Durable Response in the Markers of Cholestasis Through 36 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 agonist indicated for treatment of PBC in patients with inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.

Methods:

POISE was a Phase 3, 12-month, double-blind, placebo-controlled study in patients with PBC (n = 216). Patients on stable or no UDCA with ALp ≥1.67x ULN and/or total bilirubin >ULN to < 2x ULN were randomized to daily Placebo (PBO), OCA 5 – 10 mg (OCA titration), or OCA 10 mg. After completion of the double-blind (DB) period, 193 patients initiated OCA treatment during an ongoing open-label extension (OLE) period. This analysis evaluated efficacy and safety of OCA in patients in Austria and Germany in POISE.

Results:

Patients in Austria and Germany (N = 31) demonstrated significant reductions in ALP after 12 months of DB treatment with OCA vs. PBO (table). In patients randomized to OCA during the DB period, the reduction in ALP was sustained through an additional 36 months of treatment during the OLE. Patients who received PBO during the DB period exhibited a significant reduction in ALP upon initiation of OCA, a finding that was significant at 36 months. Total bilirubin remained generally stable in all treatment groups. Reductions in aminotransferases were observed in all treatment groups and were generally significant during the OLE in the OCA 10 mg group. Pruritus was the most common adverse event. The incidence of serious adverse events increased during the OLE, but there was no identifiable pattern.

Conclusions:

Significant improvements in ALP, ALT, and GGT that was durable over 36 months of OLE treatment were observed in the OCA 10 mg group. Sustained significant improvements in ALP and GGT were observed in the OCA 5 – 10 mg group. Safety findings were were consistent with overall POISE results.

Tab. 1

Original DB Treatment Group	PBO (n = 10)	OCA 5 – 10 mg (n = 10)	OCA 10 mg (n = 11)
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 OLE 36 months‡	-128.7 (95.6)*	-81.4 (49.1)**	-107.8 (101.6)*
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 36 months‡	-1.4 (1.9)	-0.3 (2.9)	-2.6 (4.1)
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 36 months‡	-30.9 (24.0)*	-2.7 (17.8)	-20.8 (18.0)**
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 36 months‡	-18.0 (18.4)	4.4 (18.3)	-13.5 (19.8)
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 36 months‡	-243.7 (335.9)	-59.8 (62.5)*	-127.2 (106.0)**
*p < 0.05, **p < 0.01. Values are Mean (SD). Δ is change from Baseline. †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.