Late-Breaking Phase 2b PARADIGM Data Support Continued Development of PrimeC in ALS

Alon Ben-Noon, MBA

(Credit: NeuroSense Therapeutics)

NeuroSense Therapeutics presented late breaking data from its phase 2b PARADIGM trial (NCT05357950) of PrimeC, the company's investigational oral combination therapy for amyotrophic lateral sclerosis (ALS), at the 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5–9 in San Diego, California. The results demonstrated a significant effect of PrimeC on miRNA expression and iron regulation in patients with ALS, providing a solid foundation for the company to progress the therapy to a phase 3 trial.^1,2

Among 68 patients with ALS randomized 2:1 to receive PrimeC or placebo, findings revealed that PrimeC led to differential expression of over 100 miRNAs, including downregulation of hsa-miR-199a-5p, at 6 months of treatment. Notably, researchers reported differential expressions in the placebo group, which had weaker and spanned much fewer miRNAs. Additionally, investigators noted that PrimeC treatment affected miRNA maturation, changing the mature/hairpin ratio, and downregulated miRNAs that targeted the RISC complex.

"We are excited by these results from the PARADIGM trial, which provide further compelling support of PrimeC's potential to modify disease progression in people living with ALS," Alon Ben-Noon, MBA, CEO at NeuroSense Therapeutics, said in a statement.¹ "The ability of PrimeC to affect miRNA expression and the underlying disease pathways not only validates our approach but positions PrimeC as a promising therapeutic candidate for ALS."

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Presented by author Jeffrey Rosenfeld, MD, PhD, professor of neurology and associate chairman of neurology at Loma Linda University School of Medicine, the phase 2b PARADIGM trial assessed the safety, tolerability, and efficacy of PrimeC in patients with ALS for a 6-month double-blind phase, followed by a 12-month open-label extension. In the study, researchers had secondary analyses centered on iron metabolism and miRNA gene expression. Investigators evaluated blood samples at multiple time points for miRNA expression changes alongside iron-related biomarkers. Researchers also performed global profiling of miRNAs on plasma samples to identify differentially expressed miRNAs associated with ALS progression.

All told, ferritin change at 18 months was significantly different between the two groups in favor of treatment with PrimeC. The agent also showed trends toward beneficially increasing transferrin levels compared with the placebo-toPrimeC arm. Furthermore, significant correlations on the ALS Functional Rating Scale (ALSFRS) occurred for the placebo/placebo-to-PrimeC arm during the study and seized at 18 months, which suggest target engagement. Researchers also reported that PrimeC showed favorable safety and tolerability, slowing disease progression measured using the ALSFRS-R by 32.8% (P = .007) and functional decline across ALSFRS-R sub-domains, especially for speaking and swallowing. Moreover, the investigational agent demonstrated potentially better survival by 58% (P = .11).

"What stood out to us was the consistent modulation of key miRNAs closely associated with ALS biology," senior author Noam Shomron, PhD, MSc, professor at Tel Aviv University's Faculty of Medical and Health Sciences said in a statement.¹ "Observing these changes as part of a rigorous and well-controlled analysis was particularly compelling. It speaks to the potential of PrimeC to directly influence key molecular mechanisms in ALS, in a manner that is both data-driven and unbiased."

REFERENCES
1. NeuroSense Therapeutics Announces Transformative Phase 2b MicroRNA Data, Highlighting PrimeC's Promise as a Disease-Modifying ALS Treatment. News Release. NeuroSense Therapeutics. Published April 9, 2025. Accessed July 11, 2025. https://www.neurosense-tx.com/from_the_media/neurosense-therapeutics-announces-transformative-phase-2b-microrna-data-highlighting-primecs-promise-as-a-disease-modifying-als-treatment/
2. Shapira G, Cudkowicz M, Drory V, et al. MicroRNA Profiling and Iron-Related Modulation as Key Markers for Target Engagement in ALS Treatment with PrimeC. Presented at: 2025 AAN Annual Meeting; April 5-9; San Diego, CA. Late Breaking Session.