Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: ADVANZ PHARMA Limited, Suite 17, Northwood House, Northwood Avenue, Santry, Dublin 9, Ireland
Pharmacotherapeutic group: Bile and liver therapy, bile acids and derivatives
ATC code: A05AA04
Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine. FXR is thought to be a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, as well as, by increasing transport of bile acids out of the hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.
A phase III, randomised, double-blind, placebo-controlled, parallel-group, 12-month study (POISE) evaluated the safety and efficacy of obeticholic acid in 216 patients with PBC who were taking UDCA for at least 12 months (stable dose for ≥ 3 months) or who were unable to tolerate UDCA and did not receive UDCA for ≥ 3 months. Patients were included in the trial if the alkaline phosphatase (ALP) was greater than or equal to 1.67 times upper limit of normal (ULN) and/or if total bilirubin was greater than 1 × ULN but less 2 × ULN. Patients were randomised (1:1:1) to receive once daily placebo, obeticholic acid 10 mg, or obeticholic acid titration (5 mg titrated to 10 mg at 6 months dependent on therapeutic response/tolerability). The majority (93%) of patients received treatment in combination with UDCA and a small number of patients (7%) unable to tolerate UDCA received placebo, obeticholic acid (10 mg) or obeticholic acid titration (5 mg to 10 mg) as monotherapy. ALP and total bilirubin were assessed as categorical variables in the primary composite endpoint, as well as continuous variables over time.
The study population was predominantly female (91%) and white (94%). The mean age was 56 years, with the majority of patients less than 65 years old. Mean baseline ALP values ranged from 316 U/L to 327 U/L. Mean baseline total bilirubin values ranged from 10 μmol/L to 12 μmol/L across treatment arms, with 92% of patients within normal range.
Treatment with obeticholic acid 10 mg or obeticholic acid titration (5 mg to 10 mg) resulted in clinically and statistically significant increases (p<0.0001) relative to placebo in the number of patients achieving the primary composite endpoint at all study time points (see Table 2). Responses occurred as early as 2 weeks and were dose dependent (obeticholic acid 5 mg compared with 10 mg at 6 months, p=0.0358).
Table 2. Percentage of PBC patients achieving the primary composite endpointa at month 6 and month 12 with or without UDCAb:
| Obeticholic acid 10 mgc (N=73) | Obeticholic acid Titrationc (N=70) | Placebo (N=73) | |
|---|---|---|---|
| Month 6 | |||
| Responders, n (%) | 37 (51) | 24 (34) | 5 (7) |
| Corresponding 95% CI | 39%, 62% | 23%, 45% | 1%, 13% |
| p-valued | <0.0001 | <0.0001 | NA |
| Month 12 | |||
| Responders, n (%) | 35 (48) | 32 (46) | 7 (10) |
| Corresponding 95% CI | 36%, 60% | 34%, 58% | 4%, 19% |
| p-valued | <0.0001 | <0.0001 | NA |
| Components of primary endpointe | |||
| ALP less than 1.67-times ULN, n (%) | 40 (55) | 33 (47) | 12 (16) |
| Decrease in ALP of at least 15%, n (%) | 57 (78) | 54 (77) | 21 (29) |
| Total bilirubin less than or equal to 1-times ULNf, n (%) | 60 (82) | 62 (89) | 57 (78) |
a Percentage of subjects achieving a response, defined as an ALP less than 1.67-times the ULN, total bilirubin within the normal range, and an ALP decrease of at least 15%. Missing values were considered a non-response. The Fisher’s exact test was used to calculate the 95% confidence intervals (CIs).
b In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the obeticholic acid 10 mg arm, 5 patients (7%) in the obeticholic acid titration arm, and 5 patients (7%) in the placebo arm.
c Patients were randomised (1:1:1) to receive obeticholic acid 10 mg once daily for the entire 12 months of the trial, or obeticholic acid titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mg once daily for the last 6 months, if the patient was tolerating obeticholic acid but had ALP 1.67-times the ULN or greater, and/or total bilirubin above the ULN, or less than 15% ALP reduction) or placebo.
d Obeticholic acid titration and obeticholic acid 10 mg versus placebo. P-values are obtained using the Cochran-Mantel-Haenszel General Association test stratified by intolerance to UDCA and pre-treatment ALP greater than 3-times ULN and/or AST greater than 2-times ULN and/or total bilirubin greater than ULN.
e Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[N=intention to treat (ITT) population]); percentage of patients with month 12 values are 86%, 91% and 96% for the obeticholic acid 10 mg, obeticholic acid titration and placebo arms, respectively.
f The mean baseline total bilirubin value was 0.65 mg/dL, and was within the normal range (i.e., less than or equal to the ULN) in 92% of the enrolled patients.
Mean reductions in ALP were observed as early as week 2 and were maintained through month 12 for patients who were maintained on the same dose throughout 12 months. For patients in the obeticholic acid titration arm whose obeticholic acid dose was increased from 5 mg once daily to 10 mg once daily, additional reductions in ALP were observed at month 12 in the majority of patients.
