* Neurofilament light (NfL) is a protein released when neurons are damaged and can be detected in the cerebrospinal fluid and blood. In ALS, higher NfL levels are generally associated with more rapid disease progression, at a group level. In clinical trials, NfL is evolving as a biomarker to help researchers understand whether a treatment may be reducing underlying motor neuron damage. NfL levels tend to rise during presymptomatic and early disease and then stabilize or plateau as the disease progresses, and when a substantial and sustained drop occurs with treatment, benchmarked at 30%, it is considered meaningful. Reductions of less than 30% are difficult to reliably attribute to an effect of the treatment.
EXPERTS-ALS (EXPErimental medicine Route to Success in ALS), an innovative platform trial led by Prof. Martin Turner and Prof. Chris McDermott in the United Kingdom, is designed to evaluate potential ALS therapies more quickly.
Traditionally, new therapies must progress through multiple phases of clinical testing to assess both safety and efficacy, a process that can take several years. In addition, commonly used measures of efficacy for ALS (like the ALSFRS-R scale) often cannot reliably determine whether a therapy is truly promising until a large and costly Phase 3 trial is completed. As a result, better tools and methods are needed to provide earlier clues about whether a treatment is working or not, helping researchers avoid spending time and resources on large studies that are unlikely to succeed.
Added that to the urgent need for new ALS treatments, EXPERTS-ALS was designed as a biomarker-driven “pre-trial” platform that screens potential therapies over six months to rapidly identify which drugs should directly advance to a larger, confirmatory Phase 3 study. It bypasses commonly used trial measures and focuses on blood levels of neurofilament light (NfL)*, a biomarker of nerve cell damage, to quickly assess whether a treatment is having a meaningful biological effect.
The trial recently reported interim results for two repurposed drugs: metformin and nifedipine. These therapies were selected because previous research suggested they may affect biological pathways involved in ALS. Metformin, a widely used treatment for type 2 diabetes, has been shown in preclinical studies to influence cellular energy use, inflammation, and other processes that may contribute to nerve cell damage. Nifedipine, commonly prescribed for high blood pressure, was investigated because of its potential effects on calcium signaling, a process linked to nerve cell health and function.
In the study, approximately 30 participants received each treatment for six months. It was reported that neither drug produced the desired change in NfL levels, suggesting they were unlikely to provide meaningful benefit for ALS. Based on these findings, the trial’s independent oversight committee recommended stopping enrollment in both study arms and discontinuing treatment for participants currently receiving the drugs.
Metformin continues to be investigated separately in a small clinical trial at the University of Florida, as a potential treatment for people with ALS who have variants in the C9orf72 gene, the most common genetic cause of ALS. That study is based on a mechanism that researchers in Florida have reported to be directly connected to C9orf72 biology.
While these results are disappointing, they also highlight the value of the EXPERTS-ALS platform. By using biomarkers to rapidly screen potential therapies, the study can more rapidly identify treatments that don’t have a substantial ability to rescue motor neurons in ALS, helping researchers focus time and resources on the most promising candidates and accelerating the search for effective ALS treatments.
EXPERT-ALS continues to evaluate other repurposed therapies, including:
- Ropinirole (approved for Parkinson’s disease), selected after laboratory studies suggested it may help protect motor neurons and reduce some of the cellular stress linked to ALS. An early-stage clinical trial in Japan also showed signals that warranted further investigation.
- Doxycycline, (a commonly used antibiotic), being studied because laboratory research suggests it may have anti-inflammatory and neuroprotective properties that could help reduce damage to motor neurons.
- Salbutamol, (used to treat asthma), being evaluated because studies suggest it may support muscle health and the communication between nerves and muscles, which are both affected in ALS.
The platform will help determine whether any of these therapies show early biological signs of benefit and should move forward to larger clinical trials.