European Medicines Agency approval of Ocaliva® (obeticholic acid) for the treatment of primary biliary cholangitis

European Medicines Agency approval of Ocaliva® (obeticholic acid) for the treatment of primary biliary cholangitis

About the European Medicines Agency (EMA) approval
The EMA has approved obeticholic acid (OCA) for the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.

OCA is the first new treatment to be available to European patients with PBC in nearly 20 years.

About Ocaliva
Ocaliva (obeticholic acid, OCA) is a farnesoid X receptor (FXR) agonist. FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. OCA increases bile flow from the liver and suppresses bile acid production in the liver, thus reducing the exposure of the liver to toxic levels of bile acids.

For more information about Ocaliva, please see the summary of product characteristics (SmPC) attached.

The data supporting the EMA approval
The submission to the EMA for OCA was based on data from the POISE phase 3 pivotal trial, which assessed the safety and efficacy of OCA in 216 patients with PBC who had an inadequate therapeutic response to, or were unable to tolerate, UDCA:

The primary endpoint in POISE was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level.[1]

OCA met the primary composite endpoint in 46% of patients in the 5-10 mg titration treatment arm and in 47% of patients in the 10 mg treatment arm, compared to 10% among those who received placebo.¹

In addition to POISE, OCA has been studied in two phase 2 trials and three open-label, long-term safety extension studies for the phase 2 and 3 studies. All studies met their primary endpoint, demonstrating a significant reduction in ALP levels compared to placebo.

Availability of OCA in Sweden
Following the EMA approval, OCA will be reviewed by the Health Technology Assessment body in each country.

About PBC
Primary biliary cholangitis (PBC) is a chronic, progressive, autoimmune disease that puts patients at risk of liver failure or premature death.

PBC is characterized by progressive autoimmune destruction of the bile ducts in the liver, leading to cholestasis and inflammation.[2] Inadequately controlled PBC can lead to the possibility of a liver transplant and shortened life expectancy.[3]

PBC primarily affects women, afflicting approximately one in 1,000 women over the age of 40.¹ If left untreated, survival of PBC patients is significantly worse than the general population.

The unmet need in PBC
There has been a significant unmet need for new treatments for PBC, with the standard of care UDCA, being the only approved medication for patients in Europe for nearly 20 years.[4] Research indicates that 40% of patients receiving UDCA have an inadequate response to the treatment, which could lead to an increased risk of liver failure, the need for a liver transplant and death.[5]

Safety information:

EU IMPORTANT SAFETY INFORMATION
Contraindications
Hypersensitivity to the active substance or to any of the excipients and complete biliary obstruction.

Warnings and Precautions
Elevations in alanine amino transferase (ALT) and aspartate aminotransferase (AST) have been observed in patients taking obeticholic acid. Clinical signs and symptoms of hepatic decompensation have also been observed. These events have occurred as early as within the first month of treatment. Liver-related adverse events have primarily been observed at doses higher than the maximum recommended dose of 10 mg once daily. Patients should be monitored during treatment with Ocaliva for elevations in liver biochemical tests and for the development of liver-related adverse events. Dosage adjustments are needed for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

Severe pruritus was reported in 23% of patients treated with Ocaliva 10 mg arm, 19% of patients in the Ocaliva titration arm and 7% of patients in the placebo arms. The median time to onset of severe pruritus was 11, 158 and 75 days for patients in the Ocaliva 10 mg, Ocaliva titration and placebo arms, respectively. Management strategies include the addition of bile acid binding resins or antihistamines, dose reduction, reduced dosing frequency and/or temporary dose interruption.

Adverse Reactions
The most commonly reported adverse reactions were pruritus (63%) and fatigue (22%). Other common adverse reactions observed in clinical trials (> 5%) were abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality and eczema.

Drug Interaction
Bile acid binding resins such as cholestyramine, colestipol or colesevelam adsorb and reduce bile acid absorption and may reduce efficacy of obeticholic acid. When concomitant bile acid binding resins are administered, obeticholic acid should be taken at least 4-6 hours before or 4-6 hours after taking a bile acid binding resin, or at as great an interval as possible.

For detailed safety information for Ocaliva (obeticholic acid) 5 mg and 10 mg tablets including posology and method of administration, special warnings, drug interactions and adverse drug reactions, please see the European Summary of Product Characteristics that can be found on www.ema.europa.eu once posted.

[1] Nevens, F. et al. (2016). A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. New England Journal of Medicine, 375(7), pp. 631-687.

[2] Poupon R. (2010). Primary biliary cirrhosis: a 2010 update. [online] Journal of Hepatology,52, pp. 745–58

[3] Kuiper, E. et al. (2010). Relatively high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not responding to ursodeoxycholic acid. [online] European Journal of Gastroenterology and & Hepatology, 12, pp. 1495-1502. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21389798. [Accessed June 2016].

[4] Corpechot, C. et al. (2000). The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology, 32, pp. 1196–1199.

[5] Hirschfield et al. (2015). Efficacy of obethicholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology, 148 (4), pp. 751-761. Available at: http://www.gastrojournal.org/article/S0016-5085(14)01530-3/abstract [Accessed October 2016]

EU-NP-PB-0077