In patients with primary sclerosing cholangitis (PSC), treatment with the semi-synthetic bile acid derivative norucholic acid is safe and demonstrates potential in slowing disease progression, according to the week-96 data from the pivotal phase III NUC-5 study.

The combined primary endpoint of partial normalization of alkaline phosphatase (ALP) to below 1.5 times the upper limit of normal (ULN) and no worsening of Ludwig stage occurred in 15.1 percent of norucholic acid-treated patients and in only 4.2 percent of placebo-treated patients at week 96 (odds ratio [OR], 4.16, 95 percent confidence interval [CI], 1.42?12.22; p=0.0048). [EASL 2025, abstract LBO-001]

During a late-breaking oral presentation at EASL 2024, lead researcher Dr Michael Trauner from the Medical University of Vienna in Vienna, Austria, pointed out that they used intention to treat analysis where patients without second biopsy were automatically evaluated as nonresponders.

Consistent results were obtained in the per-protocol analysis (18.2 percent vs 6.6 percent; OR, 3.36, 95 percent CI, 1.12?10.11; p=0.0155) and among patients with no missing values (eg, those who actually had a second liver biopsy) (21.7 percent vs 5.7 percent; OR, 4.88, 95 percent CI, 1.41?16.86; p=0.0123).

Importantly, the beneficial effect of norucholic acid was confirmed by using a second independent histological score, namely the modified Nakanuma staging, Trauner said. The percentage of patients who achieved partial normalization of ALP to <1.5 times ULN and no worsening of modified Nakanuma stage?the key secondary endpoint?was significantly greater in the norucholic acid group than in the placebo group (15.1 percent vs 5.2 percent; OR, 3.31, 95 percent CI, 1.24?8.85; p=0.0086).

In subgroup analysis, the effect of norucholic acid on the combined primary endpoint appeared to be less pronounced among patients who received concomitant ursodeoxycholic acid (UDCA) (12.7 percent vs 5.1 percent; OR, 2.71, 95 percent CI, 0.89?8.23; p=0.0398). Among those who did not receive UDCA, 23.4 percent achieved the primary combined outcome with norucholic acid as opposed to none with placebo (p=0.0267).

Remarkable changes in liver histology

Disease progressed by at least 1 Ludwig stage in half as many patients on nurocholic acid vs placebo (20.3 percent vs 40.4 percent; p=0.0069). Conversely, 25.2 percent of patients on norucholic acid experienced disease improvement by at least 1 Ludwig stage as compared with 10.5 percent of those on placebo (p=0.0217).

Meanwhile, progression to cirrhosis (Ludwig stage 4) occurred in 5.9 percent of norucholic acid-treated patients and in 10.7 percent of placebo-treated patients, numbers that Trauner deemed as clinically meaningful.

Looking at the subgroup defined by concomitant UDCA use, patients who received norucholic acid without UDCA showed the highest response, with disease improvement occurring in 31 percent and deterioration in 13 percent. Patients receiving UDCA had a slightly lower response to norucholic acid, with disease improvement reported in 23 percent and worsening in 23 percent. Finally, in the placebo group, disease improvement occurred in 12 percent of patients who received UDCA and in 7 percent of those who did not, whereas deterioration was documented in 40 percent of patients in each subgroup.

“The changes in liver histology can best be seen in the Sankey plot showing actually the changes across the different stages,” Trauner said. He focused on patients with stage two and stage three disease and noted that twice as many patients on placebo progressed compared with those on norucholic acid. Looking at improvement, twice as many patients with Ludwig stage 3 disease improved by 1 or even 2 stages in the norucholic acid group than in the placebo group, he added. “Quite a remarkable finding.”

As for other outcomes, norucholic acid produced a rapid and sustained reduction in liver enzymes, including ALP, gamma-GT, and ALT (p<0.0001 for treatment effect). Furthermore, noninvasive fibrosis tests and Amsterdam-Oxford scores showed disease stabilization in patients who received norucholic acid, Trauner said.

Well tolerated

In terms of safety, Trauner noted that norucholic acid was well tolerated and had a similar safety profile as placebo.

The rates of adverse events (AEs) were 97.6 percent in the norucholic acid group and 92.7 percent in the placebo group. The most common AEs were pruritus, nasopharyngitis, diarrhoea, headache, and SARS-CoV-2 infection.

The norucholic acid and placebo groups had similar rates of treatment-emergent AEs related to the study drug (47.1 percent vs 41.7 percent) and serious AEs (39.3 percent vs 35.4 percent). One patient on norucholic acid died during the 96-week study period.

For patient-reported outcomes, no notable between-group differences were seen in fatigue, pruritis, and quality of life.

NUC-5 population

The NUC-5 study enrolled adult patients with cholangiography-verified large duct PSC, who had undergone liver biopsy within 2 months prior to enrolment, and with ALP of >1.5 x ULN. Those who had been receiving a stable dose of UDCA up to 20 mg/kg/d for at least 3 months and those with inflammatory bowel disease were included.

The full analysis set included 301 patients (median age 39 years, 71.4 percent male) who were randomly assigned to receive norucholic acid at 1,500 mg (n=205) or placebo (n=96) once daily for 192 weeks. In the open-label extension, patients in the active treatment group continued to receive treatment while those in the placebo group were given norucholic acid 1,500 once daily for up to 144 weeks.

Baseline characteristics were similar between treatment groups, with slightly more severe disease in the norucholic acid group (Ludwig stage 3-4: 50.5 percent vs 37.9 percent; modified Nakanuma stage 3-4: 72.1 percent vs 55.8 percent; median ALP: 320 vs 290 U/L). Concomitant UDCA use was reported for 78.7 percent of patients.

Encouraging results

Norucholic acid is engineered to be resistant to amidation, allowing it to undergo cholehepatic shunting, according to Trauner. “[The drug] induces bicarbonate-rich hypercholeresis and cholangiocyte protection, as well as potential direct anti-inflammatory and immunomodulatory effects.”

Dr Palak Trivedi from the University of Birminghan in Birmingham, UK, described the 96-week  data from NUC-5 as “encouraging.”

“It’s a positive phase III trial, which we’ve never had before in PSC, and it gives other new medications with similar mechanisms of action in a similar population of people that were recruited to the NUC-5 trial a way forward… I’m not saying every trial in future will require a liver biopsy, but at least this gives us a framework on which to base future trial designs,” Trivedi, who was not involved in the study, said in an interview with the UK Organization PSC Support.

“And lastly, it also gives us insights into how PSC progresses over the course of time and as well as what factors may be associated with attaining disease stability. So, we’re very excited. These are the first preliminary results. It’s very much like a press release for us in the medical community. We await the full news article, which will take time, have much more nuances, [and have] much more answers to some of the questions like quality of life, [among others],” he said.