PrimeC Achieves Primary Biomarker End Point in Phase 2b PARADIGM ALS Trial

According to newly announced findings from the phase 2b PARADIGM trial (NCT05357950), the investigational oral therapy PrimeC (NeuroSense) met its primary efficacy end point, demonstrating a statistically significant reduction in neuron-derived TDP-43 compared with placebo in adults with amyotrophic lateral sclerosis (ALS). The results mark what NeuroSense described as the first randomized, double-blind, placebo-controlled study to show a treatment-associated reduction in TDP-43, a protein pathology observed in the vast majority of ALS cases and considered a hallmark of disease biology.¹

"Achieving the primary endpoint of PARADIGM with a statistically significant reduction in TDP-43 marks a defining moment for NeuroSense and for ALS research," Alon Ben-Noon, chief executive officer at NeuroSense, said in a statement.¹ "Combined with the clinically meaningful slowing of disease progression, significant survival benefit, and consistent biomarker findings previously reported from PARADIGM, these results provide a compelling and highly differentiated body of evidence supporting PrimeC's potential as a disease-modifying therapy.”

The findings build upon previously reported clinical outcomes from PARADIGM, which included slower functional decline on the ALS Functional Rating Scale–Revised (ALSFRS-R), prolonged survival, and favorable safety through 18 months of follow-up. Together, the biomarker and clinical data are expected to inform the upcoming phase 3 PARAGON trial, which has already received FDA clearance to begin enrollment.¹

The randomized, double-blind, placebo-controlled phase 2b study evaluated the safety, tolerability, biomarkers, and efficacy of PrimeC in adults with ALS. At the prespecified primary analysis time point (day 180), treatment with PrimeC resulted in a statistically significant reduction in neuron-derived TDP-43 compared with placebo (P = .0421). According to the company, reductions in TDP-43 were maintained through day 540 among patients who remained on active treatment, with differences versus placebo (P <.001).¹

Investigators measured TDP-43 using NeuroDex'sExoSORT platform, an immunoaffinity-based assay that isolates neuron-derived extracellular vesicles from blood samples. This approach was designed to quantify central nervous system–derived TDP-43 while minimizing contributions from peripheral tissues, providing a biomarker intended to more closely reflect neuronal pathology.¹

TDP-43 aggregation is observed in more than 97% of ALS cases and has long been implicated in disease pathogenesis through disruption of RNA processing, protein homeostasis, and neuronal survival. Although numerous investigational therapies have attempted to influence TDP-43 biology, demonstrating treatment-associated reductions in patients has remained challenging, making biomarker validation an important objective in ALS drug development.²

The newly reported biomarker findings complement efficacy results that NeuroSense previously disclosed from PARADIGM. At 12 and 18 months, PrimeC-treated participants experienced statistically significant slowing of ALSFRS-R decline compared with placebo, with reductions in functional decline of 36.5% (P = .008) and 32.8% (P = .007), respectively. The company also previously reported an approximately 15-month improvement in median survival (hazard ratio, 0.35; P = .004), along with favorable effects on ALS-associated microRNAs and iron-regulatory biomarkers.¹

In terms of safety, PrimeC was generally well tolerated throughout the study, according to the company, with no new safety signals identified during up to 18 months of treatment. Additional safety details were not included in the current announcement.¹

Mechanistically, PrimeC is an investigational extended-release oral therapy that combines the approved agents ciprofloxacin and celecoxib in fixed doses. The combination was developed to simultaneously target several biological pathways implicated in ALS progression, including neuroinflammation, oxidative stress, abnormal iron metabolism, and dysregulated RNA biology.

In a statement accompanying the announcement, Merit Cudkowicz, MD, MSc, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, said the TDP-43 findings provide evidence that PrimeC may be engaging a pathological process central to ALS biology. She noted that, when considered alongside the previously reported clinical and biomarker data, the findings support advancement into a confirmatory phase 3 study.¹

The FDA has already cleared NeuroSense to initiate the global phase 3 PARAGON trial, which is expected to enroll approximately 300 participants, primarily in the United States. According to the company, preparations for the study are ongoing while regulatory discussions continue in additionaljurisdictions.

Although the biomarker findings are encouraging, several questions remain. Whether reductions in neuron-derived TDP-43 consistently translate into durable clinical benefit has yet to be established, and confirmation in a larger phase 3 study will be necessary before determining the therapy's role in ALS treatment. As with many biomarker-driven studies, validation of surrogate markers alongside meaningful functional outcomes will remain an important consideration as PrimeC advances through clinical development.²

REFERENCES
1. NeuroSense Achieves Primary Endpoint in Phase 2b ALS Study with Statistically Significant Reduction of TDP-43, the Defining Pathological Hallmark of ALS. NeuroSense Therapeutics. News release. June 29, 2026. Accessed: July 1, 2026.
2. Neumann M, Sampathu D, Kwong, L, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and ALS. Science.2006;314:130-133. Doi: 10.1126/science.113410