D. Shapiro

Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS Obeticholic acid (OCA; INT-747, 6α-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. METHODS We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7α-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. RESULTS When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7α-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. CONCLUSIONS In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592.

Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid

BACKGROUND & AIMS We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. METHODS We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. RESULTS OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline. CONCLUSIONS Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.

Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver condition evolving in a proportion of patients into nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD associated with increased cardiovascular mortality and significant risk of progressive liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma. At present, no specific therapies for NASH exist. In this review, we examine the evidence supporting activation of the farnesoid X receptor (FXR), a nuclear hormone receptor regulated by bile acids (BAs), for the treatment of NASH. We also discuss the potential of the semi-synthetic BA derivative obeticholic acid (OCA), a first-in-class FXR agonist, as a safe and effective drug to address this significant unmet medical need.

A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double‐blind, placebo‐controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double‐blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6‐year open‐label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg −53.9% [−62.5, −29.3], OCA 50 mg −37.2% [−54.8, −24.6]) compared to placebo (−0.8% [−6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open‐label extension treatment. OCA improved many secondary and exploratory endpoints (including γ‐glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. Conclusion: OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long‐term clinical outcomes. Pruritus increased dose‐dependently with OCA treatment. Biochemical improvements were observed through 6 years of open‐label extension treatment. (Hepatology 2018;67:1890‐1902).

Impact of particle size and aerosolization time on the metabolic effect of an inhaled insulin aerosol.

The effects were compared of varying aerosol particle size and aerosolization time within each breath on the metabolic effect elicited by inhalation of a liquid insulin aerosol in comparison with that after subcutaneous injection (s.c.) of regular insulin. In this single-center, open-label euglycemic glucose clamp study, 13 healthy non-smoking subjects received five administrations of insulin in randomized order on separate study days, once by s.c. (0.15 U/kg of regular insulin) and four times by inhalation. Subjects inhaled 1.5 U/kg of liquid insulin aerosol administered by the Aerodose Insulin Inhaler (Aerogen Inc., Mountain View, CA) configured to deliver two aerosol particle sizes--fine [F, 4.4 +/- 0.3 microm (mean +/- SD)] or very fine (VF, 3.5 +/- 0.2 microm)--and two aerosolization times (aerosol released for the first 2 or 4 s after the start of each 5-s inhalation). Glucose infusion rate (GIR) values necessary to keep blood glucose concentrations constant at 5.0 mmol/L were determined over a 6-h period following insulin administration. After inhalation of insulin, the onset of action was substantially more rapid on all four inhalation study days than after s.c. insulin, and the time to maximal action [t(GIRmax) (min)] was reached earlier: F/2 s, 127 +/- 54; F/4 s, 128 +/- 55; VF/2 s, 158 +/- 91; VF/4 s, 132 +/- 72; s.c., 175 +/- 69 (P < 0.0001). The longer aerosolization time (4 vs. 2 s) resulted in higher maximal metabolic action [GIR(max) (mg/kg/min), F/4 s 8.1 +/- 3.6, VF/4 s 8.4 +/- 2.7 vs. F/2 s 6.6 +/- 2.4, VF/2 s 7.2 +/- 2.4 (P = 0.01 for 4 s vs. 2 s, grouped data)], total metabolic activity [area under the curve of GIR 0-6 h (g/kg), F/4 s 1.97 +/- 0.92, VF/4 s 2.14 +/- 0.86 vs. F/2 s 1.56 +/- 0.68, VF/2 s 1.78 +/- 0.60 (P = 0.01)], and relative biopotency [F/4 s 10.6 +/- 4.0%, VF/4 s 11.7% +/- 4.1% vs. F/2 s 8.5 +/- 3.2%, VF/2 s 9.7 +/- 2.4% (P = 0.01)]. None of these summary measures was significantly affected by particle size. No drug- or device-related adverse events were observed. This study shows that aerosolization time, but not particle size, in the ranges studied, had an impact on the metabolic effect elicited by inhaled insulin, allowing rational selection of delivery parameters for further clinical testing. Based on the observed biopotency and the rapid onset of action, inhalation of a liquid insulin aerosol generated by the Aerodose Insulin Inhaler shows promise for covering prandial insulin requirements.

Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease worldwide and is an increasing cause of liver-related morbidity and mortality. Nonalcoholic steatohepatitis (NASH), the progressive histological subtype of the disease, is a growing target for drug design and development. Currently, no effective drug therapies exist for the management of NASH and multiple challenges exist for NASH-related clinical trials, stressing the need for a focused deliberative approach to facilitate drug development. One such challenge includes the inconsistent measurement of baseline parameters across clinical trials, which makes interpretation and comparison of trial data difficult and impedes drug development effort.

