Two Experimental ALS Therapies Report Positive Safety Data from Early-Stage Trials

Two investigational therapies for amyotrophic lateral sclerosis (ALS) have reported positive safety results from early-stage clinical trials, offering potential new treatment approaches for the progressive neurodegenerative disease. The therapies target different mechanisms underlying ALS, with one focusing on neuroinflammation and iron accumulation, and the other addressing gut barrier dysfunction.

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

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 levels of neurofilament light change between the two groups.

The Executive Director of Mass General Brigham Neuroscience Institute and Director of the Sean M. Healey & AMG Center for ALS stated that the improved functional and biomarker signals observed support a phase 3 study to evaluate PrimeC's effectiveness and safety in a larger population. A professor of Neurology at Barrow Neurological Institute noted that multiple clinical endpoints suggest the same level of clinical benefit and that multiple biomarkers are consistent with clinical endpoints, providing a strong scientific foundation for advancing PrimeC into a Phase 3 trial.

Separately, the French biopharmaceutical company PLL Therapeutics announced positive results from a phase I/II clinical trial for its investigational therapy PLL001 to treat ALS. This first phase of the trial establishes safety and tolerability of the therapy in 12 patients with ALS at three different doses by subcutaneous injection. The trial, which was double-blind and placebo-controlled, resulted in no serious adverse events and no treatment-emergent adverse events that resulted in study discontinuation.

PLL001 is a polypeptide delivery platform based on poly-L-lysine, which can be conjugated with active compounds. This helps increase the half-life of active compounds in the body and allows them to cross the blood-brain barrier. For ALS, the focus is on restoring the gut barrier. Research has found links between ALS and increased gut permeability, which could cause microbes, LPS, and other toxins to leak into the bloodstream and travel to the brain. The goal of PLL001 is to reduce this gut permeability by delivering small-chain fatty acids (SCFAs) to the gut epithelium and the blood-brain barrier. Research has shown that SCFAs enhance the tight junctions in the gut epithelium, making it more difficult for harmful substances to cross.

The next stage of the trial will involve 140 ALS patients in Australia and New Zealand, where PLL Therapeutics had opened a subsidiary last year. This phase will determine how well PLL001 targets organs and inflammation, as well as its ability to restore the gut.

ALS is a progressive neurodegenerative and typically fatal disease marked by the loss of motor neurons and the gradual increase in muscle weakness. There is no cure for ALS and current medications focus on slowing disease progression, in addition to treating symptoms. Currently approved drugs to treat ALS, such as Riluzole and Edaravone, target neuronal protection and oxidative stress.

PARADIGM was conducted and funded by NeuroSense Therapeutics.