Products

Date: 2017-05-25

Type of information: Granting of a Market Authorisation in Canada

Product name: Ocaliva® in combination with ursodeoxycholic (UDCA)

Compound: obeticholic acid in combination with ursodeoxycholic (UDCA)

Therapeutic area: Rare diseases - Liver diseases - Hepatic diseases

Action mechanism:

• farnesoid X receptor agonist. Obeticholic acid (OCA) is a bile acid analog and a first-in-class farnesoid X receptor (FXR) agonist being developed for primary biliary cirrhosis (PBC), NASH and other chronic liver indications.
• Ocaliva®, given orally, binds to the farnesoid X receptor (FXR), a receptor found in the nucleus of cells in the liver and intestine. FXR is a key regulator of bile acid metabolic pathways. Ocaliva 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.
• OCA was also recently granted breakthrough therapy designation by FDA for the treatment of NASH with liver fibrosis.

Company: Intercept Pharmaceuticals (USA - NY)

Disease: primary sclerosing cholangitis/primary biliary cirrhosis

Latest news:

• • On May 25, 2017, Intercept Pharmaceuticals announced that Health Canada has granted a conditional approval for Ocaliva® (obeticholic acid) for the treatment of primary biliary cholangitis (PBC), when used in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. Health Canada has granted a conditional authorization, pending the results of trials to verify its clinical benefit. Intercept is now pursuing reimbursement of Ocaliva® with private insurance carriers and public drug plans across Canada.
• • On March 2, 2017, Intercept Pharmaceuticals announced that the National Institute for Health and Care Excellence (NICE) has approved Ocaliva® (obeticholic acid) for routine use by the National Health Service (NHS) in England, Wales and Northern Ireland. The NHS is expected to make Ocaliva® available to patients with PBC within 90 days of NICE's final appraisal publication and Intercept will work with local reimbursement authorities to help ensure eligible patients obtain access.
• • On December 14, 2016, Intercept Pharmaceuticals announced that the European Commission has granted conditional approval for Ocaliva® (obeticholic acid) for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid in adults with an inadequate response to ursodeoxycholic acid  or as monotherapy in adults unable to tolerate ursodeoxycholic acid . As conditions of the approval, Intercept is required to provide post-approval updates on safety and efficacy analyses for Ocaliva® from the ongoing Phase 4 COBALT outcomes study and a short-term study in patients with hepatic impairment. The marketing authorization was based on efficacy and safety data derived from three randomized double-blind, placebo-controlled clinical trials evaluating the effect of Ocaliva® on alkaline phosphatase (ALP) and bilirubin in patients with PBC. It was also supported by two clinical databases that include more than 10,000 patients from the Global PBC Study Group and UK-PBC Group, both independently confirming that achieving lower ALP and/or bilirubin levels is significantly correlated with increased transplant-free survival. In the Phase 3 POISE study, nearly half of patients (46%) in the titration group treated with Ocaliva® in combination with UDCA achieved the primary endpoint compared to 10% in the control group (placebo added to ursodeoxycholic acid ) (p<0.0001). Additionally, 77% of patients taking Ocaliva in combination with UDCA achieved a reduction of more than 15% in ALP at 12 months, compared to 29% taking ursodeoxycholic acid alone. The most commonly reported adverse reactions were pruritus (63%) and fatigue (22%). Adverse reactions leading to discontinuation were 1% in the Ocaliva titration arm and 11% in the Ocaliva 10 mg arm. The most common adverse reaction leading to discontinuation was pruritus. The majority of pruritus occurred within the first month of treatment and tended to resolve over time with continued dosing.
• • On October 13, 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a conditional marketing authorisation for Ocaliva®, intended for the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis). Ocaliva® will be available as 5 mg and 10 mg tablets. By activating the farnesoid X receptor (FXR), Ocaliva® is expected to reduce the production of bile in the liver, thus reducing the exposure of the liver to toxic levels of bile acids. The benefits with Ocaliva® are its ability to reduce alkaline phosphatase and bilirubin levels in adults with primary biliary cholangitis. This is likely to lead to clinical benefits for the patient such as delayed development of liver fibrosis, cirrhosis liver transplant and death. However, this remains to be formally demonstrated by means of the post-authorisation follow up within this conditional marketing authorisation. The most common side effects are itching and feeling tired which are also common symptoms of the disease. Elevations in alanine amino transferase (ALT) and aspartate aminotransferase (AST) have been observed in patients taking obeticholic acid. Infrequently clinical signs and symptoms of hepatic decompensation have also been observed in clinical studies even though primarily at doses higher than the maximum recommended dose. 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.
• • On May 27, 2016, Intercept Pharmaceuticals announced that the FDA has granted accelerated approval to Ocaliva® (obeticholic acid) for the treatment of primary biliary cholangitis, previously known as primary biliary cirrhosis (PBC), in combination with ursodeoxycholic in adults with an inadequate response to ursodeoxycholic acid  or as monotherapy in adults unable to tolerate ursodeoxycholic acid .  This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
• The  POISE trial studied the safety and efficacy of once-daily treatment with Ocaliva® in PBC patients with an inadequate therapeutic response to, or who are unable to tolerate ursodeoxycholic acid. The POISE data showed that Ocaliva®, at both a 10 mg dose and a 5 mg dose titrated to 10 mg, met the trial's primary endpoint of achieving a reduction in serum ALP to below a threshold of 1.67 times the upper limit of normal, with a minimum of 15% reduction in ALP level from baseline, and a normal bilirubin level after 12 months of therapy. Pruritus was the most frequently reported adverse event associated with Ocaliva® treatment. In a group of patients who initiated Ocaliva® at a 5 mg once-daily dose and titrated up to 10 mg once daily, only one patient (1%) discontinued from the study due to pruritus as compared to seven patients (10%) in the 10 mg dose group and after 12 months of treatment, efficacy was essentially equivalent to those patients who started the study at the 10 mg dose. Based on these results, a 5 mg to 10 mg titration regimen is recommended for Ocaliva® dosing in PBC. Decreases in HDL-C were observed during treatment. Ocaliva® is contraindicated in patients with complete biliary obstruction.
