Feast or famine in multiple sclerosis therapeutics

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS. Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS. Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable. Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r = 0.52 and r = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum ( p = 0.76) or CSF ( p = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed. Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.

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“…1 In contrast, a sensitive and specific biomarker for use in progressive MS remains to be established. 2…”

Section: Introductionmentioning

confidence: 99%

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis

et al. 2021

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“…Finally, some have suggested that the literature-based systematic review approach to drug selection is intrinsically flawed because it does not take into account disease specific pathophysiology (which may be largely unknown). 47 While the three drugs tested in MS-SMART were not effective, 18 we note that two other drugs on the final MS-SMART shortlist -ibudilast 20 and lipoic acid 21 have since shown promise in independent phase II trials. Lipoic acid has been identified again as a favourable candidate drug in a further, independent review in 2020.…”

Section: Open Accessmentioning

confidence: 90%

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

et al. 2023

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ObjectivesMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART:NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.MethodsWe conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.ResultsFrom the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.DiscussionFor future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

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“…Finally, some have claimed that the literature-based systematic review approach to drug selection is intrinsically flawed because it does not take into account disease specific pathophysiology (which may be largely unknown). [39] While the three drugs tested in MS-SMART were not effective, [15] we note that two other drugs on the final MS-SMART shortlist -ibudilast [17] and lipoic acid [18] -have since shown promise in independent phase II trials. Lipoic acid has been identified again as a favourable candidate drug in a further, independent review in 2020.…”

Section: Limitations Of This Approachmentioning

confidence: 99%

A Systematic Approach to Identify Neuroprotective Interventions for Motor Neuron Disease

Wong

Gregory

Liao

et al. 2022

Preprint

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Background Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Objectives Here we detail a systematic, structured, and unbiased evidence-based approach to guide selection of drugs for clinical evaluation in the Motor Neuron Disease - Systematic Multi-arm Adaptive Randomised Trial (MND-SMART, clinicaltrials.gov registration number: NCT04302870), an adaptive platform trial. Methods We conducted a two-stage systematic review and meta-analysis to identify potential neuroprotective interventions. In stage one, we identified drugs from the clinical literature tested in at least one study in MND or in two or more cognate diseases with potential shared pivotal pathways (Alzheimer's disease, Huntington's disease, Parkinson's disease, or multiple sclerosis). We scored and ranked 66 drugs thus identified using a predefined framework evaluating safety, efficacy, study size and quality of studies. In stage two, we conducted a systematic review of the MND preclinical literature describing efficacy of these drugs in animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies; 17 of these drugs were reported to improve survival in at least one preclinical study. An expert panel then shortlisted and ranked 22 drugs considering stage one and stage two findings, mechanistic plausibility, safety and tolerability, findings from previous clinical trials in MND, and feasibility for use in clinical trials. Results Based on this process, the panel selected memantine and trazodone for testing in MND-SMART. Discussion For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human induced pluripotent stem cells.

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Feast or famine in multiple sclerosis therapeutics

Cited by 4 publications

References 9 publications

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

A Systematic Approach to Identify Neuroprotective Interventions for Motor Neuron Disease

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