The Rise and Fall of High-Dose Biotin to Treat Progressive Multiple Sclerosis.
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ABSTRACT:
SUBMITTER: Goldschmidt CH
PROVIDER: S-EPMC7609671 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
The Rise and Fall of High-Dose Biotin to Treat Progressive Multiple Sclerosis.
Goldschmidt Carolyn H CH Cohen Jeffrey A JA
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20200701 3
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Project description:High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Several reports have suggested that HDB treatment may be associated with an increased risk of relapse. We aimed to determine whether HDB increases the risk of clinical relapse in PMS and describe the characteristics of the patients who experience it. We conducted a French, multicenter, retrospective study, comparing a group of PMS patients treated with HDB to a matched control group. Poisson regression was applied to model the specific statistical distribution of the annualized relapse rate (ARR). A propensity score (PS), based on the inverse probability of treatment weighting (IPTW), was used to adjust for indication bias and included the following variables: gender, primary PMS or not, age, EDSS, time since the last relapse, and co-prescription of a DMT. Two thousand six hundred twenty-eight patients treated with HDB and 654 controls were analyzed with a follow-up of 17 ± 8 months. Among them, 148 validated relapses were observed in the group treated with biotin and 38 in the control group (p = 0.62). After adjustment based on the PS, the ARR was 0.044 ± 0.23 for the biotin-treated group and 0.028 ± 0.16 for the control group (p = 0.18). The more relapses there were before biotin, the higher the risk of relapse during treatment, independently from the use of HDB. While the number of relapses reported for patients with no previous inflammatory activity receiving biotin has gradually increased, the present retrospective study is adequately powered to exclude an elevated risk of relapse for patients with PMS treated with HDB.
| S-EPMC8116391 | biostudies-literature
Project description: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.
| S-EPMC5098693 | biostudies-literature
Project description:High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Some reports have suggested that HDB treatment may be associated with an increased risk of relapse. We evaluate the relationship between exposure to HDB for treating PMS and the risk of relapse. We screened for PMS patients prospectively registered in a French regional cohort being part of the OFSEP national registry. In a case-crossover design among patients who received HDB, we first compared number of relapses before and after initiation of HDB. Second, time to the first clinical relapse was compared between patients who received HDB (biotin group) and a control group using a Cox survival analysis after a propensity score (PS) matching (1:1) and inverse probability of treatment weighting (IPTW) method. In the 42 PMS patients who received HDB, the number of relapses was statistically and clinically significant higher after biotin initiation than before biotin initiation (incident rate ratio [IRR] 7.4, 95% confidence interval [CI] 3.5-15.9, p < 0.0001). With the PS matching method, the risk of relapse was significantly higher in the biotin group compared to the control group (hazard ratio [HR] 4.3, 95% CI 1.4-13.3, p = 0.01). The IPTW method with 440 control patients revealed consistent results (HR 5.1, 95% CI 2.3-11.3, p < 0.0001). In our non-randomized study, HDB treatment for PMS was associated with an increased risk of relapse. The follow-up of PMS patients initiating HDB should include careful assessment of clinical and radiological activity to monitor the potential pro-inflammatory effect of biotin.
| S-EPMC7641290 | biostudies-literature
Project description:Secondary progressive multiple sclerosis (SPMS) is characterized by progressive accumulation of disability without intermittent recovery. Treatment of these patients is challenging due to limited understanding of pathogenesis and fewer therapeutic options. This article summarizes difficulties in defining and conducting trials in SPMS, review major clinical trials on therapies approved and unapproved in SPMS and lastly, therapies in pipeline for use in SPMS.
| S-EPMC6472227 | biostudies-literature
Project description:Progressive multiple sclerosis
| PRJNA966951 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-06-20 | GSE231587 | GEO
Project description:Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium-enhancing lesions on T1 weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short-term safety issues or adverse events.
| S-EPMC5497536 | biostudies-literature
Project description:The purpose of this study is to highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS) and also the results of clinical trial experience to date and review ongoing clinical trials and prospective new treatment options. This study will explain the challenges of clinical trial design in PMS.Multiple sclerosis (MS) has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms. The classification of the course of PMS has been reorganized into categories of active vs. inactive inflammatory disease and the presence vs. absence of gradual disease progression. This differentiation allows clearer conceptualization of PMS and possibly even more efficient recruitment of PMS patients into clinical trials. Clinical trial experience to date in PMS has been negative with anti-inflammatory medications used in relapsing MS. Simvastatin was recently tested in a phase II trial and showed a 43% reduction of annualized atrophy progression in secondary progressive MS. Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod and anti-B-cell therapy ocrelizumab. Several efforts for development of outcome measures in PMS are ongoing.PMS represents a significant challenge, as the pathogenesis of the disease is not well understood, no validated outcome metrics have been established and clinical trial experience to date has been disappointing. Advances in the understanding of the disease and lessons learned in previous clinical trials are paving the way for successful development of disease-modifying agents for this disease.
| S-EPMC4425257 | biostudies-other
Project description: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. Funding:MedDay Pharmaceuticals.
| S-EPMC7046518 | biostudies-literature
Project description:BackgroundAll-trans retinoic acid (ATRA) is an acid derivative of vitamin A which is discussed as a promising candidate to ameliorate the disease course of multiple sclerosis (MS) by immunomodulation or even by promoting regeneration in progressive MS. Here we report a patient who significantly improved for MS related disability following administration of chemotherapy including ATRA for mitoxantrone-related acute promyelocytic leukemia and assess the effect of high-dose ATRA in three additional patients with progressive MS.MethodsPatients with progressive MS who had failed previous therapies were treated with high-dose ATRA. Patients underwent clinical and routine laboratory monitoring. Additionally, PBMCs were analyzed by flow cytometry for lymphocyte subsets.ResultsATRA was well tolerated and no pathological laboratory abnormalities were observed. After initial mild (not statistically significant) improvement of EDSS and mean MSFC z-score, ongoing disease progression was observed. One patient subacutely experienced severe cognitive and motor worsening. Cerebral MRI revealed persistent gadolinium-enhancing lesions. Flow cytometric alterations of peripheral blood naïve, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasmablasts and natural killer (NK) cells did not reach statistical significance.ConclusionsStand-alone therapy with ATRA did not ameliorate progressive MS in our limited cohort and we did not observe consistent alterations of T and B cell subsets. Intriguingly, application of ATRA may have caused marked disease exacerbation in one patient.
| S-EPMC8108354 | biostudies-literature