Drug Slows Progression of Primary Sclerosing Cholangitis

Medscape

12-05-2025

AMSTERDAM — Norucholic acid (NCA), an investigational therapy, demonstrated significant superiority over placebo in halting disease progression in patients with primary sclerosing cholangitis (PSC), meeting the primary efficacy endpoint in a phase 3 trial presented on May 10 at the European Association for the Study of the Liver (EASL) Congress 2025.
NCA was four times more effective in partially normalizing the liver enzyme alkaline phosphatase (ALP) (odds ratio [OR], 4.16), without worsening of the histologic Ludwig stage of PSC. Results held true with and without concomitant ursodeoxycholic acid (UDCA).
Michael Trauner, MD
The interim 96-week efficacy and safety results were presented by Michael Trauner, MD, professor of gastroenterology and hepatology at the Medical University of Vienna, Austria, who first developed the compound two decades ago.
'In this study, NCA hit the primary and key secondary endpoint in this clinical trial that included liver histology and biochemical features,' said Trauner. 'There were higher response rates for NCA than placebo both with and without concomitant UDCA, as well as improvement and less worsening of histological disease stages with NCA compared with placebo.'
First Data to Offer Hope for Reducing PSC Progression
PSC is a rare, progressive cholangiopathy characterized by inflammation and fibrosis of the bile ducts, with no current medical therapy proven to alter its course. NCA works by inducing bicarbonate-rich hypercholeresis and promoting cholangiocyte protection, with additional anti-inflammatory and immunomodulatory effects.
The multicenter, international, randomized, placebo-controlled, double-blind phase 3 study builds on earlier phase 2 findings in which NCA improved cholestasis markers in a dose-dependent manner and was well tolerated.
Patients (n = 301) were randomized in a 2:1 ratio to receive either NCA 1500 mg once daily (n = 205) or placebo (n = 96), stratified by concomitant UDCA use. Biopsies were done 4-8 weeks prior to randomization and again at week 96 and will be repeated at week 192. The study remains ongoing, with 2 additional years of blinded treatment planned.
The combined primary endpoint was defined as partial normalization of ALP to less than 1.5 times the upper limit of normal and no worsening of Ludwig histologic stage. Secondary endpoints included modified Nakanuma staging, liver stiffness measurement (FibroScan), enhanced liver fibrosis and Amsterdam-Oxford scores, patient-reported pruritus and fatigue, and overall quality of life.
'The population was typical of PSC, with men in their 40s making up 74% of participants, and around 70% had inflammatory bowel disease,' reported Trauner. Baseline ALP was approximately 300 U/L, and liver stiffness and enhanced liver fibrosis scores were around 10. Most patients presented with Ludwig stage 2 or 3 disease.
Statistically Significant Benefit Compared With Placebo
By week 96, 27.3% of patients in the NCA group and 37.5% in the placebo group had discontinued the trial. In the intention-to-treat analysis, the combined primary endpoint was achieved by 15.1% of patients in the NCA group vs 4.2% in the placebo group, a difference of 10.96% (95% CI, 4.6%-17.3%) and an OR of 4.16 (95% CI, 1.42-12.22; P = .0048). Patients without a second biopsy were considered nonresponders.
In the per-protocol analysis, which included only participants who completed both biopsies, the benefit remained significant: 18.2% for NCA vs 6.6% for placebo, with a difference of 11.7% (95% CI, 3.0%-20.3%) and an OR of 3.36 (95% CI, 1.12-10.11; P = .0155).
The key secondary endpoint of ALP less than 1.5 times the upper limit of normal and no worsening according to modified Nakanuma staging was also met. NCA again outperformed placebo: 15.1% vs 5.2%, a difference of 9.9% (95% CI, 3.3%-16.5%).
Consistent Efficacy, With or Without UDCA
Trauner noted that NCA demonstrated greater efficacy than placebo in both subgroups, with and without concomitant UDCA. The treatment difference with UDCA was 7.5% (95% CI, 0.4%-14.7%), whereas without UDCA, the difference increased to 23.4% (95% CI, 11.3%-35.5%).
'Those not receiving UDCA had a much higher response rate at 23% with NCA,' he said.
Histologic and Biochemical Improvements; Safety Good
Histologic improvement by at least one Ludwig stage occurred in 25.2% of patients in the NCA group compared with 10.5% in the placebo group ( P = .0217). Notably, progression to cirrhosis (Ludwig stage 4) occurred less frequently in the NCA group (5.9% vs 10.7%).
Significant improvements were also seen in liver enzymes, including ALP, alanine aminotransferase, and gamma-glutamyltransferase, with greater reductions in the NCA group at week 96. The Amsterdam-Oxford prognostic score increased significantly more in the placebo group, indicating greater disease progression.
NCA was generally well tolerated, with a safety profile comparable to that of placebo. Treatment-emergent adverse events occurred in 97.6% of the NCA group and 92.7% of the placebo group. The most common adverse events included diarrhea, SARS-CoV-2 infection, and nasopharyngitis.
Expert: 'Desperate Need for Treatment'
Ahmed Elsharkawy, MD, consultant hepatologist at University Hospitals Birmingham NHS Foundation Trust, United Kingdom, who co-moderated the session, underscored the importance of these findings.
'There is a desperate need for patients with PSC to have access to treatments that slow down the progression of their condition, as we currently do not have any available drugs to treat them,' he explained.
Reflecting on the study's impact, he added, 'This study provides the first-ever data that offers some hope that norucholic acid can help reduce progression of the disease for some but unfortunately not yet all patients with the condition. This is hopefully the first step towards developing a cure for this devastating condition that disproportionately affects young individuals.'