Background Collecting high quality, patient level data demands significant efforts and resources. A potential solution, well-suited for exploratory hypothesis testing, gathering evidence, and assessing the heterogeneity and generalizability of estimates, is the usage of synthetic data. Synthetic data are newly generated data from real, original data. They share a fundamental set of statistical properties, which is sufficient to replicate statistical analysis findings. Aim of this work is to explore the feasibility of obtaining clinically relevant insights from analyses on synthetic data. Methods We used baseline characteristics and follow-up data from the 641 subjects with progressive multiple sclerosis enrolled in the SPI2 randomized controlled clinical trial evaluating the effect of high dose biotin on disability improvement. We used four strategies (noise addition, chains of conditional distributions, multivariate modeling, and generative adversarial networks) to generate artificial data from the original SPI2 data. We simulated six research scenarios with different methodology, complexity, and data usage level. For each strategy we generated multiple samples and averaged the results of each scenario. Then, we compared synthetic-data-analysis results with original-data-analysis results by standardized mean difference (SMD) and percentage of confidence interval overlap (CIO). All the Python and R code used to produce these findings is available and public. Results Median SMD was 0.73 with inter-quartile range from 0.28 to 2.25. Median CIO was 77.3% with inter-quartile range from 46.4–89.2%. Bias direction was an underestimate 66.7% of the times (16/24) but largely differed accordingly to the research scenario. In 75% of the cases (18/24) the formal test of the null hypothesis of the corresponding scenario on synthetic data offered the same answer of the original data. Conclusion Although the selected synthesis approaches may not be exhaustive or state-of-the-art, and methods were minimally optimized, it is feasible to obtain clinically relevant insights from synthetic data, particularly for exploratory purposes, albeit with certain caveats. Assessing the quality of synthetic data before initiating any analysis is crucial. While a consistent underestimation of an association may occur, the bias inconsistency by synthesis strategy implies that a combination of these methods could enhance future synthetic generation strategies.

Background We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept. Methods Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables. Results The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product. Conclusions Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory. Trial registration ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother’s milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials.

Objective: To evaluate the efficacy and safety of MD1003 (high dose Pharmaceutical grade Biotin) in patients with progressive forms of multiple sclerosis (MS). Background: An unmet need exists for treating primary or secondary progressive MS (PPMS, SPMS). Biotin is a coenzyme for carboxylases that function in energy metabolism and fatty acid synthesis. In the first controlled trial of MD1003 in progressive MS, MS-SPI, treatment resulted in a significant sustained improvement in disability vs placebo. SPI2 is a phase 3, randomized, double-blind, placebo-controlled study of MD1003 in PPMS and SPMS patients receiving or not receiving concomitant, approved disease modifying therapy (NCT02936037). Design/Methods: SPI2 inclusion required documented, relapse-free, disability progression in EDSS over the 2 years before entry. Patients were randomized (1:1) to receive MD1003 100mg tid or placebo. The primary endpoint was the proportion of patients with improvement: decrease in EDSS (0.5 or 1.0) or improved timed 25-foot walk (T25FW) of ≥20% from baseline to month (M) 12, confirmed at M15. Secondary endpoints were time to 12-week confirmed disability (EDSS) progression up to M27, clinical global impression (CGI/SGI), and mean change in T25FW. Results: Overall, 642 patients were randomized: Europe (n=338), North America (n=290), and Australia (n=14). At the time of submission, baseline demographics and disease characteristics were: mean age 52.7 years; 53.7% female; 64.6% SPMS; overall mean time since diagnosis 12.6 years [PPMS 6.9, SPMS 15.6]; mean time since conversion to SPMS 5.0 years; overall mean EDSS 5.4; overall mean T25FW 11.6 seconds. The last patient last visit will be in November 2019 and database lock will be in early 2020. Final results from primary and secondary efficacy endpoints, as well as an analysis of safety will be presented. Conclusions: Results of the phase 3 SPI2 study of MD1003 in this progressive MS population will be presented. Disclosure: Dr. Cree has received personal compensation from Akili, Alexion, Atara, Biogen, EMD Serono, Novartis, TG Therapeutics.Dr. Cutter has received personal compensation from AMO Pharma, Argenix, Atara Bio-therapeutics, Axon, Biogen, BioLineRx, Bio-therapeutics, Brainstorm Cell Therapeutics, Charleston Laboratories, Inc., Click Therapeutics, Genentech, Genzyme, GW Pharma, Horizon Pharmaceuticals, Klein Buendel Inc., MedDay, MedImmune, Merck, Merck/Pfizer, Neurim, Novartis OPKO Biologics, Orphazyme, Pythagoras, Inc, Reata Pharmaceuticals, Receptos/ Celgene, Sanofi- Aventis, Roche, SciFluor, Somahlution, Teva Pharma-ceuticals, TG Therapeutics, UTHealth Houston Teva NeuroscienceDr. Wolinsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for consulting, scientific advisory boards, or other activities with Alkermes, Actelion, Acorda Therapeutics, Celgene, EMD Serono, GeNeuro, GW Pharma, MedDay Pharmaceuticals, Novartis, Otsuka, PTC Therapeutics, Roche/Genentech, Sanof. Dr. Wolinsky has received royalty, license fees, or contractual rights payments from Royalties are received for out-licensed monoclonal antibodies through UTHealth from Millipore Corporation.Dr. Freedman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Bayer Healthcare, Biogen Idec, Chugai, Clene Nanomedicine, EMD Serono Canada, Genzyme, Merck Serono, Novartis, F. Hoffmann-La Roche Ltd, Sanofi-Aventis and Teva Canada Innovation. Dr. Freedman has received compensation for serving on the Board of Directors of Actelion, Bayer Healthcare, Biogen Idec, Clene Nanomedicine, F. Hoffmann-La Roche Ltd, Merck Serono, MedDay Pharmaceuticals, Novartis and Sanofi-Aventis. Dr. Freedman has received research support from Genzyme Canada. Dr. Comi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with honoraria for consultancy and/or speaking activities from Almirall, Biogen, Bayer, Chugai, Genzyme, Merck Serono, Novartis, Roche, Receptos, Sanofi, Serono Symposia International Foundation, and Teva.. Dr. Comi has received personal compensation in an editorial capacity for Clinical Investigation; European Journal of Neurology and Multiple Sclerosis; Neurological Sciences. Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Actelion, Atara Biotherapeutics, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GSK, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB. Dr. Giovannoni has receive research support from AbbVie, Actelion, Atara Biotherapeutics, Bayer, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GSK, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB.Dr. Hartung has received personal compensation from Bayer Healthcare, Biogen Idec, CSL Behring, GeNeuro, Genzyme, MedImmune, Merck Serono, Novartis, Opexa, Receptos, Roche, Sanofi, Teva, and Viela Bio.Dr. Sedel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with MedDay Pharmaceuticals. Dr. Sedel has received compensation for serving on the Board of Directors of MedDay Pharmaceuticals. Dr. Sedel holds stock and/or stock options in MedDay Pharmaceuticals. Dr. Lublin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen; EMD Serono; Novartis; Teva; Actelion; Sanofi/Genzyme; Acorda; Roche/Genentech; MedImmune; Receptos/Celgene; Forward Pharma; TG Therapeutics; Abbvie; Regeneron; Medday; Atara Biotherapeutics; Polpharma; Mapi Pharma; Innate Immunotherapeutics; Apito. Dr. Lublin has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders- Co-Chief Editor. Dr. Lublin has received research support from Acorda Therapeutics, Biogen Idec, Genzyme, National MS Society, Novartis, Sanofi, Teva Neuroscience.

