Prof Michael TraunerPatients with primary sclerosing cholangitis (PSC) who received norucholic acid (NCA), with or without ursodeoxycholic acid (UDCA) background therapy, were more likely to achieve histological and biochemical improvements than those receiving placebo, according to the subgroup analysis of the NUC-5 trial presented at EASL 2026.
After 96 weeks, a higher proportion of patients treated with NCA than with placebo achieved the combined primary endpoint of no worsening in Ludwig histological disease stage and a reduction in serum alkaline phosphatase (s-ALP) to <1.5x upper limit normal (ULN), irrespective of UDCA background therapy (23.4 percent vs 0 percent; p<0.0001 [without] and 12.7 percent vs 5.1 percent; p=0.076 [with]). [EASL 2026, abstract OS-007]
Prof Michael Trauner from the Medical University of Vienna, Austria, who presented the study, highlighted that patients who did not receive UDCA had a higher response to the combined primary endpoint. However, each patient had to meet both parameters (histology and ALP).
Accordingly, when assessed individually, patients treated with NCA alone showed similar rates of improvement and no worsening in Ludwig histological disease stage (30 percent vs 7 percent and 12 percent vs 40 percent, respectively), as did those treated with NCA and UDCA (23 percent vs 12 percent and 23 percent vs 40 percent, respectively), compared with placebo.
With regard to reductions in ALP to <1.5x ULN, a greater percentage of patients receiving NCA achieved this outcome compared with those receiving placebo, regardless of UDCA background therapy (25.5 percent vs 5.6 percent; p=0.098 [without] and 18.4 percent vs 14.1 percent; p=0.377 [with]). Trauner noted that response rates were markedly higher in patients treated with NCA alone than in those treated with the combined NCA and UDCA regimen.
Additionally, those who achieved a 40-percent reduction in ALP from baseline were higher in the NCA group than the placebo group among UDCA nonusers (31.9 percent vs 0 percent; p<0.0001) and users (14.6 percent vs 11.5 percent; p=0.501).
Taken together, NCA treatment led to a reduction in mean ALP from baseline, both with and without UDCA use. However, the effects were more pronounced with NCA monotherapy, as stated by Trauner.
In terms of safety, adverse events (AEs) rates were comparable between the NCA and placebo groups.
Two fatal AEs occurred in patients treated with NCA plus UDCA; however, none were related to the study drug.
“Co-therapy with NCA plus UDCA was tolerated as well as NCA monotherapy,” Trauner noted.
The study evaluated 301 patients with PSC whose ALP levels were >1.5x ULN. Participants were randomized in a 2:1 ratio to receive either once-daily NCA 1,500 mg (n=47) or a placebo (n=158). They were then stratified according to background UDCA therapy, with a limited dose of ≤20 mg/kg/day, and approximately 80 percent of the patients received UDCA during the trial.
“Overall, this study suggests that NCA stabilizes liver histology, which is the most meaningful clinical surrogate endpoint, primarily in both patients with and without UDCA background therapy,” Trauner concluded.