2025 American Academy of Neurology Abstract Website

Merit Cudkowicz¹, Vivian Drory², Adriano Chio³, Christian Lunetta⁴, Christen Shoesmith⁵, Shiran Zimri⁶, Niva Russek-Blum⁶, Diana Shtossel⁶, Ruben van Eijk⁷, Guy Shapira⁸, Noam Shomron⁸, Ferenc Tracik⁶, Jeffrey Rosenfeld⁹, Jeremy Shefner¹⁰
¹Massachusetts General Hospital, ²Tel Aviv Sourasky Medical Center, ³University of Turin, ⁴Istituti Clinici Scientifici Maugeri IRCCS, ⁵London Health Sciences Centre, ⁶NeuroSense Therapeutics, ⁷Department of Neurology, University Medical Center Utrecht, ⁸Faculty of Medical and Health Science, Tel Aviv University, ⁹Department of Neurology, Loma Linda University School of Medicine, ¹⁰Barrow Neurological Institute

Objective:

Evaluating safety, tolerability, and efficacy of PrimeC in people living with ALS (PwALS) through a randomized, placebo-controlled, double-blind Phase 2b trial (PARADIGM; NCT05357950); a 6-month double-blind phase (DB) followed by a 12-month open-label extension (OLE). Primary outcomes are safety, tolerability and key biomarkers, with ALS-progression and other ALS-related biomarkers as secondary and exploratory measures.

Background:

PrimeC, a combination therapy targeting multiple disease pathways, is designed to slow ALS progression by modulating inflammation, oxidative stress, iron metabolism, and microRNA dysregulation.

Design/Methods:

Sixty-eight PwALS were randomized 2:1 and received PrimeC for 12 months, or placebo for 6-months followed by 6-months of OLE. Secondary outcomes measured ALSFRS-R, SVC, survival, and QoL. microRNAs and iron-related markers were assessed as exploratory outcomes.

Results:

At 12 months, PrimeC treatment attenuated disease progression (ALSFRS-R) by 36% compared to the placebo-to-PrimeC arm (Mean difference=6.561, 95% CI:1.744-11.378, p=0.009). Survival probability was 43% higher in the PrimeC-treated group compared to the placebo-to-PrimeC group, though this difference did not reach statistical significance (95% CI:0.15-2.17, p=0.41). This effect built upon earlier findings from the DB, where PrimeC slowed disease progression by 29% compared to placebo (Mean difference=2.232, 95% CI:-0.606-5.069; p=0.12). Similar trends were observed across secondary clinical outcomes.

PrimeC modified iron metabolism, significantly reducing pathologically elevated ferritin levels (p=0.18), and increasing transferrin levels (p=0.09). The placebo-to-PrimeC arm showed ALSFRS-R correlations with ferritin (p=0.0019) and transferrin (p=0.097), which were abolished in the PrimeC-treated group. Modulation of microRNA metabolism was demonstrated by 24 differentially-expressed microRNAs in the PrimeC-treated arm, including miR-199a, with no changes in the placebo group.

Findings from the 18-month analysis will be presented at the meeting.

Conclusions:

PrimeC demonstrated a statistically significant reduction in ALSFRS-R over 12 months, with a favorable safety and tolerability profile. PrimeC not only slows disease progression and suggests improved survival, but also effectively modulates ALS-related biomarkers, demonstrating strong target-engagement.