PMID- 36106817 OWN - NLM STAT- MEDLINE DCOM- 20230424 LR - 20230427 IS - 2167-9223 (Electronic) IS - 2167-8421 (Linking) VI - 24 IP - 3-4 DP - 2023 May TI - Combination of ciprofloxacin/celecoxib as a novel therapeutic strategy for ALS. PG - 263-271 LID - 10.1080/21678421.2022.2119868 [doi] AB - 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. FAU - Salomon-Zimri, Shiran AU - Salomon-Zimri S AD - NeuroSense Therapeutics, Ltd, Herzliya, Israel. FAU - Pushett, Avital AU - Pushett A AD - NeuroSense Therapeutics, Ltd, Herzliya, Israel. FAU - Russek-Blum, Niva AU - Russek-Blum N AD - NeuroSense Therapeutics, Ltd, Herzliya, Israel. AD - The Dead Sea Arava Science Center, Auspices of Ben Gurion University, Central Arava, Israel. FAU - Van Eijk, Ruben P A AU - Van Eijk RPA AD - Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands. AD - Biostatistics and Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. FAU - Birman, Nurit AU - Birman N AD - Neuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. FAU - Abramovich, Beatrice AU - Abramovich B AD - Neuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. FAU - Eitan, Erez AU - Eitan E AD - NeuroDex Incorporated, Natick, MA, USA. FAU - Elgrart, Katya AU - Elgrart K AD - NeuroDex Incorporated, Natick, MA, USA. FAU - Beaulieu, Danielle AU - Beaulieu D AD - Origent Data Sciences, Inc, Vienna, VA, USA. FAU - Ennist, David L AU - Ennist DL AD - Origent Data Sciences, Inc, Vienna, VA, USA. FAU - Berry, James D AU - Berry JD AD - Department of Neurology Massachusetts General Hospital, Harvard Medical School, Sean M. Healey and AMG Center for ALS at Mass General and Neurological Clinical Research Institute, Boston, MA, USA. FAU - Paganoni, Sabrina AU - Paganoni S AD - Department of Neurology Massachusetts General Hospital, Harvard Medical School, Sean M. Healey and AMG Center for ALS at Mass General and Neurological Clinical Research Institute, Boston, MA, USA. FAU - Shefner, Jeremy M AU - Shefner JM AD - Barrow Neurological Institute, Phoenix, AZ, USA, and. FAU - Drory, Vivian E AU - Drory VE AD - Neuromuscular Diseases Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. AD - Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20220915 PL - England TA - Amyotroph Lateral Scler Frontotemporal Degener JT - Amyotrophic lateral sclerosis & frontotemporal degeneration JID - 101587185 RN - 0 (Biomarkers) RN - JCX84Q7J1L (Celecoxib) RN - 0 (DNA-Binding Proteins) RN - 5E8K9I0O4U (Ciprofloxacin) SB - IM MH - Humans MH - *Amyotrophic Lateral Sclerosis/diagnosis/drug therapy MH - Biomarkers MH - Celecoxib/therapeutic use MH - *COVID-19 MH - Disease Progression MH - DNA-Binding Proteins MH - Double-Blind Method MH - *Neurodegenerative Diseases MH - Ciprofloxacin/therapeutic use OTO - NOTNLM OT - ALS OT - PrimeC OT - biomarker OT - clinical trial OT - combined therapy EDAT- 2022/09/16 06:00 MHDA- 2023/04/21 06:41 CRDT- 2022/09/15 08:43 PHST- 2023/04/21 06:41 [medline] PHST- 2022/09/16 06:00 [pubmed] PHST- 2022/09/15 08:43 [entrez] AID - 10.1080/21678421.2022.2119868 [doi] PST - ppublish SO - Amyotroph Lateral Scler Frontotemporal Degener. 2023 May;24(3-4):263-271. doi: 10.1080/21678421.2022.2119868. Epub 2022 Sep 15.