Cambridge, Mass. — NeuroSense Therapeutics Ltd. reported that its Phase 2b PARADIGM study of PrimeC in amyotrophic lateral sclerosis met its primary efficacy endpoint, showing a statistically significant reduction in TDP-43 levels compared with placebo.
The late-stage biotechnology company said the trial was the first randomized, double-blind, placebo-controlled clinical study to demonstrate a treatment-associated reduction of TDP-43 in people with ALS.
TDP-43 pathology is present in more than 97% of ALS cases and is considered a central factor in disease progression. NeuroSense said the reduction provides evidence that PrimeC is engaging an underlying disease mechanism.
The Phase 2b study evaluated PrimeC’s safety, tolerability, biomarker effects and efficacy in people with ALS. At Day 180, the trial’s prespecified primary endpoint, patients receiving PrimeC showed a statistically significant reduction in TDP-43 compared with placebo, with a p-value of 0.0421.
The effect continued during the full 18-month study. Participants who remained on PrimeC had lower TDP-43 levels than the placebo group at Day 540, with a p-value of less than 0.001.
The analysis used NeuroDex’s ExoSORT procedure, an immunoaffinity-based method that isolates neuron-derived extracellular vesicles. The approach allows researchers to measure neuron-derived TDP-43 and distinguish it from the protein released by non-neuronal cells and peripheral tissues.
NeuroSense said previously reported results from PARADIGM showed a 36.5% slowing of decline on the ALS Functional Rating Scale-Revised at 12 months and a 32.8% slowing at 18 months. The company also reported an approximately 15-month median survival benefit.
PrimeC was generally well tolerated, with no new safety signals observed during as many as 18 months of treatment, according to the company.
“Achieving the primary endpoint of PARADIGM with a statistically significant reduction in TDP-43 marks a defining moment for NeuroSense and for ALS research,” said Alon Ben-Noon, Chief Executive Officer of NeuroSense. “For decades, TDP-43 has been recognized as the pathological signature of ALS, yet demonstrating a treatment-associated reduction in people with ALS has remained elusive. 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. We believe this growing dataset further validates our scientific approach and positions PrimeC as one of the most comprehensively supported therapeutic candidates in ALS today.”
The company said PrimeC demonstrated effects across TDP-43, iron-regulatory mechanisms and ALS-associated microRNA, supporting its potential activity against multiple disease pathways.
“One of the central questions in ALS drug development is whether a therapy is truly affecting the underlying biology of the disease,” said Prof. Merit 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. “The TDP-43 findings reported in PARADIGM are particularly important because they suggest target engagement of a pathological process present in the majority of people with ALS. When viewed together with the previously reported safety, biomarker and clinical outcome data, and the high unmet need, these results provide compelling data supporting advancement into a confirmatory Phase 3 clinical trial.”
“It is remarkable to see that the increase in NDE-associated TDP-43 observed in the placebo group follows the same trajectory as that identified in our longitudinal studies. This effect, together with the positive outcome of PARADIGM, highlights the promise of TDP-43 as a biomarker for monitoring treatment response,” said Erez Eitan, Chief Executive Officer of NeuroDex.
NeuroSense has received clearance from the U.S. Food and Drug Administration to begin its global Phase 3 PARAGON study. The company is preparing the trial while continuing regulatory discussions in several jurisdictions, including Canada.
