Clinical Trials

Date: 2017-04-19

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European Association for the Study of the Liver (EASL)

Company: Intercept Pharmaceuticals (USA - NY)

Product: Ocaliva® (obeticholic acid - OCA)

Action mechanism:

• farnesoid X receptor agonist. Obeticholic acid (OCA) is a bile acid analog and first-in-class agonist of the farnesoid X receptor (FXR) in development for PBC, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC) and other chronic liver diseases.
• Ocaliva® has been approved on May 27, 2016 in the U.S. The FDA granted accelerated 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. An improvement in survival or disease-related symptoms has not been established.

Disease: primary biliary cirrhosis, primary biliary cholangitis

Therapeutic area: Autoimmune diseases- Liver diseases - Hepatic diseases

Country: Australia, Austria, Belgium, Canada, France, Germany, Italy, The Netherlands, Poland, Spain, Sweden, UK, USA

Trial details:

• 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, completed in March 2014, was 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 one of three groups in the trial: placebo, 10 mg OCA, or 5 mg OCA for six months titrated to 10 mg OCA based on clinical response; 216 patients were dosed. Patients completing the double-blind phase had the option to continue in an open-label, long-term safety extension (LTSE) phase for another five 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. (NCT01473524)

Latest news:

• • On April 19, 2017, Intercept Pharmaceuticals announced the presentation of multiple obeticholic acid abstracts at the International Liver Congress 2017, the 52nd Annual Meeting of the European Association for the Study of the Liver (EASL), in Amsterdam, the Netherlands, from April 19-23, 2017. "Effect of obeticholic acid treatment in patients with primary biliary cholangitis on categorical shifts in GLOBE score" (Abstract LBP-527).
• • On November 11, 2016, Intercept Pharmaceuticals announced results from three new exploratory analyses of the Phase 3 POISE trial of Ocaliva® (obeticholic acid) in patients with primary biliary cholangitis. The analyses will be presented at the American Academy for the Study of Liver Diseases (AASLD) Annual Meeting (The Liver Meeting®), taking place in Boston, MA from November 11-15. The POISE trial evaluated the safety and efficacy of once-daily treatment with Ocaliva® in primary biliary cholangitis patients with an inadequate therapeutic response to, or who are unable to tolerate, ursodeoxycholic acid (UDCA). Of 216 patients randomized to three treatment arms—placebo, Ocaliva® 5 mg titrated to 10 mg or Ocaliva 10 mg—93% continued receiving UDCA. The first POISE presentation (abstract #209) evaluated the effects of Ocaliva® on non-invasive assessments of liver fibrosis using both transient elastography (Fibroscan™) and the AST to Platelet Ratio (APRI). These tests have been shown to be effective in predicting clinical outcomes in primary biliary cholangitis, and Ocaliva®-treated patients experienced improvements in both compared with those receiving placebo. In patients with transient elastography assessments at baseline and month 12 (approximately 43% of the study population), only Ocaliva®-treated patients experienced a reduction in liver stiffness below 16.9 kPa, a threshold associated with the presence of cirrhosis. Mean liver stiffness reduction was observed in the 10 mg Ocaliva® group compared to placebo. In patients with a baseline APRI score above 0.54 (a threshold associated with increased risk of adverse clinical outcomes in primary biliary cholangitis patients), 35% of Ocaliva®treated patients compared to 13% of placebo-treated patients experienced an improvement to below 0.54 at the end of the 12 month double-blind phase.
• The second POISE presentation (abstract #366) evaluated the efficacy and safety of Ocaliva® in the subset (17%) of patients with cirrhosis who were at the greatest risk of progression to liver-related adverse outcomes or death. At month 12, more Ocaliva®-treated patients with cirrhosis achieved the primary composite study endpoint compared to placebo. Ocaliva® treatment improved markers of both cholestasis (alkaline phosphatase) and hepatic impairment (bilirubin) relative to placebo in patients with cirrhosis. Consistent with previous study results, pruritus (itch) was the most common adverse event associated with Ocaliva® treatment. Additional side effects observed during the trial included fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.
• The third POISE presentation (abstract #401) examined the effects of Ocaliva® in primary biliary cholangitis patients with mild and moderate renal impairment. In this exploratory analysis, Ocaliva demonstrated comparable efficacy regardless of renal status and enabled patients with renal impairment to achieve significant improvements in markers of cholestasis and hepatic damage. Ocaliva® had no apparent effect on renal safety, with mild to moderate pruritus the most commonly occurring adverse event in all renal function groups.
