Intercept Pharmaceuticals, a subsidiary of Alfasigma S.p.A., announced the publication of results from the COBALT trial in The American Journal of Gastroenterology, demonstrating the long-term benefits of obeticholic acid (OCA) in patients with primary biliary cholangitis (PBC). The study, which included an external control arm, showed a statistically significant and clinically meaningful reduction in death, liver transplant, and hepatic decompensation in OCA-treated patients compared to a matched, non-OCA-treated control group.
The COBALT trial, a phase 3b/4 double-blind randomized controlled trial (RCT), aimed to evaluate the association of OCA with clinical outcomes in a high-risk PBC population. Due to challenges in enrolling and maintaining patients in a placebo-controlled study for a rare disease where the study drug is commercially available, the RCT was terminated early. To address these limitations, the study incorporated a pre-specified external control (EC) group derived from the Komodo Health U.S. claims database.
Key Findings from COBALT + External Control Analysis
The analysis compared outcomes of OCA-treated subjects in the COBALT RCT to a non-OCA-treated EC group, assessing the time to first occurrence of PBC disease progression (hepatic decompensation), liver transplant, or death. The EC group was carefully matched to the OCA-treated patients based on baseline characteristics and disease severity.
Key results included:
- A statistically significant reduction in death, liver transplant, and hepatic decompensation in OCA-treated patients compared to the untreated control group.
- 17 (10.1%) events occurred in the OCA arm, while 35.4 (21.5%) events occurred in the weighted non-OCA-treated arm (HR, 0.39; 95% CI, 0.22–0.69; P=0.0010).
- Patients treated with OCA had an approximately 61% lower relative risk of negative outcomes than the non-treated control patients.
The Role of External Control Arms in Rare Disease Research
Dr. Kris V. Kowdley, Director of Liver Institute Northwest and Professor at Washington State University, emphasized the importance of external control data in confirmatory trials, especially for rare diseases like PBC. He noted that external control studies are beneficial when patient recruitment and retention are challenging and using a placebo group could be considered unethical.
About Primary Biliary Cholangitis
Primary biliary cholangitis (PBC) is a rare, progressive, chronic autoimmune disease affecting the bile ducts in the liver. It is most prevalent in women over 40, affecting approximately 1 in 10,000 individuals. PBC leads to bile acid buildup in the liver, causing inflammation, scarring (fibrosis), and potentially cirrhosis, liver transplant, or death if untreated.
Ocaliva (Obeticholic Acid) and its Safety Profile
Ocaliva (obeticholic acid) is a farnesoid X receptor (FXR) agonist indicated for treating adult patients with PBC, either without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension. It can be used in combination with ursodeoxycholic acid (UDCA) when there is an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.
It is important to note that Ocaliva carries a boxed warning regarding hepatic decompensation and failure in PBC patients with cirrhosis. The drug is contraindicated in patients with decompensated cirrhosis, a prior decompensation event, or compensated cirrhosis with evidence of portal hypertension. Patients should be monitored for progression of PBC and hepatic adverse reactions, and the drug should be permanently discontinued if hepatic decompensation occurs.
Implications for PBC Treatment
The COBALT + EC analysis provides further evidence of the potential long-term clinical benefit of OCA in PBC patients. Sangeeta Sawhney, Senior Vice President, Head of U.S. Research and Development, Intercept, stated that these findings are consistent with other real-world analyses and contribute to the growing body of evidence supporting the impact of OCA on clinical outcomes in PBC.
