Investigational oral therapy shows safety and potential benefits in ALS trial

In a phase 2b clinical trial, an investigational oral therapy called PrimeC was found to be safe and well tolerated in people living with amyotrophic lateral sclerosis (ALS), with exploratory findings suggesting target engagement and potential clinical benefits. Results of the PARADIGM study, led by researchers at Mass General Brigham Neuroscience Institute and Barrow Neurological Institute, were published in JAMA Neurology.

ALS is a progressive neurodegenerative and typically fatal disease marked by the loss of motor neurons and the gradual increase in muscle weakness. PrimeC, a combination of celecoxib and ciprofloxacin, is designed to target the neuroinflammation, excess iron accumulation, and abnormal microRNA activity that occurs in ALS.

The multicenter trial randomized 68 participants 2:1 to receive PrimeC or placebo for six months, followed by a 12-month open-label extension in which all received PrimeC. While drug-related adverse events were more common with PrimeC (20.0% vs 4.3%), most of the adverse events were mild to moderate and temporary.

Although the study was not powered to assess efficacy, participants in the PrimeC arm had better functional outcomes, especially for speech and swallowing, as measured by an ALS Functional Rating Scale Revised (ALSFRS-R) score. At 6 months, participants taking PrimeC scored 2.23 points higher than those taking placebo. By 18 months, participants originally assigned to PrimeC scored 7.92 points higher, on average, than their counterparts. Early, continuous treatment was also associated with a 64% reduced risk of ALS-related complications, including hospitalization, respiratory failure or death.

Exploratory biomarker analyses showed those initially assigned to PrimeC had lower levels of ferritin, a key protein involved in storing iron in the body. Treatment was also associated with lower levels of microRNA molecules that have been linked to ALS. There were no treatment related changes in blood levesl of neurofilament light change between the two groups.

"The improved functional and biomarker signals we observed support a phase 3 study to evaluate PrimeC's effectiveness and safety in a larger population," said first author Merit Cudkowicz, MD, MSc, Executive Director of Mass General Brigham Neuroscience Institute and Director of the Sean M. Healey & AMG Center for ALS. "The importance of following up on potential therapies that can slow the course of ALS is extraordinarily high for patients and families. We are determined to accelerate the development of therapies for people living with ALS."

"What stands out about the PARADIGM study is that multiple clinical endpoints suggest the same level of clinical benefit and that multiple biomarkers are consistent with clinical endpoints," said Jeremy M. Shefner, MD, PhD, professor of Neurology at Barrow Neurological Institute and corresponding author of the publication. "Together, these findings provide a strong scientific foundation for advancing PrimeC into a Phase 3 trial designed to validate its impact for patients."