Primary Biliary Cirrhosis

Primary Biliary Cirrhosis

PBC is a rare liver disease that primarily results from autoimmune destruction of the bile ducts that transport bile acids out of the liver, resulting in cholestasis. As the disease progresses, persistent toxic build-up of bile acids causes progressive liver damage marked by chronic inflammation and fibrosis. In response to the bile acid–mediated toxicity seen in PBC, liver cells release alkaline phosphatase, or ALP, a liver enzyme that is a key biomarker of the disease pathology. Elevated blood levels of ALP are used as the primary means of diagnosis of PBC and are closely monitored in patients as the most important indicator of treatment response and prognosis.

While PBC is rare, it is the most common cholestatic liver disease. An estimated 90% of patients are women, with approximately 1 in 1,000 women over the age of 40 afflicted by the disease. The mean age of diagnosis is about 40 years and the typical initial presentation occurs between the ages of 30 and 65 years. In the United States, the disease is the fifth most common cause of liver transplant and accounts for approximately 2 percent of deaths attributed to cirrhosis. A majority of PBC patients are asymptomatic at the time of initial diagnosis, but most develop symptoms over time. Fatigue and pruritus, or itching, are by far the most common symptoms in PBC patients. Less common symptoms include dry eyes and mouth, as well as jaundice, which can be seen in more advanced disease. Based on the guidelines of the American Association for the Study of Liver Disease, or AASLD, and the European Association for the Study of the Liver, or EASL, the clinical diagnosis of PBC is established based on the presence of (i) a positive anti-mitochondrial antibody, or AMA, a marker of this autoimmune disease seen in up to 95% of PBC patients, and (ii) elevated serum levels of ALP. In the earlier stages of PBC, ALP is often the only abnormally elevated liver enzyme, rising to between 2 to 10 times higher than normal values. Bilirubin is a marker of liver function and is also monitored in PBC to provide an indication of how well the liver is functioning. Liver biopsy can be used to confirm the diagnosis of PBC, but is not required and is becoming less frequently performed.

Disease progression in PBC varies significantly but usually is relatively slow, with median survival in untreated patients of 7.5 years if symptomatic at diagnosis and up to 16 years if asymptomatic at diagnosis. PBC patients whose disease is progressing have persistently elevated levels of ALP and other liver enzymes, with abnormal bilirubin levels heralding more advanced disease. Data from published long-term studies demonstrate that a significant portion of such patients with advancing disease progress to liver failure, transplant or death within 5 to 10 years, despite receiving ursodiol, the standard-of-care therapy.

Our Solution: OCA for PBC


Our lead product candidate, OCA, is a bile acid analog and first-in-class FXR agonist derived from the primary human bile acid chenodeoxycholic acid, or CDCA. CDCA, a natural FXR agonist, has historically been used safely as a chronic therapy for cholesterol gallstone disease. We are initially developing OCA for the second-line treatment of PBC for patients with an inadequate therapeutic response to ursodiol or who are unable to tolerate ursodiol. OCA has received orphan drug designation in the United States and Europe for the treatment of PBC and a related disease called primary sclerosing cholangitis, or PSC.

We have completed 2 randomized, placebo-controlled Phase 2 trials of OCA in PBC patients, 1 with OCA in combination with ursodiol and 1 with OCA as monotherapy. The first trial enrolled 165 patients to evaluate the addition of OCA to ursodiol in patients with an inadequate response to ursodiol therapy, and the second trial enrolled 59 patients to evaluate OCA given as monotherapy. Both trials showed that, over a 12-week period, single daily doses of OCA at the lowest dose of 10 mg met the primary and secondary endpoints of those trials, producing statistically significant reductions in levels of ALP of greater than 20% and statistically significant reductions in levels of other important liver enzymes. We consider reductions in ALP levels of greater than 10% to be a clinically meaningful improvement. Further, long-term, open-label extension phases of these trials have demonstrated that the majority of patients taking OCA for at least 12 months, with some on therapy for more than 4 years, maintained a durable treatment response. Pruritus, or itching, a very common symptom in PBC patients, was the most common adverse event reported in our Phase 2 trials, with severity increasing with dose.

Phase 3 PBC Program for OCA

The POISE trial studied the safety and efficacy of a once-daily treatment with OCA in PBC patients with an inadequate therapeutic response to, or who are unable to tolerate, ursodiol. The primary endpoint of the 12-month double-blind portion of the trial is the achievement of both an ALP level < 1.67x ULN with a ≥ 15% reduction from baseline and a normal bilirubin level, as compared to placebo. Patients with ALP and bilirubin levels below these thresholds have been shown in long-term clinical studies to have a significantly lower risk of progressing to liver transplant and death. There were 217 patients randomized to 1 of 3 groups in the trial: placebo, 10 mg OCA, or 5 mg OCA for 6 months, titrated to 10 mg OCA based on clinical response; 216 patients were dosed.

Patients completing the double-blind phase of the POISE trial had the option to continue in an open-label, long-term safety extension (LTSE) phase for another 5 years, during which all patients receive OCA treatment with daily doses starting at 5 mg and potentially titrating up to 25 mg a day, as clinically indicated. Of the 198 patients who completed the double-blind phase, more than 95% continued in the LTSE phase of the trial.

In March 2014, Intercept announced the primary endpoint in POISE was achieved.