• • On August 17, 2016, Intercept Pharmaceuticals announced that the New England Journal of Medicine published the key results of the Phase 3 POISE trial of Ocaliva® (obeticholic acid) for the treatment of patients with primary biliary cholangitis, formerly known as primary biliary cirrhosis. On a background of standard of care or given as monotherapy, Ocaliva® met the primary endpoint of the POISE trial and improved multiple biochemical disease markers as compared to placebo with high statistical significance. The POISE trial evaluated the safety and efficacy of once-daily treatment with Ocaliva® in primary biliary cirrhosis patients with an inadequate therapeutic response to, or who are unable to tolerate, ursodeoxycholic acid. The trial's primary endpoint was a reduction in alkaline phosphatase to below a threshold of 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a total bilirubin level at or below the upper limit of the normal range after 12 months of Ocaliva® therapy. These liver biomarkers have been shown to be reasonably likely to predict progression to liver failure and resulting liver transplant or premature death in patients with PBC. Ocaliva® 5-10 mg (46%) and Ocaliva® 10 mg (47%) were both statistically superior to placebo (10%) in achieving the primary endpoint (p<0.001). Most Ocaliva®-treated patients had liver biochemical improvements even if they did not achieve the composite primary endpoint, with a significantly higher percent of patients achieving ?15% ALP reduction with Ocaliva 5-10 mg and Ocaliva® 10 mg (both groups 77%) compared to placebo (29%) (p<0.001). The majority of patients (93%) continued receiving ursodeoxycholic acid therapy during the trial. Efficacy: In addition to the primary composite endpoint, the POISE study evaluated the effect of Ocaliva® on biochemical disease markers of PBC using descriptive statistics with nominal p-values. ALP improved in both Ocaliva® groups versus placebo at all visits (p<0.001), with reductions from baseline of -113±14 U/L in the Ocaliva® 5-10 mg group and -130±15 U/L in the Ocaliva® 10 mg group, compared to -14±15 U/L for placebo at 12 months. Reductions were observed as early as two weeks and were maintained at each time point thereafter. There was additional benefit observed in patients who titrated from 5 mg to 10 mg, compared to those who remained on a 5 mg dose. An exploratory secondary analysis showed that patients treated with placebo experienced total bilirubin increases over the 12-month study period, while Ocaliva®-treated patients experienced decreases in total bilirubin. While the changes in total bilirubin were within the normal range, the difference between groups was statistically significant (p<0.001). Additional exploratory secondary analyses indicated that other liver enzymes (gamma-glutamyl transferase, alanine transaminase, aspartate transaminase and conjugated bilirubin) all improved from baseline in both Ocaliva® groups (pSafety and Tolerability: Pruritus (itch) is the most common symptom in patients with PBC and was also the most common adverse event in the trial, with a higher incidence reported in the Ocaliva 5-10 mg (56%) and Ocaliva 10 mg (68%) groups, compared to placebo (38%). The implementation of the Ocaliva® 5-10 mg titration strategy decreased the incidence of pruritus and was associated with a lower discontinuation rate due to pruritus (one patient, 1%) compared with starting at a higher dose of 10 mg (seven patients, 10%). Additional side effects observed during the trial included fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema. High density lipoprotein cholesterol, which was elevated at baseline (consistent with PBC-associated hyperlipidemia), decreased within two weeks in Ocaliva-treated patients, but stabilized and remained within the normal range after 12 months. In an exploratory assessment, the rates of bone fracture were similar among the trial groups, but dual energy X-ray absorption indicated a smaller decrease in femoral bone mineral density T-score in both Ocaliva groups versus placebo (p<0.05). Open-Label Extension: The majority (97%) of the patients who completed the double-blind phase of the POISE trial entered an open-label extension (which will continue for five years). Patients who had received Ocaliva® in the double-blind phase experienced sustained improvements in ALP and bilirubin, demonstrating a durable response through two years of treatment. Placebo patients initiating treatment with Ocaliva in the open-label extension demonstrated similar improvements in ALP and bilirubin to the Ocaliva-treated patients in the double-blind phase, including reversal of previous increases in total bilirubin to levels comparable to baseline. The severity and incidence of pruritus were reduced in the open-label extension compared to the double-blind phase in patients originally randomized to Ocaliva. Other adverse events during the open-label extension were observed at comparable rates to the double-blind phase and no new safety findings were observed.
