Workstream 2

Drug Prioritisation Platform

Lead Sites for Workstream 2

Aims and Objectives of Workstream 2

Workstream 2 is the core patient-based study to look for a human signal of likely clinical benefit to prioritise candidate drugs for future Phase III trials.

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, 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 or harm, 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.

What is NfL?

Neurofilament light (NfL), also known as neurofilament light chain, is a building block of neurofilaments. Neurofilaments are proteins found in nerve cells (neurons) which play a crucial role in maintaining their structural integrity, as well as various other cell functions such as the transport of materials within the neuron.

Neurofilaments are mainly found in the axons of neurons, the long projections that transmit electrical signals to other neurons or muscles.

EXPERTS-ALS uses NfL to measure whether a drug is having an effect. In healthy brain states, NfL should be almost undetectable in the blood, but it has been shown to be raised in people with ALS. This is because the damaged nerves resulting from ALS release NfL into the blood. The NfL level at the time of diagnosis is strongly associated with the rate of disability progression (higher is faster, lower is slower). It therefore seems intuitive to want to try to reduce the NfL level as much as possible in those with ALS.

NfL tends to stay at the same level for an individual throughout their disease course. Therefore, if a drop in NfL levels is seen in study participants, this is likely to be directly related to the drug being tested, suggesting that it may be having a positive effect. If we see a large reduction in NfL, we will recommend that drug for prioritisation in future studies.

Recent studies suggest that NfL may be a better predictor of how well a drug works than other clinical outcome markers. At the moment, there is no better candidate to use as a biomarker for drug efficacy in ALS. However, EXPERTS-ALS could be adapted to accommodate emerging biomarkers if they are identified in the future.

Quick facts about the patient-based study

This is a Bayesian, Phase II, open label, randomised, platform trial.

Recruitment Target: 700
Centres Involved: 11
Length of Study: 43 months
Target Number of Drugs to Screen: 9-12
Duration of treatment and follow-up: 24 weeks
Participants: People over 18 years of age, newly diagnosed with ALS according the Gold Coast criteria and being seen within an established MND care centre.
Recruitment strategy: Continuous

Click here to watch a video about the study

How will the patient-based study work?

At the point of diagnosis, people with MND will be offered the opportunity to take one of three drugs being tested at any one time. Initially these will be so-called ‘repurposed’ drugs i.e. medicines already licensed for use in other diseases, but with some laboratory data suggesting possible benefit in MND. People will know what drug they are receiving and there will be no placebo or dummy drug.

The individual will take the drug for a maximum of 6 months, with blood NfL levels measured at regular intervals and continuous monitoring of the overall group level.

If the overall group NfL level for each drug is not changing significantly, or if it is rising, then the drug will be assumed as not slowing disease activity to any large degree and so of lower priority. However, if the group NfL level is found to be significantly falling (i.e. potentially slowing disease activity), then that drug will be prioritised for one of the larger Phase 3 trial platforms such as MND-SMART, so that its potential as a treatment for MND can be tested properly.

Which drugs will be used in the study?

The first 3 drugs used in the study will be so-called repurposed drugs. These are drugs that are already being used to treat other diseases, but are not currently used to treat ALS. These have been selected for the EXPERTS-ALS platform trial due to the strength of their preclinical data, being easy to take (all come in tablet form), and having a very good safety profile.

Other promising drugs will be selected by a group with experience in early drug discovery based on explicit criteria as part of Workstream 1.

Where will the study take place?

The study will be a UK multi-centre, academic-led study involving 11 centres of excellence in ALS care and research.

This will include NIHR Biomedical Research Centres: