PrimeC (NeuroSense Therapeutics), an oral extended-release fixed-dose combination of ciprofloxacin and celecoxib, significantly reduced plasma neuron-derived exosomal TDP-43 (NDE-TDP-43) compared with placebo in the phase 2b PARADIGM trial (NCT05357950), and the difference widened through 18 months of treatment. It also modulated iron-regulatory proteins and ALS-associated microRNAs, findings that informed the design of the global phase 3 PARAGON trial.^1,2

Lead author Merit E. Cudkowicz, MD, MSc, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital and professor of neurology at Harvard Medical School, recently presented at the analysis at the 2026 Network of Excellence for ALS (NEALS) Annual Meeting, held October 27-30, 2026, in Clearwater, Florida. When NeuroSense previously announced the TDP-43 results in June 2026, Cudkowicz said in a statement that the findings suggest “target engagement of a pathological process present in the majority of people with ALS.”²

Study Overview and Key Findings

PARADIGM was a randomized, double-blind, placebo-controlled trial of PrimeC added to standard of care. It included a 6-month double-blind period followed by a 12-month open-label extension. The trial enrolled 68 participants in Canada, Italy, and Israel.³ Investigators isolated neuron-derived exosomes from plasma by neuron-specific immunocapture and measured TDP-43 centrally. They also assessed iron-regulatory proteins, circulating microRNAs, neurofilament light chain (NfL), and ALS Functional Rating Scale-Revised (ALSFRS-R) scores. Longitudinal changes were analyzed with mixed models for repeated measures.

At day 180, the prespecified primary end point time point, NDE-TDP-43 was approximately 20% lower with PrimeC than with placebo (P = .042). Notably, the separation grew through day 540 (P <.001). Over the 6-month double-blind period, PrimeC slowed ALSFRS-R decline by 29.2% compared with placebo, though the difference was not statistically significant (P = .12).

Other biomarker effects included preserved transferrin (P = .03), reduced ferritin (P = .05), and downregulation of ALS-associated miR-199a-3p/5p and miR-181a/b-5p (false discovery rate < .005). NfL showed a favorable trend, particularly among participants at an earlier stage of disease. PrimeC was well tolerated through 18 months.

READ MORE: AL-S Pharma Details Planned Phase 3 Trial Design for AP-101 in ALS

Clinical Context and Interpretation

TDP-43 proteinopathy is a defining pathological feature of ALS. In the DESCRIBE study, plasma NDE-TDP-43 was elevated in patients with ALS and correlated with clinical severity, which supports its use as a minimally invasive marker of disease progression and target engagement. PrimeC is designed to address several interconnected ALS mechanisms. These include neuroinflammation, iron dysregulation, impaired autophagy, altered microRNA expression, and TDP-43 pathology.

NeuroSense previously reported statistically significant slowing of ALSFRS-R decline at 12 and 18 months (36.5% and 32.8%, respectively) and a median survival benefit of approximately 15 months (HR, 0.35; P = .004) from longer-term PARADIGM analyses.²

The investigators concluded that the alignment between NDE-TDP-43 reduction and slower functional decline supports NDE-TDP-43 as a pharmacodynamic marker of target engagement. The concurrent effects on iron homeostasis and ALS-associated microRNAs are consistent with PrimeC’s proposed multitarget mechanism.

Limitations and Future Research

The PARADIGM study was limited by its small sample size, with differences in ALSFRS-R scores at 6 months failing to reach statistical significance and longer-term clinical comparisons relying on data from the open-label period. Additionally, NDE-TDP-43 remains an emerging assay that has not been validated as a surrogate for clinical benefit, while several biomarker findings were only borderline statistically significant.

NeuroSense has FDA clearance to begin PARAGON, which is expected to enroll approximately 300 participants, primarily in the United States.² The trial will test whether PARADIGM’s biomarker and clinical signals hold up in a larger randomized population, and it may clarify the role of NDE-TDP-43 in ALS drug development.

Click here for more of our NEALS 2026 coverage.

REFERENCES
1. Cudkowicz M, Drory VE, Chio A, et al. From PARADIGM to PARAGON: converging clinical and biomarker findings informing phase 3 development of PrimeC. Presented at: 2026 NEALS Annual Meeting; October 27-30, 2026; Clearwater, FL.
2. NeuroSense achieves primary endpoint in phase 2b ALS study with statistically significant reduction of TDP-43, the defining pathological hallmark of ALS. News release. NeuroSense Therapeutics. June 29, 2026. Accessed November 6, 2026. https://www.prnewswire.com/news-releases/neurosense-achieves-primary-endpoint-in-phase-2b-als-study-with-statistically-significant-reduction-of-tdp-43-the-defining-pathological-hallmark-of-als-302813175.html
3. NeuroSense’s PARADIGM ALS clinical trial demonstrates up to 73% improved complication-free survival following statistically significant slowing of disease progression. News release. NeuroSense Therapeutics. July 9, 2024. Accessed November 6, 2026. https://www.biospace.com/neurosenses-paradigm-als-clinical-trial-demonstrates-up-to-73-improved-complication-free-survival-following-statistically-significant-slowing-of-disease-progression