The most recent results from a pivotal phase 3 clinical trial, zaptem, indicate high promise. Norucholic acid (NCA) would be the first medicine to slow the progression of PSC, a rare, chronic liver disease for which no therapies are available. Conducted in more than 70 centers around the world, this randomized, double-blind, placebo-controlled trial originally enrolled 301 patients with PSC. Patients received either NCA, administered at a dose of 1500 mg once daily, or a placebo, with the randomization occurring in a 2:1 ratio. 205 patients received NCA while 96 received placebo.
The trial was designed primarily to assess the efficacy of the drug in histological improvement of liver histology and biochemical picture. The researchers stratified participants according to whether they were UDCA users at baseline. The findings show strong benefit for NCA as part of the treatment approach to this challenging liver disease that most often strikes younger patients.
Study Overview and Results
The clinical trial included patients with a baseline ALP level of ~300 U/L. It further assessed liver stiffness and fibrosis scores, which ranged in mean values ~10. The majority of participants enrolled at baseline were at Ludwig stage 2 or 3 disease, showing that most participants had established advanced liver destruction.
Interestingly, in the study, 25.2% of patients treated with NCA had histologic improvement of at least one Ludwig stage. Only 10.5% of patients in the placebo group reached comparable outcomes, resulting in a finding statistically significant for superiority (P = .0217). The NCA treatment group reached the combined primary endpoint through 15.1 percent of patients. In comparison, just 4.2% of patients in the placebo cohort achieved the same composite endpoint (P = .0048).
Created by Michael Trauner, MD two decades ago, NCA. Now a professor at the Medical University of Vienna, he stressed the importance of these findings.
“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.” – Michael Trauner, MD
Efficacy in Subgroups
The NCA had strong efficacy even outside the overall efficacy. It was better than placebo in both patient subgroups – those already receiving UDCA and those not receiving it. Among patients not previously treated with UDCA, the response rate increased to 23% with treatment with NCA.
Patients receiving NCA had a significantly lower progression to cirrhosis (Ludwig stage 4). Only 5.9% of these patients progressed compared with 10.7% in the placebo group. This important finding underscores the ability of NCA to significantly change the trajectory of this complex and rapidly progressive disease for the better.
“In this study, NCA hit the primary and key secondary endpoint in this clinical trial that included liver histology and biochemical features.” – Michael Trauner, MD
While these results are very promising, safety is always the first priority, especially with an AV. Overall, 97.6% of patients in the NCA group had treatment-emergent adverse events. In contrast, just 92.7% of patients in the placebo group experienced these events. By week 96, 27.3% of participants who had received NCA were no longer participating in the trial. By contrast, only 37.5% of participants with placebo discontinued their participation.
Safety and Tolerability
Dr. Ahmed Elsharkawy, who is involved in PSC research, underscored the urgency for effective treatments:
While the study shows that NCA is not a cure for PSC just yet. It stands as a landmark move toward more effective treatment alternatives for these patients.
“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.” – Ahmed Elsharkawy, MD
The study’s findings indicate that while NCA is not yet a cure, it presents a significant advancement in treatment options for PSC patients.
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