Combination of ciprofloxacin/celecoxib as a novel therapeutic strategy for ALS.

OBJECTIVE: This study aimed to evaluate the safety and tolerability of a fixed-dose co-formulation of ciprofloxacin and celecoxib (PrimeC) in patients with amyotrophic lateral sclerosis (ALS), and to examine its effects on disease progression and ALS-related biomarkers. METHODS: In this proof of concept, open-label, phase IIa study of PrimeC in 15 patients with ALS, participants were administered PrimeC thrice daily for 12 months. The primary endpoints were safety and tolerability. Exploratory endpoints included disease progression outcomes such as forced vital capacity, revised ALS functional rating scale, and effect on algorithm-predicted survival. In addition, indications of a biological effect were assessed by selected biomarker analyses, including TDP-43 and LC3 levels in neuron-derived exosomes (NDEs), and serum neurofilaments. RESULTS: Four participants experienced adverse events (AEs) related to the study drug. None of these AEs were unexpected, and most were mild or moderate (69%). Additionally, no serious AEs were related to the study drug. One participant tested positive for COVID-19 and recovered without complications, and no other abnormal laboratory investigations were found. Participants' survival compared to their predictions showed no safety concerns. Biomarker analyses demonstrated significant changes associated with PrimeC in neural-derived exosomal TDP-43 levels and levels of LC3, a key autophagy marker. INTERPRETATION: This study supports the safety and tolerability of PrimeC in ALS. Biomarker analyses suggest early evidence of a biological effect. A placebo-controlled trial is required to disentangle the biomarker results from natural progression and to evaluate the efficacy of PrimeC for the treatment of ALS. Summary for social media if publishedTwitter handles: @NeurosenseT, @ShiranZimri•What is the current knowledge on the topic? ALS is a severe neurodegenerative disease, causing death within 2-5 years from diagnosis. To date there is no effective treatment to halt or significantly delay disease progression.•What question did this study address? This study assessed the safety, tolerability and exploratory efficacy of PrimeC, a fixed dose co-formulation of ciprofloxacin and celecoxib in the ALS population.•What does this study add to our knowledge? This study supports the safety and tolerability of PrimeC in ALS, and exploratory biomarker analyses suggest early insight for disease related-alteration.•How might this potentially impact the practice of neurology? These results set the stage for a larger, placebo-controlled study to examine the efficacy of PrimeC, with the potential to become a new drug candidate for ALS.