LP18 : Obeticholic acid for NASH: benefits in a high risk subgroup and the effects of concomitant statin use

of cirrhosis is highly desirable because it simplifies post-LT management. Material and Methods: In this adaptive open-label, prospective randomized phase III North American clinical trial (Study 988, NCT01804829) conducted in 2 parts, any antiviral therapy (AVT) pre-LT (resulting in RNA <100 IU/ml prior to transplant) is followed in the active treatment arms by Hepatitis C Immune Globulin (HCIG, Civacir) periand post-LT to prevent HCV infection after LT. In part I (dose finding), patients were randomized 1:1:1 to active (200 or 300mg/kg) or control arms. Active group patients received 16 infusions of Civacir in the periand immediate post-LT period for 10 weeks. Control patients received standard of care (no treatment) immediately after LT. The primary endpoint is sustained virologic response SVR12. Results: Three quarters (N=63 as of 27 Jan 2015) of 84 planned patients have been enrolled. Preliminary efficacy evaluations justified continued enrollment in the 300mg/kg arm but not in the 200mg/kg low dose arm (closed by amendment). Treatment and control arms are comparable at baseline. Mean age of patients is 61 and 84% are male. 93% of patients were treated with sofosbuvirbased regimens pre-LT, for a median duration of 63.5 days including 9.4% with treatment <4 weeks. To date, 1/21 (5%) reinfection was observed in the 300mg/kg arm. In the control and 200mg/kg arm 7/22 (32%) and 6/20 (30%) reinfections occurred, respectively. At day 6, 14, 21 and 28 post-LT the median anti-HCV antibody titer was 440, 312, 274 and 215 U/ml in the 300mg/kg and 39, 44, 53 and 63 U/ml in the control arm. Civacir has been well tolerated with no drug-related serious adverse events to date. The most frequent reported AEs were those well-known for human immunoglobulins, underlying disease, and surgical associated events.

952 LONG-TERM (LT) THERAPY OF A FARNESOID X RECEPTOR (FXR) AGONIST OBETICHOLIC ACID (OCA) MAINTAINS BIOCHEMICAL RESPONSE IN PRIMARY BILIARY CIRRHOSIS (PBC)

Response in Primary Biliary Cirrhosis (PBC) Gideon Hirschfield1, Kris Kowdley2, Andrew Mason3, Velimir Luketic4, Stuart Gordon5, Catherine Vincent6, Marlyn Mayo7, Albert Parés8, Roger Chapman9, Keith Lindor10, Maria Esguerra11, Lise Eliot11, David Shapiro11 University of Toronto1, Virginia Mason Medical Center, Seattle2, University of Alberta3, Virginia Commonwealth University, Richmond4, Henry Ford Health Center, Detroit5, Hopital Saint-Luc/CHUM Montréal6, UT Southwestern Medical Center, Dallas7, University of Barcelona8, John Radcliffe Hospital, Oxford9, Mayo Clinic, Rochester10, Intercept Pharmaceuticals, San Diego.11

P1137 : Integrated efficacy summary for obeticholic acid in subjects with primary biliary cirrhosis

Background and Aims: Obeticholic acid (OCA), a modified bile acid and farnesoid x receptor (FXR) agonist, is currently in late-phase development for the treatment of primary biliary cirrhosis (PBC), a rare cholestatic liver disease. In two Phase 2 trials (3 months) and in the Phase 3 POISE trial (12 months) 5mg to 50mg OCA, once daily as monotherapy or add-on to UDCA, produced significant improvements in markers of cholestasis and inflammation. The objective of this integrated analysis was to evaluate the efficacy of ≤10mg OCA, the proposed indicated doses for the treatment of PBC, as monotherapy or in combination with UDCA in an integrated fashion across the 3 trials compared to placebo. Methods: Individual subject data from 3 completed, randomized, controlled double-blind trials of OCA once daily were pooled for this analysis (OCA ≤10mg N=201; placebo N=134; OCA 25mg N=48; OCA 50mg N=57). All placebo subjects were pooled as were OCA doses of 5mg, titration from 5 to 10mg, and 10mg (≤10mg OCA). Inclusion criteria included ALP ≥1.67×ULN or total bilirubin >ULN but <2×ULN. Analyses were repeated based on baseline concomitant UDCA use. Efficacy was evaluated using a composite endpoint shown to correlate with long-term survival (ALP <1.67 ULN with a minimum 15% reduction and a normal bilirubin) (Lammers 2014) and assessment of liver biochemistry and inflammation. Results: Baseline characteristics were generally similar between treatment groups. Baseline ALP was higher in monotherapy subjects compared to UDCA combination subjects. Efficacy data are presented in the Table. At the end of double blind treatment significantly more OCA-treated subjects achieved the composite endpoint compared to placebo when used as monotherapy or in combination with UDCA. OCA treatment was associated with statistically significant and clinically meaningful decreases in ALP as well as GGT, ALT, and AST. While the subjects in the monotherapy group had higher ALP at baseline than the OCA plus UDCA group, the two groups reached similar ALP levels by the end of the double-blind period. Pruritus was the most common adverse event associated with PBC and showed a dose-related increase in incidence with OCA.

Relationship Between Three Commonly Used Non-invasive Fibrosis Biomarkers and Improvement in Fibrosis Stage in Patients With NASH.

Non‐invasive biomarkers are needed for monitoring changes in liver histology in patients with non‐alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non‐invasive fibrosis markers and liver fibrosis improvement.