Long-Term Data From PARADIGM Trial Suggest Survival Benefit With PrimeC in ALS

New long-term follow-up from the phase 2b PARADIGM trial suggests that treatment with the investigational therapy PrimeC (NeuroSense Therapeutics) was associated with significantly improved overall survival in patients with amyotrophic lateral sclerosis (ALS) compared with those initially assigned to placebo. The updated analysis, based on extended follow-up of trial participants, adds survival data to previously reported findings of slowed disease progression and biomarker effects, potentially strengthening the evidence base supporting further late-stage development of the therapy.¹

ALS remains a progressive neurodegenerative disorder characterized by degeneration of upper and lower motor neurons, leading to progressive weakness, respiratory failure, and death, typically within 3 to 5 years of symptom onset.² Despite advances in supportive care and several approved therapies that modestly slow progression, disease-modifying treatments capable of substantially altering survival remain limited.

Long-Term Survival Findings From PARADIGM

The updated survival analysis stems from the completed PARADIGM phase 2b study (NCT05357950), a randomized, double-blind, placebo-controlled trial evaluating PrimeC in 68 patients with ALS. In the study, participants were randomized in a 2:1 ratio to receive PrimeC or placebo during the 6-month double-blind phase, after which patients could enter an open-label extension.

According to Kaplan–Meier estimates from extended follow-up, patients who received continuous PrimeC treatment across both the double-blind and open-label phases achieved an estimated median survival of 36.3 months. By comparison, patients initially assigned to placebo during the blinded portion—who later crossed over to active treatment during the extension—had an estimated median survival of 21.4 months. This difference represented an improvement of more than 14 months and approximately a 70% increase in median survival.

A log-rank test comparing survival curves demonstrated statistical significance (P = .0218). In addition, a Cox proportional hazards model adjusting for baseline risk factors suggested that PrimeC treatment was associated with a 65% reduction in risk of death compared with placebo (hazard ratio, 0.35; 95% CI, 0.17–0.71; P = .0037).¹

Commenting on the findings, Alon Ben-Noon, chief executive officer of NeuroSense Therapeutics, said the updated results “further validate the magnitude and durability of PrimeC's effect in ALS,” noting that the observed survival extension may represent a clinically meaningful signal in a disease where improvements in survival have historically been modest.

The newly reported survival outcomes derive from the same trial that previously demonstrated statistically significant slowing of disease progression along with favorable safety and tolerability, according to earlier reports from the PARADIGM program.¹

Prior PARADIGM Findings: Disease Progression and Biomarker Effects

Earlier analyses from the PARADIGM study provided evidence suggesting that PrimeC may influence both clinical progression and biological markers associated with ALS. In previously reported data, treatment with the therapy was associated with a 36% slowing of disease progression compared with placebo (P = .009), along with improved complication-free survival in treated participants.³

PrimeC is an extended-release oral combination therapy composed of ciprofloxacin and celecoxib—two agents already approved by the FDA for other indications. The combination was designed to target multiple biological pathways implicated in ALS, including neuroinflammation, RNA regulation, and mitochondrial dysfunction.

In a 2024 analysis of PARADIGM participants, investigators also reported changes in biomarkers associated with iron metabolism. Iron levels remained stable over the 12-month treatment period, with a mean difference of 4.536 µmol (95% CI, 1.143-7.929; P = .01) compared with those who started on placebo and transitioned to PrimeC after the initial 6-month double-blind phase. In addition, patients receiving PrimeC demonstrated significant decreases in ferritin levels and increases in transferrin levels over 12 months, while iron concentrations remained stable. These findings were interpreted as evidence of target engagement involving iron-regulation pathways, which have been implicated in ALS pathophysiology.³

Merit Cudkowicz, MD, MSc, chair of neurology and director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, previously commented that the results from the PARADIGM study were encouraging and supported further evaluation of PrimeC in phase 3 trials.

Disturbances in iron metabolism have been observed in ALS and other neurodegenerative disorders, with elevated ferritin and reduced transferrin levels reported in several studies of patients with the disease.⁴

Clinical Context and Next Steps

The newly reported survival data provide longer-term context to previously published PARADIGM findings and may inform discussions with regulatory authorities regarding future clinical development of PrimeC. NeuroSense indicated it is continuing interactions with regulators as it evaluates potential late-stage trial pathways.

Interpretation of the survival findings should consider the relatively small sample size of the phase 2b study and the crossover design, which may have influenced survival comparisons between treatment groups. The company noted that confirmation of survival benefits would require validation in larger, adequately powered trials.

Nonetheless, the extended follow-up contributes to a growing dataset suggesting that multi-pathway therapeutic approaches may hold promise in ALS, where the complex pathophysiology of motor neuron degeneration has historically limited the impact of single-target treatments.

REFERENCES
1. NeuroSense Therapeutics Ltd. NeuroSense reports long-term survival data from PARADIGM Phase 2b trial of PrimeC in amyotrophic lateral sclerosis. Press release. February 18, 2026. Accessed March 5, 2026. https://www.prnewswire.com/news-releases/neurosense-therapeutics-announces-additional-long-term-survival-data-from-paradigm-phase-2b-trial-302377261.html
2. Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071. https://doi.org/10.1038/nrdp.2017.71
3. NeuroSense Therapeutics Ltd. NeuroSense announces positive biomarker data from ALS Phase 2b PARADIGM clinical trial. Press release. August 1, 2024. https://www.prnewswire.com/news-releases/neurosense-therapeutics-announces-positive-biomarker-data-from-als-phase-2b-clinical-trial-302212321.html
4. Wang L, Li C, Chen X, Li S, Shang H. Abnormal serum iron-status indicator changes in amyotrophic lateral sclerosis: a meta-analysis. J Neurol Sci. 2020;410:116673. https://doi.org/10.1016/j.jns.2020.116673