Examining PrimeC's target-engagement in miRNA expression and iron dysregulation, crucial mechanisms underlying ALS pathophysiology.

PrimeC, an innovative oral combination therapy targeting ALS-associated pathomechanisms, is designed to modulate neuroinflammation, iron accumulation, and microRNA dysregulation. The Phase 2b PARADIGM trial evaluated safety, tolerability, and efficacy of PrimeC in people living with ALS (PwALS). Secondary analyses focused on iron metabolism and miRNA gene expression.

68 PwALS were randomized 2:1 to receive PrimeC or placebo for a 6-month double-blind phase, followed by a 12-month open-label extension. Blood samples were analyzed at multiple timepoints throughout the study for miRNA expression changes alongside iron-related biomarkers (ferritin, transferrin, and iron). Global profiling of miRNAs was performed on plasma samples, focusing on identifying differentially expressed miRNAs associated with ALS progression.

At 6 months, PrimeC treatment led to differential expression of over 100 miRNAs, including downregulation of hsa-miR-199a-5p, a known ALS-progression biomarker. Conversely, differential expression observed in the placebo group was weaker and spanned much fewer miRNAs. PrimeC treatment affected miRNA maturation, shifting the mature/hairpin ratio, and downregulated miRNAs targeting the RISC complex (e.g., hsa-miR-877-5p).

At 18 months, ferritin change from baseline showed a significant difference in favor of PrimeC treatment. PrimeC demonstrated trends toward beneficially increasing transferrin levels compared to the placebo-to-PrimeC arm. Significant correlations to ALSFRS-R occurred for the placebo/placebo-to-PrimeC arm throughout the study, seizing at 18 month- suggesting target engagement.

PrimeC showed favorable safety and tolerability, slowing disease progression (ALSFRS-R) by 32.8% (p=0.007) and functional decline across ALSFRS-R sub-domains, especially speaking and swallowing. PrimeC also demonstrated potentially better survival by 58% (p=0.11).

These findings demonstrate a significant effect of PrimeC on miRNA expression and iron regulation, highlighting the utility of our multimodal approach in disentangling treatment responses in ALS. These positive clinical and biomarker outcomes provide a solid foundation to progress to a Phase 3 trial.