Background: Oligodendrocytes (OGs) provide metabolic support to motor neurons (MNs) and are implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). MD1003, or high-dose Pharmaceutical grade Biotin (hdPB), may improve disability in progressive multiple sclerosis patients via augmentation of OG or MN energy levels. Here, we assessed the safety and efficacy of MD1003 in ALS patients. Methods: This single centre, randomised, double-blind, placebo-controlled trial included patients aged 25-80 years with probable or definite ALS. Patients were assigned (2:1), using a computer-generated randomisation list, to receive oral MD1003 (300 mg/day) or placebo treatment for 24 weeks. The primary outcome, safety, was analysed in all patients who received at least one dose of study drug. This study, registered with ClinicalTrials.gov, NCT03114215, has been completed. Findings: Between June and December 2016, 30 patients were enrolled (MD1003, n = 20; placebo, n = 10). Baseline characteristics were representative of the ALS population. MD1003 and placebo groups were not well balanced at screening, with the MD1003-treated group having a higher rate of ALSFRS-R decline prior to screening versus placebo (-6.0 IQR [-8.5, -5.0] vs. -5.0 IQR [-5.0, -3.0]) and a predominance of ALS with upper limb onset compared to placebo (35% vs. 10%). MD1003 had a favourable safety profile and was well tolerated. The occurrence of adverse events was similar in both groups (60%). Two deaths occurred in the MD1003 group versus 1 in the placebo group. ALSFRS-R median change from baseline to month 6 was not significantly different between the two groups (p = 0.49); the mean difference between groups was -1.6 (SEM=3.3). Interpretation: MD1003 treatment was safe and well tolerated. It was not possible to establish MD1003 efficacy in this relatively small study. Given the favourable safety profile of MD1003 and an imbalance between treatment groups favouring placebo, additional, larger studies in ALS are warranted. (C) 2019 Published by Elsevier Ltd.

Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high-dose pharmaceutical-grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high-dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, theAbcd1(-)mouse model of adrenomyeloneuropathy. High-dose biotin restored redox homeostasis driven by NRF-2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP-1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High-dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high-dose biotin of relevance for neurodegenerative and metabolic disorders.

Thursday, April 30April 14, 2020Free AccessRemotely Monitored Ambulatory Activity Correlates with Disability in Progressive MS: A Baseline Analysis from the SPI2 Phase 3 Clinical Trial of MD1003 (High Dose Pharmaceutical Grade Biotin) (1235)Valerie J. Block, Amber Alexander, Nico Papinutto, Anand Rajesh, Tristan Gundel, Jeffrey M. Gelfand, Roland G. Henry, Frédéric Sedel, and Bruce A. C. CreeAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1235 Letters to the Editor

BACKGROUND:There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. METHODS:SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). FINDINGS:From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. INTERPRETATION:This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. FUNDING:MedDay Pharmaceuticals.

