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

Abstract

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 published

• Twitter 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.

Keywords:

• ALS
• PrimeC
• biomarker
• combined therapy
• clinical trial

Acknowledgements

In memory of our colleague and friend, Shay Rishoni. PrimeC is our tribute to him. We thank the trial participants along with their families and caregivers, for choosing to participate in this study. We also thank Toby Ferguson for contributing to the analysis of the serum neurofilament, and Ariel Gordon, NeuroSense Therapeutics’ first investor, for providing the basis with which this work came to fruition. We extend our appreciation to Alon Ben-Noon and Dr. Ferenc Tracik, for their support and inputs on the manuscript, and to our unexpendable scientific advisory board members: Dr. Jeremy Shefner, Dr. Merit Cudkowicz, Dr. Orla Hardiman, Dr. Jinsy Andrews and Dr. Jeffery Rosenfeld, for their valued advice. Data used in the preparation of this article were obtained from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database. As such, the following organizations and individuals within the PRO-ACT Consortium contributed to the design and implementation of the PRO-ACT Database and/or provided data, but did not participate in the analysis of the data or the writing of this report: ALS Therapy Alliance, Knopp Biosciences, Neuraltus Pharmaceuticals, Inc., Neurological Clinical Research Institute, MGH, Northeast ALS Consortium, Novartis, Prize4Life Israel, Regeneron Pharmaceuticals, Inc., Sanofi, Teva Pharmaceutical Industries, Ltd., The ALS Association. We acknowledge the NEALS Biorepository for providing part of the biofluids from the healthy controls used in this study.

Author contributions

SSZ, AP, BA, JMS and VED contributed to the conception and design of the study. SSZ, AP, NRB, RPAvE, NB, BA, EE, EG, DB, DLE, JDB, SP and VED contributed to the acquisition and analysis of data. SSZ, AP, NRB, RPAvE, JDB and SP contributed to drafting the text and preparing the figures.

Declaration of interest

SSZ, AP and NRB are employees of NeuroSense Therapeutics (NST). RPAvE serves as statistical consultant and receives consultancy fees from NST. DLE and DB are employees of Origent Data Sciences. EE is a NeuroDex Ltd employee. JMS received compensation as a consultant for NST. NST owns patent rights to Cipro/Celecox combination that was used in this study. The other authors declare no conflicts of interest.

Additional information

Funding

This study was funded by NeuroSense Therapeutics Ltd.