PrimeC PARADIGM Phase 2b Trial — Ciprofloxacin/Celecoxib for ALS
PrimeC is an extended-release oral tablet combining ciprofloxacin (an antibiotic) and celecoxib (a COX-2 anti-inflammatory) that NeuroSense Therapeutics has developed as an ALS treatment. The PARADIGM Phase 2b trial enrolled 68 adults with ALS and randomized them 2:1 to PrimeC or placebo. In the per-protocol adherent group — those who consistently took the medication — PrimeC slowed ALS progression by 37.4% on the ALSFRS-R functional scale. At 12 months, those who started PrimeC early had a 43% higher survival rate than those who crossed over from placebo later. The FDA authorized a Phase 3 trial, PARAGON, in December 2025. PARAGON is now enrolling.
Mechanism of action: why combine an antibiotic and an anti-inflammatory?
The combination targets what NeuroSense describes as overlapping pathological pathways in ALS: neuroinflammation, iron accumulation in motor neurons, and dysregulated microRNA expression.
Ciprofloxacin, beyond its antibiotic properties, has been shown in preclinical work to reduce iron-mediated oxidative stress and to modulate certain microRNA pathways implicated in neurodegeneration. Celecoxib is a selective COX-2 inhibitor with established anti-inflammatory activity that reduces prostaglandin-mediated neuroinflammation. The hypothesis is that using both agents together creates a combined effect on multiple disease mechanisms simultaneously — addressing neuroinflammation through the celecoxib component while ciprofloxacin targets iron metabolism and microRNA dysregulation.
This is not a novel biological target in the way that a gene therapy or ASO would be. Both components are known drugs with established safety profiles, which is both an advantage (lower toxicity risk) and a limitation (less precision than a molecularly targeted agent).
What they did
PARADIGM (NCT05357950) enrolled 68 adults with ALS and randomized them 2:1 to receive PrimeC (the extended-release ciprofloxacin/celecoxib combination tablet) or placebo. Participants took the drug orally for six months as the primary study period, with a 12-month follow-up analysis that included a placebo-to-PrimeC crossover.
The primary endpoint was ALSFRS-R slope over 6 months. Secondary and exploratory endpoints included survival at 12 months, complications (hospitalizations, requirement for additional medical interventions), and biomarker changes including ferritin levels and disease-associated microRNA expression.
What they found
In the per-protocol population — participants who adhered consistently to the medication regimen — PrimeC slowed ALSFRS-R decline by 37.4% compared to placebo. This is a meaningful magnitude of effect by ALS trial standards, where slowing progression by 25–30% has historically been considered clinically significant.
At the 12-month mark, participants who had started PrimeC early (at randomization) had a 43% higher survival rate than those who had been on placebo and crossed over to PrimeC at the 6-month point. This early-start advantage was one of the most clinically compelling findings — it suggests that earlier initiation of treatment produces better long-term outcomes, consistent with a neuroprotective mechanism.
At 18 months, PrimeC participants showed ALSFRS-R scores 7.92 points higher than placebo crossovers — a difference that represents meaningful preserved function on a scale where each point corresponds to a specific functional ability. Additional findings included: 64% reduced risk of ALS-related complications including hospitalization, and lower ferritin levels and reduced disease-associated microRNA expression in the PrimeC group, consistent with the proposed mechanism. No treatment-related changes in neurofilament light chain were observed.
The safety profile was consistent with the known profiles of the individual components. No unexpected serious adverse events were attributed to the combination.
Why it matters
PARADIGM is a Phase 2b trial, and Phase 2b results should be interpreted with appropriate caution — the history of ALS drug development includes multiple agents that showed Phase 2 signal and failed Phase 3 confirmation. The 68-patient sample is small enough that results could reflect chance, particularly in the per-protocol (rather than intention-to-treat) analysis, which excludes non-adherent participants and may inflate apparent efficacy.
That said, the magnitude of the effect — 37.4% slowing in the per-protocol group, 43% survival advantage at 12 months — is large enough to merit the Phase 3 investigation that PARAGON represents. The FDA's authorization of PARAGON in December 2025, and the ongoing enrollment of approximately 300 patients across US and EU sites, reflects regulatory confidence that the Phase 2b signal is worth pursuing.
For ALS patients and families, PrimeC is currently accessible only through the PARAGON trial or through compassionate use arrangements. It is not an approved treatment. If PARAGON confirms the PARADIGM results in a 300-patient randomized population, PrimeC would become a candidate for FDA approval.
PLS relevance
PrimeC is being studied in ALS only. The mechanisms it targets — neuroinflammation, iron accumulation, microRNA dysregulation — are biologically relevant to motor neuron disease broadly, and some degree of neuroinflammation is present in PLS. However, there is no PLS-specific data, and PLS patients are not enrolled in PARAGON. The applicability of PARAGON results to PLS, if the trial succeeds, would be speculative without further study.
How this connects
PrimeC is one of several active ALS drug programs that could, if successful, become relevant to PLS patients through extrapolation or future PLS-specific trials. For context on where it fits in the broader pipeline, see Drug Trial Research. For other Phase 2 results with positive signals, see the SPG302 Phase 2a review. For information on how to participate in trials currently enrolling, see Clinical Trials.
Citation
NeuroSense Therapeutics. PARADIGM Phase 2b trial results (NCT05357950). Published in JAMA Neurology, March 2026. FDA authorized Phase 3 PARAGON trial December 2025. PARAGON target enrollment: ~300 participants, US and EU.