• In two 3-month, placebo-controlled clinical trials a dose-response relationship was observed for the occurrence of liver-related adverse reactions including jaundice, ascites and primary biliary cholangitis flare with dosages of Ocaliva® of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with Ocaliva®.
• In a pooled analysis of three placebo-controlled trials in patients with PBC, the exposure-adjusted incidence rates for all serious and otherwise clinically significant liver-related adverse reactions, and isolated elevations in liver biochemical tests, per 100 patient exposure years (PEY) were: 5.2 in the Ocaliva 10 mg group (highest recommended dosage), 19.8 in the Ocaliva 25 mg group (2.5 times the highest recommended dosage) and 54.5 in the Ocaliva 50 mg group (5 times the highest recommended dosage) compared to 2.4 in the placebo group.
• Monitor patients during treatment with Ocaliva for elevations in liver biochemical tests and for the development of liver-related adverse reactions. Weigh the potential risks against the benefits of continuing treatment with Ocaliva in patients who have experienced clinically significant liver-related adverse reactions. The maximum recommended dosage of Ocaliva is 10 mg once daily. Adjust the dosage for patients with moderate or severe hepatic impairment. The most common adverse reactions from subjects taking Ocaliva (?5%) were pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia thyroid function abnormality and eczema.
• Ocaliva® is expected to be available to PBC patients in the U.S. within 7-10 days and will be distributed through a specialty pharmacy network. Intercept has launched Interconnect™, a comprehensive and personalized patient support services program. Through Interconnect, dedicated Care Coordinators will guide patients through disease education, treatment support and, for eligible patients, financial assistance options, which may include reimbursement support, co-pay assistance or access to Ocaliva® at no cost.
• • On April 7, 2016, Intercept Pharmaceuticals announced that the FDA's Gastrointestinal Drugs Advisory Committee voted 17 to 0 to recommend accelerated approval of Ocaliva™ (obeticholic acid) for the treatment of patients with primary biliary cirrhosis, recently renamed primary biliary cholangitis (PBC). The target date for the FDA to take action under the Prescription Drug User Fee Act (PDUFA) is May 29, 2016.
• • On December 17, 2015 , Intercept Pharmaceuticals announced that the FDA has extended the Prescription Drug User Fee Act (PDUFA) date for its Priority Review of obeticholic acid (OCA) in primary biliary cirrhosis, recently renamed primary biliary cholangitis. In response to an information request from the FDA, additional clinical data analyses have been submitted. To provide time for a full review of the submission, the original PDUFA date of February 29, 2016 has been extended by three months, resulting in a new PDUFA date of May 29, 2016. The FDA has also notified Intercept of a planned advisory committee meeting date of April 7, 2016. Intercept is seeking approval of OCA for the treatment of PBC in combination with ursodeoxycholic acid in adults with an inadequate response to ursodeoxycholic acid or as monotherapy in adults unable to tolerate ursodeoxycholic acid .
• • On August 31, 2015, Intercept Pharmaceuticals announced the FDA has accepted for review the company's New Drug Application and granted Priority Review for obeticholic acid for the treatment of primary biliary cirrhosis. The FDA has set a target date of February 29, 2016 to take action under the Prescription Drug User Fee Act (PDUFA).
• • On June 29, 2015, Intercept Pharmaceuticals announced the achievement of two important regulatory milestones for obeticholic acid in primary biliary cirrhosis : submission of a New Drug Application for accelerated approval to the FDA and acceptance of the Marketing Authorization Application by the European Medicines Agency. Intercept is seeking approval for the treatment of primary biliary cirrhosis in combination with ursodeoxycholic acid in adults with an inadequate response to ursodeoxycholic acid  or as monotherapy in adults unable to tolerate ursodeoxycholic acid .
• The submissions include a total of 1,507 subjects exposed to at least a single dose of obeticholic acid. Of these subjects, 432 were patients with primary biliary cirrhosis, with 290 treated for at least six months and 232 treated for at least one year. The key efficacy and safety data are derived from three randomized double-blind, placebo-controlled clinical trials in patients with primary biliary cirrhosis evaluating the effect of obeticholic acid on ALP and bilirubin. All three trials met their primary endpoints with high statistical significance and improvements were seen in secondary endpoints including markers of liver injury, immunity, inflammation and apoptosis. The treatment was generally well-tolerated, with primarily mild or moderate pruritus being the most common adverse event.
• The regulatory submissions are also supported by two clinical databases that include more than 10,000 patients from the Global PBC Study Group and UK-PBC Group, both independently confirming that achieving lower ALP and/or bilirubin levels is significantly correlated with increased transplant-free survival.
• In December 2014, Intercept initiated its rolling NDA submission for accelerated approval of obeticholic acid in  primary biliary cirrhosis and began a Phase 3b confirmatory clinical outcomes trial in  primary biliary cirrhosis, in accordance with FDA accelerated approval regulations. This trial is anticipated to enroll approximately 350 patients with advanced  primary biliary cirrhosis at 150 centers in more than 20 countries, and is expected to be completed on a post-marketing basis.
• • On December 10-12 2013, the Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending the granting of an orphan designation for obeticholic acid for the treatment of primary sclerosing cholangitis.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2016-05-26

