Summary Background Seladelpar is a potent and selective peroxisome proliferator‐activated receptor‐δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‐cholestatic, anti‐inflammatory and anti‐pruritic effects. Aims To evaluate the long‐term safety and efficacy of seladelpar in patients with PBC. Methods In an open‐label, international, long‐term extension study, patients with PBC completing seladelpar lead‐in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‐alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. Results There were no serious treatment‐related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. Conclusions Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‐003910‐16.
Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease that causes progressive hepatic fibrosis, often leading to liver failure. The severity of PBC is typically determined by grading the extent of fibrosis in a liver biopsy using a 4-point histological scale: 0 = no fibrosis, 1 = non-bridging fibrosis, 2 = bridging fibrosis, and 3 = cirrhosis. However, liver biopsy is prone to sampling error, and it is sometimes a painful and dangerous procedure. The utility of serial liver biopsies to detect disease progression has not been studied, but it is a critical issue for clinical investigators and physicians.
Null Hypothesis
The average change of fibrosis in serial liver biopsies in patients with PBC is not a reliable indicator of clinical progression.
Methods
Serial liver biopsies were collected every 2 years on 265 subjects with PBC as part of a multicenter double-blind randomized controlled study, which demonstrated that methotrexate, when added to ursodiol treatment, had no effect on PBC. Mean follow-up was 7.4 years, and 935 samples were collected. Four pathologists, who were blinded to the sample order, graded each biopsy. A mean fibrosis score was calculated for each biopsy. Clinical decompensation was defined as development of one or more of the following: varices, ascites, encephalopathy, variceal bleed, liver transplant or liver death. The rate of change of fibrosis over time was compared between the patients who experienced clinical decompensation (n = 83) and those who did not (n = 162) using the Wilcoxon rank sum test.
Results
Fibrosis increased an average of 0.05 stages per year in the group who developed clinical decompensation and decreased 0.01 stages per year in the group who did not. This difference was statistically significant (p<.01). However, a cumulative proportions analysis revealed that fibrosis changed no more than 0.25 stages per year in 86% of individuals with clinical events and in 92% without events.
Conclusion
In a large group of PBC patients, serial liver biopsies can detect a statistical difference in the change of fibrosis between patients who develop clinical decompensation versus patients who do not. However, the average rate of change in fibrosis associated with clinical decompensation is too small to be appreciated in an individual patient. Thus serial liver biopsies are not useful clinical tools to assess disease progression in individuals with PBC taking ursodiol.
Pairs of morphological mutants, of which six were obtained from single basidiospores of one homothallic wild stock, were found to anastomose readily and to form heterokaryons.
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator–activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.
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