Alan Bonder, MD: Phase 2 Data for Combination Obeticholic Acid, Bezafibrate in PBC

Alan Bonder, MD

Credit: Beth Israel Deaconess Medical Center

Phase 2 data presented at Digestive Disease Week (DDW) 2024 suggest the short-term administration of combination obeticholic acid and bezafibrate may normalize multiple key serum biomarkers of primary biliary cholangitis (PBC)-related liver damage.

The ongoing phase 2, dose-ranging, double-blind, randomized, parallel-group trial enrolled 75 patients who were randomly assigned in a 1:1:1:1 ratio to receive oral once-daily bezafibrate 200 mg (B200) immediate release, bezafibrate 400 mg (B400) sustained release, obeticholic acid 5 mg titrated to 10 mg at week 4 + bezafibrate 200 mg immediate release (OCA/B200), or obeticholic acid 5 mg titrated to 10 mg at week 4 + bezafibrate 400 mg sustained release (OCA/B400), all for 12 weeks.

In total, 19 patients each received either B200, OCA/B200, or B400, while 18 patients received OCA/B400. Results showed OCA/B400 induced the greatest percent change from baseline in total cholesterol (−17.8%; P = .008 vs B400; P <.0001 vs baseline), high-density lipoprotein cholesterol (−15.7%; P <.001 vs B400; P = .0047 vs baseline), and low-density lipoprotein cholesterol (−17.7%; P = .190 vs B400; P <.0001 vs baseline) at week 12. Additionally, at week 12, the greatest rate of normalization of total cholesterol occurred in the combination OCA/B200 (57.9%; P = .095 vs B200) and OCA/B400 (55.6%; P = .279 vs B400) cohorts, and that of low-density lipoprotein cholesterol occurred with OCA/B400 (38.9%; P = .327 vs B400).

Investigators pointed out OCA/B400 induced the greatest percent change from baseline (−60.6%; P = .025 vs B400) and rate of normalization (66.7%; P = .108 vs B400) of alkaline phosphatase at week 12. At week 12, 84.2%, 78.9%, 89.5%, and 83.3% of patients met the phase 3 POISE study primary endpoint criteria for alkaline phosphatase <1.67x the upper limit of normal with a reduction of ≥15% from baseline and total bilirubin ≤ the upper limit of normal in the B200, OCA/B200, B400, and OCA/B400 cohorts, respectively.

For more insight into the use of combination obeticholic acid and bezafibrate in PBC, HCPLive spoke with Alan Bonder, MD, associate professor of medicine at Harvard Medical School and medical director of liver transplantation at Beth Israel Deaconess Medical Center.

HCPLive: Can you explain the mechanism of action seen with this combination of obeticholic acid and bezafibrate? Why is it being explored in PBC?

Bonder: OCA is a selective, potent farnesoid X receptor (FXR) agonist that regulates multiple pathways relevant to PBC including bile acid (BA) cytotoxicity (reducing the production of BA and reducing BA absorption), inflammation (repressing inflammation and reducing bacterial translocation from the intestine to the liver), and fibrogenesis (reducing fibrosis, or scarring in the liver). Bezafibrate is a pan-agonist of the peroxisome proliferator–activated receptors (PPAR), which are nuclear receptors that play a key role in lipid metabolism.

FXR and PPAR are distinct pathways that each play a role in PBC. Simultaneously targeting both pathways may offer the greatest potential to impact bile acid synthesis, metabolism, and clearance that underly cholestatic liver diseases. The OCA-bezafibrate combination has synergistic mechanisms of action with a potential to lower key biochemical measures that predict long-term outcomes in PBC, while also improving tolerability.

HCPLive: What’s the importance of normalizing ALP as a therapeutic target in PBC?

Bonder: ALP is a serum biomarker of PBC-related liver damage. Normalizing ALP has been correlated with improved transplant-free and decompensation-free survival. People with PBC have elevated levels of ALP in their blood. Since an ALP level above normal could mean an increased risk of liver damage, lowering that number is an important goal of treatment and a sign that treatment is working.

While ALP is an important biomarker of PBC-related liver damage, it is important to note that it is just one of several biomarkers that should be considered when managing the disease. Previous studies of OCA and bezafibrate have shown that the combination drove normalization of key biomarkers beyond ALP including total bilirubin, ALT, AST, and GGT.

HCPLive: What were some of the key findings from this 6-month analysis?

Bonder: This specific analysis presented at DDW showed that six-month administration of OCA and bezafibrate has therapeutic potential to normalize levels of ALP, a serum biomarker of PBC-related liver damage that has been correlated with improved transplant-free and decompensation-free survival. It also showed that OCA and bezafibrate combination therapy has an acceptable metabolic profile, which includes normalization of total cholesterol and a substantial reduction of LDL cholesterol, even without concomitant statin use.

HCPLive: What’s the clinical significance of this data? Where do we go from here with this research?

Bonder: These data add to a growing body of evidence showing that the combination of OCA and bezafibrate may provide additive clinical efficacy and tolerability benefits in the treatment of PBC. Research is ongoing, and future analyses are planned for other lipids, such as apolipoprotein B and lipoprotein (a), to further inform metabolic outcomes.

Bonder has relevant disclosures with Intercept, GSK, Ipsen, Miriam, and others.

Reference:

^{Bonder A, Jones DE, Levy C, et al. METABOLIC OUTCOMES AND KEY EFFICACY DATA FROM A PHASE 2 TRIAL EVALUATING COMBINATION OBETICHOLIC ACID AND BEZAFIBRATE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS. Abstract presented at Digestive Disease Week (DDW) 2024 Annual Meeting. Washington, DC. May 17-21, 2024.}