Durable Response in the Markers of Cholestasis through 18 Months of Open-Label Extension with Obeticholic Acid in Austrian and German Patients with Primary Biliary Cholangitis

Background:

Obeticholic acid (OCA) is a potent and selective farnesoid X receptor (FXR) agonist indicated for treatment of primary biliary cholangitis (PBC) in patients with inadequate response to ursodeoxycholic acid (UDCA) or intolerability. This analysis evaluated efficacy and safety of OCA in Austrian and German patients with PBC.

Methods:

POISE was a Phase 3, 12-month, double-blind, placebo-controlled study. Patients on stable or no UDCA with alkaline phosphatase (ALP) > 1.67x ULN and/or total bilirubin >ULN to < 2x ULN were randomized to daily Placebo, OCA 5 – 10 mg, or OCA 10 mg. After completion of the double-blind phase, all patients initiated OCA treatment during an ongoing open-label extension (OLE).

Results:

Thirty-one of 216 patients were treated at Austrian and German sites (Placebo, n = 10; OCA 5 – 10 mg, n = 10; OCA 10 mg, n = 11). Compared to Placebo, both OCA groups demonstrated significant reductions in ALP after 12 months of double-blind treatment (table). The reduction in ALP was durable through an additional 18 months of treatment during the OLE. Patients receiving Placebo had no change in ALP during the double-blind phase; 18 months after initiating OCA treatment in the OLE, these patients had significantly reduced ALP. Total bilirubin remained stable in all groups except the OCA 10 mg group, in which it significantly decreased during the OLE. Patients on OCA in the double-blind phase showed a decrease in treatment emergent pruritus incidence during the OLE (double-blind: 25 – 64%; OLE: 10 – 33%).

Conclusions:

OCA treatment of Austrian and German patients resulted in significant improvements in markers of cholestasis. Consistent with the overall POISE cohort, the improvements were durable through an additional 18 months of OCA treatment in the OLE. The incidence of pruritus lessened with longer OCA treatment.

Original Treatment Group	Placebo	OCA 5 – 10 mg	OCA 10 mg
ALP (U/L)
Baseline	353.2 (106.7)	311.6 (89.8)	348.5 (141.3)
Δ Double-blind 12 months†	18.3 (88.2)	-115.2 (49.2)**	-122.7 (73.3)**
Δ OLE18 months‡	-91.3 (70.1)*	-110.4 (52.0)**	-99.6 (113.8)*
Total bilirubin (µmol/L)
Baseline	12.1 (8.2)	10.9 (5.2)	12.6 (7.5)
Δ Double-blind 12 months†	1.0 (5.5)	-0.3 (3.6)	-1.9 (4.2)
Δ OLE 18 months‡	-2.7 (4.9)	-1.4 (3.7)	-2.9 (2.6)*
ALT (U/L)
Baseline	66.8 (45.1)	53.7 (27.0)	54.8 (27.5)
Δ Double-blind 12 months†	-2.7 (19.5)	-20.3 (10.8)**	-21.4 (17.5)**
Δ OLE 18 months‡	-34.4 (48.4)	-12.6 (9.0)**	-17.4 (15.7)*
AST (U/L)
Baseline	50.3 (23.3)	46.1 (23.3)	50.4 (30.6)
Δ Double-blind 12 months†	0.03 (14.5)	-14.9 (12.5)**	-16.0 (18.4)**
Δ OLE 18 months‡	-12.6 (21.3)	-6.3 (9.5)	-14.6 (18.1)*
GGT (U/L)
Baseline	628.1 (1033.4)	188.3 (78.3)	212.3 (113.3)
Δ Double-blind 12 months†	-33.4 (350.6)	-91.7 (70.7)*	-127.1 (95.3)**
Δ OLE 18 months‡	-529.8 (1040.9)	-99.7 (47.3)**	-127.4 (98.1)**
*p < 0.05, **p < 0.01. Values are Mean (SD). †P-value for comparing active treatments to Placebo is obtained using an ANCOVA model with Baseline value as a covariate and fixed effects for treatment and randomization strata factor. ‡P-value for the within treatment comparisons are obtained using the Student's t-test.

No conflict of interest has been declared by the author(s).