Phase 2 Studies Show OCA-Bezafibrate Achieves Biochemical Remission, ALP Reduction

Cynthia Levy, MD

Credit: American Porphyria Foundation

Data from a pair of phase 2 studies presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) showed combination obeticholic acid (OCA)-bezafibrate caused normalization of multiple biomarkers for predicting improved clinical outcomes in primary biliary cholangitis (PBC).

Patients treated with a combination of OCA and bezafibrate achieved biochemical remission including normalized alkaline phosphatase (ALP), total bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in 40-44% of patients after 12 weeks. In both studies, OCA and bezafibrate 400 mg showed a >60% reduction in ALP and >20% reduction in total bilirubin.¹

“Results from these studies illustrate the OCA-bezafibrate combination’s potential to deliver biochemical responses across a range of biomarkers that predict improved clinical outcomes in PBC,” said Cynthia Levy, MD, hepatologist at the University of Miami Hospital and professor of medicine at the University of Miami.² “These positive findings, including low rates of pruritus, are an important milestone for the PBC community.”

A farnesoid X receptor (FXR) agonist, OCA was granted accelerated approval for the treatment of PBC by the US Food and Drug Administration in 2016.3 Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, is not approved in the US for any indication. Both FXR and PPAR play a role in PBC, leading to speculation regarding the additive clinical efficacy and tolerability benefits of a combination therapy.²

Studies 747-213 and 747-214 assessed the effects of combination OCA and bezafibrate compared to bezafibrate monotherapy on safety, tolerability, serum biomarker levels, and rates of biochemical remission. A range of doses and formulations were examined in patients with PBC who had inadequate response to or were unable to tolerate ursodeoxycholic acid.¹

The primary endpoint of both studies was change in ALP from baseline to week 12. The pair of studies also assessed percentage change and normalization rates of ALT, AST, GGT, and total bilirubin. Biochemical remission was defined as ALP, GGT, ALT, and AST levels ≤ upper limits of normal (ULN), with total bilirubin ≤0.6xULN at week 12.¹

Study 747-213

In total, 75 participants were randomly assigned in a 1:1:1:1 ratio to receive 12 weeks of once-daily oral therapy in addition to ongoing ursodeoxycholic acid treatment in 1 of 4 treatment arms: bezafibrate 200 mg immediate release (IR) (n=19), bezafibrate 400 mg sustained release (SR) (n=19), bezafibrate 200 mg IR with OCA 5 mg titrated to 10 mg at week 4 (n=19), and bezafibrate 400 mg SR with OCA 5 mg titrated to 10 mg at week 4 (n=18). The median dose of ursodeoxycholic acid at baseline was 14.068.^1,2

OCA5-10 with bezafibrate 400 mg SR showed a −60.6% change in ALP from baseline at week 12 and induced biochemical remission in 44.4% of patients compared to 31.6% in bezafibrate 400 mg SR, 31.6% in OCA5-10 with bezafibrate 200 mg IR, and 15.8% in bezafibrate 200 mg IR. Normalization of ALP (≤ULN) was prevalent among 66.7% of patients in the OCA5-10 with bezafibrate 400 mg SR arm, all of whom achieved total bilirubin ≤0.6xULN at week 12.^1,2

OCA with bezafibrate 400 mg resulted in a 24.7% reduction in total bilirubin. Normalization rates of GGT, ALT, and AST (≤ULN) for OCA5-10 with bezafibrate 400 mg SR at week 12 were 58.86%, 94.1%, and 82.4% respectively.^1,2

A single patient in the OCA with bezafibrate 400 mg cohort discontinued treatment due to severe pruritus. The rate of new events of pruritus or worsening of baseline pruritus was lower in the OCA with bezafibrate 400 mg SR cohort of Study 747-213 (11%) compared to preliminary data for the OCA with bezafibrate 400 mg IR cohort of Study 747-214 (70%).^1,2

Study 747-214

The interim analysis of study 747-214 included the first 41 of the planned 72 participants. Patients were randomly assigned in a 1:1:1:1 ratio to receive 12 weeks of once-daily oral therapy in addition to ongoing ursodeoxycholic acid treatment in 1 of 4 treatment arms: bezafibrate 100 mg IR (n=11), bezafibrate 400 mg IR (n=11), bezafibrate 100 mg IR with OCA 5 mg (n=9), and bezafibrate 400 mg IR with OCA 5 mg (n=10). The median dose of ursodeoxycholic acid at baseline was 11.364.^1,2

OCA 5 mg with bezafibrate 400 mg IR showed a −65.4% change in ALP from baseline at week 12 and induced biochemical remission in 40.0% of patients compared to 18.2% in B400 IR, 11.1% in OCA 5 mg with bezafibrate 100 mg IR, and 9.1% in bezafibrate 100 mg IR. Normalization of ALP was prevalent among 70.0% of patients in the OCA 5 mg with bezafibrate 400 mg IR arm, 90.0% of whom achieved total bilirubin ≤0.6xULN at week 12. Normalization rates of GGT, ALT, and AST (≤ULN) for OCA with bezafibrate 400 mg IR at week 12 were 40.0%, 100%, and 90.0%, respectively.^1,2

A single patient in the OCA 5 mg with bezafibrate 100 mg IR cohort experienced severe pruritus, but no treatment-emergent adverse events led to study discontinuation.²

“The results of both Phase 2 studies reinforce our excitement for the combination of OCA-bezafibrate to build on the improved transplant-free survival seen in patients with PBC taking OCA across multiple real-world studies,” said Michelle Berrey, MD, MPH, president of research and development and chief medical officer of Intercept.² “These data support progression to Phase 3 trials of the sustained release formulation of bezafibrate with low doses of OCA, an important step as we continue to prioritize Intercept’s investment in PBC.”

References:

1. Levy C, Hejda V, Louvet A, et al. 5019-C COMBINED EFFECT OF OBETICHOLIC ACID AND BEZAFIBRATE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS AND INADEQUATE RESPONSE TO OR INTOLERANCE OF URSODEOXYCHOLIC ACID: RESULTS FROM TWO PHASE 2 CLINICAL TRIALS. Paper presented at: The Liver Meeting. Boston, MA. November 10 - 14, 2023.
2. Intercept. Intercept Announces New Phase 2 Data Showing Significant Impact of OCA-Bezafibrate Combination on Normalization of Multiple Key Biomarkers of PBC-Induced Liver Damage at AASLD The Liver Meeting® 2023. Newsroom. November 13, 2023. Accessed November 15, 2023. https://ir.interceptpharma.com/news-releases/news-release-details/intercept-announces-new-phase-2-data-showing-significant-impact
3. Drugs.com. Ocaliva FDA Approval History. FDA History. Accessed November 15, 2023. https://www.drugs.com/history/ocaliva.html