PrimeC in ALS: PARADIGM Reports Safety, Function, And Biomarkers

Key Takeaways

• During the double-blind phase, overall adverse events were similar between groups, while drug-related events were more common with PrimeC and were usually mild to moderate and transient.
• The month 6 ALSFRS-R comparison favored PrimeC without statistical significance, while month 18 scores remained separated by original assignment after crossover to open-label treatment.
• Earlier PrimeC exposure was associated with fewer ALS-related complications by month 18, and exploratory transferrin and microRNA changes were reported, while the prespecified exosomal biomarker endpoint remains pending.

Participants originally assigned to PrimeC in the PARADIGM trial report had a 7.92-point ALSFRS-R separation from those first assigned to placebo at month 18, after all participants received open-label PrimeC during extension follow-up. Overall adverse event rates were similar during the randomized double-blind phase, although treatment-related events were more frequent with PrimeC. By month 18, comparisons reflected original assignment rather than an ongoing placebo-controlled contrast. The trial was designed primarily to assess safety and tolerability.

PARADIGM was a randomized, double-blind, placebo-controlled phase 2b trial with a 6-month masked period and a 12-month open-label extension. Adults aged 18 to 75 years with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened participants, 69 were randomized and 68 entered the intent-to-treat population, with 45 assigned to PrimeC and 23 to placebo. The study ran at four ALS referral centers in Italy, Canada, and Israel, with background standard care continued and plasma neuron-derived-exosomal TDP-43 or prostaglandin J2 as the prespecified primary biomarker outcome.

Randomization was 2:1 to PrimeC or placebo, and most participants were taking riluzole at baseline while edaravone use was rare. PrimeC was given twice daily at a total daily dose of celecoxib 136 mg and ciprofloxacin 1360 mg. During the double-blind phase, any adverse event occurred in 66.7% of the PrimeC group and 65.2% of the placebo group, while study drug-related adverse events occurred in 20.0% and 4.3%, respectively; these events were mostly mild to moderate and transient, and no treatment-related deaths or life-threatening events were observed. At month 6, the mean ALSFRS-R difference was 2.23 points favoring PrimeC, with a 95% CI of -0.61 to 5.07 and P=.12, leaving the masked comparison consistent with tolerability but not statistically significant for function.

By month 18, after crossover to open-label treatment for all participants, ALSFRS-R scores remained separated by original assignment. The mean difference was 7.92 points favoring those originally assigned to PrimeC, with a 95% CI of 2.25 to 13.60 and P=.007. The largest functional subdomain difference was in bulbar function, with a mean difference of 3.18 points, a 95% CI of 1.32 to 5.04, and P=.001. Continuous treatment was associated with a lower risk of ALS-related complications, including hospitalization, respiratory failure, or death, with HR 0.36, 95% CI 0.15-0.85, and P=.02, although interpretation remained limited by the crossover design.

Exploratory biomarker analyses showed preserved transferrin with PrimeC at month 6, with a between-group difference of 1.90 μmol/L and P=.03. Ferritin increased in the placebo group and remained relatively stable with PrimeC during the double-blind period, and the month 18 mean difference was -0.24 nmol/L with a 95% CI of -0.47 to -0.001 and P=.05. Investigators also reported downregulation of miR-199a-3p, miR-199a-5p, miR-181a-5p, and miR-181b-5p in exploratory analyses, while the prespecified neuron-derived exosome TDP-43/PgJ2 endpoint will be reported separately after assay development and analyses are complete.

The authors noted that the trial was not powered for definitive efficacy or survival conclusions, that secondary and exploratory end points were not adjusted for multiplicity, and that open-label crossover constrained long-term interpretation.