Workstreams
EXPERTS-ALS completes a bench to bedside ALS drug pipeline, enabling prioritisation of the many candidates arising from University- and industry-based research for use in Phase III studies, such as the UK’s MND-SMART platform and the pan-European TRICALS consortium. The platform is divided into three workstreams.
WORKSTREAM 1: Investigational medicinal product (IMP) identification
Aim: To deliver a continuous pipeline of drugs for workstream 2 using the best available evidence from pre-clinical models and a wide range of data resources, including genomics, AI drug discovery programs and evidence from other neurodegenerative diseases.
Primary objective: To select the most appropriate compounds for prioritisation in EXPERTS-ALS, based on disease relevance, safety profile and central nervous system penetration.
Secondary Objectives: Data from workstream 3 in response to drugs can be fed back to preclinical modelling in workstream 1 to identify new, or refine existing, pathways of disease relevance, and ultimately those which best predict a positive outcome in Phase III trials.
WORKSTREAM 2: Drug Prioritisation Platform
Aim: To evaluate the effect of candidate drugs on blood NfL levels in a multi-centre open label study as the basis for prioritising formal testing in a Phase III randomly controlled trial (RCT).
Primary objectives:
To determine:
whether a candidate drug is associated with a significant decrease in group NFL level from baseline (likely predictor of clinical benefit, and so prioritised for Phase III definitive study)
whether a candidate drug is associated with no significant change or an increase in group NFL level from baseline ('futility', and so not prioritised)
how a candidate drug ranks compared with previously or concurrently randomised competitor drugs
Secondary objectives:
To evaluate the safety and tolerability of candidate drugs in patients with ALS.
To assess the effect of candidate drugs on standard clinical measures of daily functioning (e.g. ALS revised functional rating scale ALS-FRS-R), respiratory function, and clinical (King’s) stage.
To deeply characterise study participants clinically and create an ALS bioresource for workstream 3.
WORKSTREAM 3: Nested biomarker development studies
Aim: To study the changes of the molecular environment in biofluids that occur with disease progression, in parallel with alterations observed in NfL concentration. To develop additional biomarkers of disease activity and drug response.
Primary objectives:
Unbiased identification of additional biomarkers of prognosis using NFL trajectories and risk scores as proxies of predicted outcomes.
Targeted analyses of markers associated with immune dysregulation and dysmetabolism.
Genotype and phenotype correlations in the trial populations with different NFL trajectories to support biomarkers discovery.
Identify IMP-specific changes in the biofluids proteome that inform target engagement.
Secondary objective: Work towards integration into the broader UK MND Research Institute (MNDRI) initiative to create a national clinical data and biological samples repository through NIHR and Telehealth in MND (TiM) platforms.