Oral Celecoxib and Ciprofloxacin Slow Functional Decline in ALS

Targeting Multiple Pathways in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder characterized by the loss of upper and lower motor neurons, typically leading to death from respiratory failure within two to four years [1]. The complex pathophysiology of the disease involves interacting mechanisms, including neuroinflammation, aberrant protein aggregation such as TAR DNA-binding protein 43 (TDP-43), and dysregulated iron homeostasis [1, 2]. Because single-target therapies have historically yielded limited clinical benefits, researchers are increasingly exploring combination regimens designed to simultaneously modulate multiple neurotoxic pathways [3]. One such strategy pairs the nonsteroidal anti-inflammatory drug celecoxib with the fluoroquinolone antibiotic ciprofloxacin, an oral co-formulation that has demonstrated synergistic neuroprotective effects and improved motor neuron survival in preclinical human induced pluripotent stem cell and animal models [3, 4]. Moving this concept into human subjects, an open-label phase IIa clinical trial involving 15 patients with ALS evaluated this multi-target therapy administered thrice daily for 12 months, demonstrating that the combination was safe, well-tolerated, and significantly altered neural-derived exosomal levels of TDP-43 and the autophagy marker LC3 [5].

Trial Design and Patient Demographics

To address the urgent need for disease-modifying therapies, researchers developed PrimeC, a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target neuroinflammation, iron homeostasis, and dysregulated microRNAs. The objective of this phase 2b trial was to evaluate the safety, tolerability, and potential efficacy of this combination in patients living with ALS. Conducted at four ALS referral centers from May 2022 to November 2023, the study utilized a randomized, double-blind, placebo-controlled design. Participants were randomized in a 2:1 ratio to receive either PrimeC or a placebo for six months. Following this double-blind period, all participants entered a 12-month open-label extension to assess long-term outcomes. Eligible participants were adults with definite or probable ALS and a disease duration of 30 months or less, ensuring the cohort represented early-stage disease where interventions might have the greatest clinical impact.

Of 73 screened individuals, 69 were randomized and 68 were included in the intent-to-treat population. The cohort was well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. Similarly, in the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. The primary outcome of the trial was safety and tolerability. To measure biological activity, the prespecified primary biomarker outcome focused on plasma neuron-derived exosomes (tiny cellular vesicles that cross the blood-brain barrier, offering a window into central nervous system pathology) containing TDP-43 or prostaglandinJ2, an inflammatory lipid mediator. Secondary outcomes tracked clinical progression using the ALS Functional Rating Scale-Revised (ALSFRS-R) at 6 and 18 months, alongside survival and time-to-composite events such as respiratory failure or hospitalization. Exploratory biomarkers included neurofilament light chains (a well-established marker of axonal damage), iron-regulatory proteins, and circulating microRNAs.

Safety Profile and Functional Outcomes at 18 Months

The trial results demonstrated that PrimeC was safe and well tolerated over 18 months. During the study, the overall adverse event rate was 66.7% for PrimeC compared to 65.2% for placebo. Physicians should note that drug-related adverse events were more frequent with PrimeC (20.0%) than placebo (4.3%), but these were mostly mild to moderate and transient. This safety profile is a critical consideration for clinicians managing patients with ALS, as maintaining quality of life while minimizing treatment burden is paramount.

To assess clinical progression, the study tracked changes in the ALSFRS-R, a validated tool measuring motor and bulbar function. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, -0.61 to 5.07; P = .12), indicating a trend toward slowed decline that did not reach statistical significance during the initial double-blind phase. However, the long-term open-label extension revealed more pronounced clinical benefits for those who started the drug early. At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference of 7.92 points (95% CI, 2.25 to 13.60; P = .007) compared to those who had initially received the placebo. Notably, this sustained functional preservation included a significant bulbar difference of 3.18 points (95% CI, 1.32 to 5.04; P = .001) for participants continuously treated with PrimeC. For practicing neurologists, preserving bulbar function directly translates to a prolonged ability to speak and swallow, which are vital for patient survival and autonomy.

Beyond functional scores, the combination therapy demonstrated a protective effect against severe disease milestones. Continuous treatment with PrimeC was associated with a lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15 to 0.85; P = .02). This reduction in hazard risk for critical clinical events underscores the potential of targeting multiple neurodegenerative pathways simultaneously. The authors concluded that although the trial was not powered for efficacy, functional and biomarker findings support a confirmatory trial, providing a strong rationale for larger phase 3 studies.

Biomarker Modifications and Iron Homeostasis

To understand the biological mechanisms driving these clinical outcomes, the researchers analyzed exploratory biomarkers related to iron homeostasis, a pathway known to contribute to oxidative stress and motor neuron degeneration in ALS. During the initial six months of the study, in the double-blind period, transferrin levels were preserved with PrimeC (1.90 micromol/L difference; P = .03). Transferrin is a key glycoprotein responsible for transporting iron through the blood plasma, and its preservation indicates a stabilization of systemic iron metabolism. Furthermore, the treatment altered the relationship between functional decline and ferritin, an intracellular protein that stores iron and releases it in a controlled fashion. Specifically, the negative ferritin-ALSFRS-R correlation observed in placebo (rho = -0.50; P = .02) was abolished with PrimeC. For clinicians, this means the typical disease pattern where elevated iron storage markers correlate with worsening motor and bulbar function was disrupted by the combination therapy.

The study also evaluated circulating microRNAs, which are small non-coding RNA molecules that regulate gene expression and frequently exhibit dysregulation in neurodegenerative diseases. The researchers found that ALS-associated microRNAs were downregulated with PrimeC, including miR-199a-3p (log 2 fold change, -1.87; false discovery rate [FDR] P = .004), miR-199a-5p (-2.23; FDR P < .001), miR-181a-5p (-1.89; FDR P = .001), and miR-181b-5p (-1.62; FDR P = .005). The false discovery rate is a statistical method used to correct for multiple comparisons, adding robustness to these findings. Downregulating these specific genetic regulators suggests the therapy actively modifies the underlying molecular environment associated with disease progression. While these exploratory biomarkers provide insight into the systemic effects of the drug, the primary biomarker outcomes targeting pathological protein aggregation and neuroinflammation are still pending. The authors noted that prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses.

References

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3. Salomon‐Zimri S, Kerem N, Linares G, Russek‐Blum N, Ichida JK, Tracik F. Elucidating the Synergistic Effect of the PrimeC Combination for Amyotrophic Lateral Sclerosis in Human Induced Pluripotent Stem Cell-Derived Motor Neurons and Mouse Models. Pharmaceuticals. 2025. doi:10.3390/ph18040524

4. Goldshtein H, Muhire A, Légaré VP, et al. Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis. Annals of Clinical and Translational Neurology. 2020. doi:10.1002/acn3.51174

5. Salomon-Zimri S, Pushett A, Russek‐Blum N, et al. Combination of ciprofloxacin/celecoxib as a novel therapeutic strategy for ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2022. doi:10.1080/21678421.2022.2119868