METABOLIC OUTCOMES AND KEY EFFICACY DATA FROM A PHASE 2 TRIAL EVALUATING COMBINATION OBETICHOLIC ACID AND BEZAFIBRATE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

Introduction: Obeticholic acid (OCA), a potent farnesoid X receptor agonist, is indicated as a second-line treatment for patients (pts) with primary biliary cholangitis (PBC) who have an inadequate response or intolerance to ursodeoxycholic acid. Bezafibrate (BZF), a pan-agonist of the peroxisome proliferator–activated receptors, has also shown benefit in pts with PBC. Here, we present metabolic outcomes and key efficacy data from an ongoing phase 2, dose-ranging, double-blind, randomized, parallel group trial evaluating the efficacy, safety, and tolerability of combination OCA and BZF vs BZF monotherapy in pts with PBC.

Methods: Pts were randomized 1:1:1:1 to receive oral once-daily BZF 200 mg (B200) immediate release (IR), BZF 400 mg (B400) sustained release (SR), OCA 5 mg titrated to 10 mg at week 4 + BZF 200 mg IR (OCA/B200), or OCA 5 mg titrated to 10 mg at week 4 + BZF 400 mg SR (OCA/B400), all for 12 weeks. Metabolic outcomes included mean percent change from baseline in total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), in addition to rate of normalization at week 12 of total cholesterol and LDL-C. Mean percent change from baseline and rate of normalization at week 12 of alkaline phosphatase (ALP) as well as the proportion of pts at week 12 who met the primary endpoint criteria from the phase 3 POISE study (ALP <1.67x the upper limit of normal [ULN], with a reduction of ≥15% from baseline, and total bilirubin ≤ULN) were also assessed.

Results: A total of 75 pts were evaluated; 19 pts each received either B200, OCA/B200, or B400, while 18 pts received OCA/B400. OCA/B400 induced the greatest percent change from baseline in total cholesterol (−17.8%; p=0.008 vs B400; p<0.0001 vs baseline), HDL-C (−15.7%; p<0.001 vs B400; p=0.0047 vs baseline), and LDL-C (−17.7%; p=0.190 vs B400; p<0.0001 vs baseline) at week 12 (Figure 1). At week 12, the highest rate of normalization of total cholesterol occurred in the combination OCA/B200 (57.9%; p=0.095 vs B200) and OCA/B400 (55.6%; p=0.279 vs B400) cohorts, and that of LDL-C occurred with OCA/B400 (38.9%; p=0.327 vs B400). OCA/B400 induced the greatest percent change from baseline (−60.6%; p=0.025 vs B400) and rate of normalization (66.7%; p=0.108 vs B400) of ALP at week 12. At week 12, 84.2%, 78.9%, 89.5%, and 83.3% of pts met the POISE study primary endpoint criteria in the B200, OCA/B200, B400, and OCA/B400 cohorts, respectively.

Conclusions: The short-term administration of OCA and BZF has therapeutic potential to normalize multiple key serum biomarkers of PBC-related liver damage that have been correlated with improved transplant-free and decompensation-free survival. Combination OCA and BZF therapy has an acceptable metabolic profile, which includes a positive impact on total cholesterol and LDL-C.