Why there is some very good news in the first EXPERTS-ALS analysis

On the face of it, another negative trial result, let alone two simultaneously, seems like negative news for people living with ALS. We share the disappointment that neither Metformin or Nifedipine were able to lower neurofilament light chain (NFL) levels in EXPERTS-ALS.

However, EXPERTS-ALS is the first platform of its kind and this result, at this stage of the study, has exceeded our expectations of how it might perform.

The precise causes of ALS are not certain to any scientist, and so all drug trials (new drugs as well as repurposed ones) are always a ‘best guess’ on the available evidence. The laboratory evidence behind Metformin and Nifedipine, as for all of the drug candidates put forward for EXPERTS-ALS, was compelling. Motor neurons grown in a dish and non-human animal models of ALS showed signals of benefit when exposed to these drugs. However, there is no substitute for testing in people, for what is a uniquely human disease. With a growing number of drug candidates to try, it is essential to deliver human trials much more quickly. We strongly believe that the global ALS research community must prioritise the investment in large, lengthy trials needed to prove patient benefit, focusing on drugs that have first been shown to give a human signal of likely disease-slowing. This is what Experimental Medicine means and in EXPERTS-ALS we are basing this on the very strong science behind showing a consistent fall in NFL levels.

This is why the outcome of the first EXPERTS-ALS data analysis is such an important moment in progress to effective treatments. With relatively few participants (around 30 at baseline), each taking one of these drugs for up to 24 weeks, it was possible to see clearly that there was no change occurring in the overall group NFL level. This confirms that, in a real-world trial setting, individual participant NFL trajectories are stable and predictable. It also shows the power of so-called Bayesian statistical modelling, which EXPERTS-ALS is pioneering. Instead of needing hundreds of participants each taking a drug or a placebo for at least 12 months, to detect group-level change in the rate of increase in physical disability, the answer from a prior screening study tuned to NFL lowering was available in only a few months. Plus, this was done at a fraction of the cost of the larger trials. 

Faster human drug screening methods mean a shorter time to find the eventual winners that benefit patients. Two new candidate drugs now move into position for testing in EXPERTS-ALS. While we still anticipate the day when the data analysis will show a successful lowering of NFL, every faster negative result means less time testing drugs that are not likely to have any benefit and means we quickly move on to test the next possible effective treatment. 

None of this can be done without the dedication of those living with ALS and those who support them, who give their time to push the boundary towards success for everyone. The UK’s National Institute for Health & Care Research (NIHR) funded this study, with support from the Motor Neurone Disease Association, My Name’5 Doddie Foundation and LifeArc, with the Darby Rimmer Foundation joining soon We are thrilled at the successful involvement of so many centres across the UK in EXPERTS-ALS, many new to the field, as part of the shared desire to build capacity in ALS trials. The skilful coordination of so many moving parts by the Sheffield Clinical Trials Unit, Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield BRC, for a trial with no prior off-the-shelf blueprint has been extraordinary. It is coupled to the precision of the setup and delivery of what is the first dedicated NFL laboratory for an ALS trial, with a novel Bayesian statistical analysis pioneered by colleagues at Oxford University. EXPERTS-ALS is a world-leading initiative that the UK ALS research community can all feel proud to be a part of.