May 5, 2019April 9, 2019Free AccessBeneficial Effects of High-dose Biotin (MD1003) in Models of X-linked adrenoleukodystrophy (P1.2-084)Stéphane Fourcade, Janani Parameswaran, Leire Goicoechea, Nathalie Launay, Montserrat Ruiz, Frédéric Sedel, and Aurora PujolAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P1.2-084 Letters to the Editor

Objective: To evaluate the effects of MD1003 during the open-label extension phase of the MS-SPI study. Background: MS-SPI was a 12-month (M) double-blind study of MD1003 (n=103) vs placebo (n=51) in patients (pts) with nonactive progressive multiple sclerosis (PMS). As reported previously, expanded disability status scale (EDSS) and/or timed 25-foot walk improvement, mean EDSS (mEDSS) score, and clinical/subject global impression (CGI/SGI) score were all significantly (P MD1003 [MM] vs placebo>MD1003 [PM]). Design/Methods: A total of 133 pts (MM: 91; PM: 42) entered the extension phase. We assessed time to first decreased/increased EDSS (Kaplan-Meier), mEDSS change from baseline, and CGI/SGI. Results: In time to first decreased/increased EDSS analyses up to 12M, the results favored MD1003 over placebo (hazard ratio [HR], 3.55 and 0.42, respectively), though they were not significant (P>0.05) in this relatively small study. In similar analyses up to 48M, the probability of improvement/worsening again favored MD1003 over placebo (HR, 2.47, P>0.05 and 0.80, P>0.05, respectively). Throughout the extension phase, the mean change in EDSS score was numerically lower in the MM group (vs PM group); the difference in mEDSS score between the MM and PM groups was significant at M18 (P Conclusions: Results from the MS-SPI study at 4 years of follow-up indicate that 1) delayed MD1003 treatment results in higher disability over time, 2) pts show improvement when switching from placebo to MD1003, and 3) the effects of MD1003 observed in the double-blind phase are sustained over time. Disclosure: Dr. De Seze has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sanofi-Genzyme, Teva, Novartis, Roche, Chugai, and Alexion. Dr. De Seze has received research support from Sanofi. Dr. Edan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck, Novartis, Sanofi, Roche, LFB, Bayer AG. Dr. Edan has received research support from Novartis, Sanofi, Merck, Biogen, Roche and Teva. Dr. Moreau has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis, Biogen, Merck, Roche, MedDay, Teva, and Sanofi-Genzyme. Dr. Moreau has received research support from Novartis, Biogen, Merck, Roche, MedDay, Teva, and Sanofi-Genzyme. Dr. Brochet has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis, Biogen, Genzyme, Medday. Dr. Brochet has received research support from Teva, Biogen, MedDay, Novartis, Roche, Actelion, Sanofi-Genzyme, Merck, Bayer. Dr. SEDEL has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with MedDay. Dr. SEDEL holds stock and/or stock options in MedDay stocks as part of employee’s compensation, which sponsored research in which Dr. SEDEL was involved as an investigator. Dr. Tourbah has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, MedDay, Merck Serono, Roche, Sanofi-Genzyme, Teva. Dr. Tourbah has received research support from Biogen, Novartis, MedDay, Merck Serono, Roche, Sanofi-Genzyme, Teva.

May 7, 2019April 9, 2019Free AccessEffect of MD1003 (high dose Pharmaceutical grade Biotin) in the Treatment of Progressive MS: Long-term Safety Data at 48 Months of Follow-up (P3.2-043)Jerome De Seze, Gilles Edan, Thibault Moreau, Bruno Brochet, Frederic SEDEL, and Ayman TourbahAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P3.2-043 Letters to the Editor

May 6, 2019April 9, 2019Free AccessAxonal Integrity in Primary and Secondary Progressive Multiple Sclerosis: a Baseline Subgroup Analysis of Sex, Age, and Disease Severity from the Phase III SPI2 Study (S12.005)Sridar Narayanan, Gary Cutter, Jerry Wolinsky, Mark Freedman, Giancarlo Comi, Gavin Giovannoni, Hans-Peter Hartung, Frederic SEDEL, Fred Lublin, Samson Antel, Bruce Cree, and Douglas ArnoldAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.S12.005 Letters to the Editor

May 7, 2019April 9, 2019Free AccessEDSS and Timed 25 Foot Walk Correlate with Spinal Cord Areas: Baseline Results from the SPI2 Clinical Trial of MD-1003 (high-dose biotin) in Progressive Multiple Sclerosis (P3.2-023)Valerie J. Block, Amber M. Alexander, Nico Papinutto, Anand Rajesh, Tristan Gundel, Douglas Arnold, Frederic Sedel, Bruce Cree, and Roland G. HenryAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P3.2-023 Letters to the Editor