UE authorization: 2016-12-12

Favourable opinion UE: 2016-10-13

Favourable opinion USA:

Orphan status USA: 2008-04-09

Orphan status UE: 2010-07-27

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

• • On February 1, 2018, the FDA has warned that Ocaliva®  has been incorrectly dosed daily instead of weekly in patients with moderate to severe primary biliary cholangitis, increasing the risk of serious liver injury.  To ensure correct dosing and reduce the risk of liver problems, the aagency is clarifying the current recommendations for screening, dosing, monitoring, and managing primary biliary cholangitis patients with moderate to severe liver disease taking Ocaliva®.  A new Boxed Warning will be added to highlight this information in the prescribing information of the drug label. Ocaliva Dosage Regimen by Patient Population

  Staging / Classification	Non-Cirrhotic or Compensated  Child-Pugh Class A	Child-Pugh Class B or C or  Patients with a Prior  Decompensation Eventa
  Starting OCALIVA Dosage for first 3 months	5 mg once daily	5 mg once weekly
  OCALIVA Dosage Titration after first 3 months, for patients who have not achieved an adequate reduction in ALP and/or total bilirubin and who are tolerating OCALIVAb	10 mg once daily	5 mg twice weekly (at least 3 days apart) Titrate to 10 mg twice weekly (at least 3 days apart) based on response and tolerability
  Maximum OCALIVA Dosage	10 mg once daily	10 mg twice weekly (at least 3 days apart)
  a Gastroesophageal variceal bleeding, new or worsening jaundice, spontaneous bacterial peritonitis, etc. b Prior to dosage adjustment, re-calculate the Child-Pugh classification

• • On September 8, 2017, Intercept issued a prescribing information letter warning physicians that liver injury, liver decompensation, liver failure, and death have been reported in primary biliary cholangitis patients with moderate or severe hepatic impairment (Child-Pugh B and C) when Ocaliva® was dosed more frequently than recommended in labeling for such patients. In addition, serious liver adverse events have been reported in patients initiating therapy without cirrhosis or with mild liver impairment. Liverrelated adverse events have occurred both early in treatment and after months of treatment. In clinical trials, a dose-response relationship was observed for the occurrence of liver related adverse reactions with Ocaliva®. Systemic and hepatic concentrations of Ocaliva® increase significantly in patients with moderate to severe hepatic impairment. Consequently, the current US Package Insert recommends a longer dosing interval (i.e., 5 mg once weekly) for patients with moderate to severe hepatic impairment (Child-Pugh B and C).
• • On June 22, 2017, Intercept Pharmaceuticals announced that Ocaliva® (obeticholic acid) has been granted the 2017 Premio Galeno Italia (Prix Galien) Chemical Synthesis Drug Award.  The Scientific Board that awarded the prize stated that Ocaliva is "very innovative both from the point of view of patients and therapeutically" and noted that the mechanism of action is both different and complementary to UDCA, allowing Ocaliva® to more directly, and effectively, modulate the molecular and cellular mechanisms which underlie the disease. The Ocaliva® story began in Italy. Professor Roberto Pellicciari and a team of researchers at the University of Perugia pioneered research in the field of bile acid chemistry in the 1990s, which led to the discovery of obeticholic acid. Professor Pellicciari helped found Intercept in 2002 to advance obeticholic acid and discover other molecules under an ongoing collaboration.

Is general: Yes