• • On November 14, 2015, Intercept Pharmaceuticals announced results from three studies in primary biliary cirrhosis, recently renamed primary biliary cholangitis, that will be presented at the American Academy for the Study of Liver Diseases (AASLD) Annual Meeting (The Liver Meeting®) in San Francisco, CA from November 14-16 . The studies evaluate investigational use of obeticholic acid (OCA), Intercept's lead farnesoid X receptor (FXR) agonist, for the treatment of PBC, the epidemiology of PBC, and both patient and physician perceptions of PBC care. In an oral presentation, researchers will share results from an analysis of a clinical database of more than 575,000 patients who received an anti-mitochondrial antibody (AMA) test, the principal autoimmune marker used to diagnose PBC in patients with elevated alkaline phosphatase (ALP) levels. Of those patients, 6,107 were classified as having probable PBC based on a positive AMA test and ALP greater than the upper limit of normal at any time prior to AMA testing or up to one month following AMA testing. The study found that the majority (69%) of these likely PBC patients continued to have elevated ALP two years after the first positive AMA test. A Trial-Based Model of Liver Transplant and Liver-Related Death in Patients with Primary Biliary Cirrhosis: In this oral presentation, researchers will discuss an analysis of data from the Phase 3 POISE trial of OCA in PBC using the UK -PBC predictive model of transplant-free survival based on ALP, bilirubin, alanine transaminase (ALT), albumin and platelet count. Risk was assessed at 5, 10 and 15 years based on a 12-month change from baseline in patients treated with OCA ± ursodiol or placebo ± ursodiol at the end of the POISE study. In the analysis, the UK -PBC risk algorithm showed a significantly lower risk of liver transplant or liver-related death in OCA-treated patients compared to placebo ± ursodiol. Physician versus Patient Perceptions of Medical Care Quality in Primary Biliary Cirrhosis: This poster will highlight results from a survey examining perceptions of PBC among gastroenterologists (262), hepatologists (60) and patients (214). Patient and physician responses to questions about PBC-related information, PBC diagnosis and treatment, and patient quality of life were broadly similar. However, only approximately one in three PBC patients surveyed knew their most recent ALP score, despite 64% of physicians stating they rely on ALP to monitor the disease. Additionally, although most physicians reported discussing the relationship between PBC symptoms and disease progression with their patients, just one in three patients surveyed understood that worsening PBC symptoms are not an indication of worsening disease. The researchers concluded that improving communication between physicians and patients could enhance patient care.
• • On November 8, 2014, Intercept Pharmaceuticals announced new analyses of data from clinical trials on obeticholic acid (OCA) in patients with primary biliary cirrhosis (PBC). Six posters, including posters with new analyses of data from POISE are being presented at the poster session at the American Association for the Study of Liver Disease (AASLD) Annual Meeting. In March 2014, Intercept announced that OCA met the primary endpoint of the POISE trial with high statistical significance (p < 0.0001). The posters to be presented at AASLD provide the following information relating to OCA in PBC: Poster 318 provides new subgroup analyses of the treatment effect for OCA across a range of patient characteristics associated with greater risk of adverse clinical outcomes, including age at diagnosis, duration of PBC and baseline alkaline phosphatase (ALP). Poster 295 presents analyses on the effects of OCA treatment versus placebo on markers of cholestasis (ALP, bilirubin) and hepatobiliary damage (GGT, AST, and ALT), as well as markers of inflammation (C-reactive protein or CRP) and apoptosis (cytokeratin-18 or CK-18). Poster 309 presents POISE results in relation to the proportion of patients achieving a response defined by different response criteria, other than the POISE endpoint, such as Paris I, Paris II and Rotterdam. Posters 305 and 310 cover new information relating to the titration arm of POISE, where approximately half the patients in the titration arm had their OCA dose increased from 5 mg to 10 mg after six months of treatment based on clinical response. These posters present new data regarding the potential utility of titration as a dosing strategy in the context of managing pruritus, the primary tolerability issue of OCA treatment, while investigating the effects of titration on the efficacy of OCA treatment. Poster 319 describes the long-term safety and efficacy results from open-label treatment of OCA for over four years as part of the long-term safety extension trial on patients who participated in a Phase 2 PBC trial that evaluated OCA monotherapy.

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