The mean (95% CI) reduction in GGT was 178 (137, 219) U/L in the obeticholic acid 10 mg arm, 138 (102, 174) U/L in the obeticholic acid titration arm, and 8 (-32, 48) U/L in the placebo arm.
Fifty-one PBC patients with baseline ALP 1.67-times ULN or greater and/or total bilirubin greater than ULN were evaluated for a biochemical response to obeticholic acid as monotherapy (24 patients received obeticholic acid 10 mg once daily and 27 patients received placebo) in a pooled analysis of data from the phase III randomised, double-blind, placebo-controlled 12-month study (POISE) and from a randomised, double-blind, placebo-controlled, 3-month study. At month 3, 9 (38%) obeticholic acid-treated patients achieved a response to the composite endpoint, compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP in obeticholic acid-treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.
The European Medicines Agency has waived the obligation to submit the results of studies with Ocaliva in all subsets of the paediatric population in PBC (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review any new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Obeticholic acid is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2 hours. Co-administration with food does not alter the extent of absorption of obeticholic acid.
Human plasma protein binding of obeticholic acid and its conjugates is greater than 99%. The volume of distribution of obeticholic acid is 618 L. The volumes of distribution of glyco- and tauro-obeticholic acid have not been determined.
Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation. The conjugates can be deconjugated in the ileum and colon by intestinal microbiota, leading to the conversion to obeticholic acid that can be reabsorbed or excreted in faeces, the principal route of elimination.
After daily administration of obeticholic acid, there was accumulation of the glycine and taurine conjugates of obeticholic acid which have in vitro pharmacological activities similar to the parent drug. The metabolite-to-parent ratios of the glycine and taurine conjugates of obeticholic acid were 13.8 and 12.3, respectively, after daily administration. An additional third obeticholic acid metabolite, 3-glucuronide is formed but is considered to have minimal pharmacologic activity.
After administration of radiolabeled obeticholic acid, greater than 87% is excreted in faeces. Urinary excretion is less than 3%.
Following multiple-dose administration of 5, 10, and 25 mg once daily for 14 days, systemic exposures of obeticholic acid increased dose proportionally. Exposures of glyco- and tauro-obeticholic acid, and total obeticholic acid increase more than proportionally with dose.
There are limited pharmacokinetic data in elderly patients (≥65 years). Population pharmacokinetic analysis, developed using data from patients up to 65 years old, indicated that age is not expected to significantly influence obeticholic acid clearance from the circulation.
No pharmacokinetic studies were performed with obeticholic acid in patients less than 18 years of age.
Population pharmacokinetic analysis indicated that gender does not influence obeticholic acid pharmacokinetics.
Population pharmacokinetic analysis indicated that race is not expected to influence obeticholic acid pharmacokinetics.
In a dedicated single-dose pharmacokinetic study using 25 mg of obeticholic acid, plasma exposures to obeticholic acid and its conjugates were increased by approximately 1.4- to 1.6-fold in subjects with mild (modification of diet in renal disease [MDRD] eGFR ≥60 and <90 mL/min/1.73 m²), moderate (MDRD eGFR ≥30 and <60 mL/min/1.73 m²) and severe (MDRD eGFR ≥15 and <30 mL/min/1.73 m²) renal impairment compared to subjects with normal renal function. This modest increase is not considered to be clinically meaningful.
Obeticholic acid is metabolised in the liver and intestines. The systemic exposure of obeticholic acid, its active conjugates, and endogenous bile acids is increased in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C, respectively) when compared to healthy controls (see sections 4.2, 4.3 and 4.4).
The impact of mild hepatic impairment (Child-Pugh Class A) on the pharmacokinetics of obeticholic acid was negligible, therefore, no dose adjustment is necessary for patients with mild hepatic impairment.
In subjects with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively), mean AUC of total obeticholic acid, the sum of obeticholic acid and its two active conjugates, increased by 1.13-, 4- and 17-fold, respectively, compared to subjects with normal hepatic function following single-dose administration of 10 mg obeticholic acid.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to fertility, reproduction and development.
Oral administration of obeticholic acid above the NOAEL to mice, rats, and dogs in pivotal, repeat dose toxicity studies resulted primarily in effects on the hepatobiliary system. These included increased liver weights, alterations in serum chemistry parameters (ALT, AST, LDH, ALP, GGT, and/or bilirubin), and macroscopic/microscopic alterations. All changes were reversible with discontinued dosing, and are consistent with and predict the dose-limiting toxicity in humans (systemic exposure at NOAEL was up to 24-fold higher than that seen at the maximum recommended human dose). In a pre- and post-natal toxicity study in rats, the tauro-conjugate of obeticholic acid was found in pups nursing from dams dosed with obeticholic acid.
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