previous presentation of data have been likely very limited, given the low proportion of patients treated with natalizumab (13.8% in the MD1003 This work has been presented in part at the 68th American group and 3.6% in the placebo group) and the fact that the Academy of Neurology Annual Meeting, Vancouver, MD1003 in Multiple Sclerosis-Related Chronic Optic Neuropathy 671 author(s) and the source, provide a link to the Creative Commons Canada (15–21 April 2016). Tourbah et al. Neurology license, and indicate if changes were made. 2016;86(16 Suppl.):S49.005 Acknowledgements This study, and editorial support for the prepa- ration of this manuscript, was funded by MedDay Pharmaceuticals. We thank all patients and their families for their participation in this References study and the entire study team. We also thank Jamie Ashman, PhD, of Prism Ideas for medical writing support. We also acknowledge the 1. Confavreux C, Vukusic S, Moreau T, et al. Relapses and pro- contribution of Floriana DeAngelis, University College London, gression of disability in multiple sclerosis. N Engl J Med. Marie Braisher, University College London, Charlotte Rawlinson, 2000;343:1430–8. University College London Hospitals NHS Foundation Trust, and 2. Koch M, Kingwell E, Rieckmann P, et al. The natural history of Lucas B. Kipp, Stanford University, as study investigators. primary progressive multiple sclerosis. Neurology. 2009;73:1996–2002. Compliance with ethical standards 3. Lublin FD. New multiple sclerosis phenotypic classiﬁcation. Eur Neurol. 2014;72:1–5. Funding This study, and editorial support for the preparation of this 4. Levin MC, Douglas JN, Meyers L, et al. 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