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Cynthia Levy, MD, professor of medicine at the University of Miami, provided further insight into unmet needs in PBC, the use of OCA-bezafibrate in PBC, and the significance of results from a pair of phase 2 studies presented at The Liver Meeting.
Combination obeticholic acid (OCA)-bezafibrate causes normalization of multiple biomarkers for predicting improved clinical outcomes in primary biliary cholangitis (PBC), according to 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).
Normalized alkaline phosphatase (ALP), total bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were observed 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.
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.
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.
The editorial team of HCPLive Hepatology reached out to Cynthia Levy, MD, professor of medicine at the University of Miami, for further insight into the burden of PBC, our current understanding of OCA-bezafibrate in PBC, and a breakdown of the study’s results.
HCPLive Hepatology: What burdens do patients with PBC face, especially considering the rare nature of their disease and there currently being no cure?
Levy: PBC can cause a variety of symptoms, including but not limited to pruritus, fatigue, dry eyes and mouth, and trouble remembering/concentrating. These symptoms can be difficult to manage. While PBC can be completely asymptomatic, most patients eventually develop symptoms during the course of the disease. The presence of symptoms can have a significant negative impact in their quality of life, with chronic itching being associated with sleep deprivation, social isolation, self-mutilation, and depression. Severe itching is so debilitating that its impact on health utility scores is comparable to that of Parkinson’s disease!
HCPLive Hepatology: Can you describe the current unmet need in patients with PBC?
Levy: The estimated prevalence of PBC in the United States is 40.9 cases per 100,000 people and it is most prevalent in women, who make up an estimated 83% of people who are diagnosed with PBC. Research also shows that about 40% of people do not adequately respond to first-line PBC therapy, namely ursodeoxycholic acid (UDCA). Currently available FDA-approved second-line therapy, OCA, can rescue approximately half of the incomplete responders to UDCA. Therefore, additional therapies are needed for people living with PBC who remain with elevated ALP despite available drugs. Studies have shown that normalization of ALP is associated with lower rate of liver-related events in high-risk patients with PBC. In addition, there is a critical need for comprehensive review of treatment response beyond ALP to better manage patients living with PBC. Importantly, currently available therapies in the US do not address symptoms – mitigating pruritus and fatigue should be a priority when caring for people living with PBC.
HCPLive Hepatology: What is our current understanding of OCA-bezafibrate? How does it address some of these unmet needs for patients with PBC?
Levy: OCA and bezafibrate have synergistic mechanisms of action and have shown the potential to normalize multiple biochemical of PBC-induced liver damage that are associated with improved clinical outcomes. The investigational OCA and bezafibrate combination therapy presents an opportunity to optimize the doses of each medicine and ultimately, further improve the treatment of PBC. With the data presented at The Liver Meeting from Study 747-213 and Study 747-214, we’ve seen reductions from baseline in serum ALP, which we know is an important treatment goal for PBC. Additionally, we saw this combination achieve high rates of biochemical remission in the first 12 weeks. This is especially important because each of these biomarkers contribute to the assessment of total liver health; we have learned that patients who normalize liver chemistries have a potential for improved survival free of hepatic decompensation. Other potential benefits of the combination OCA-bezafibrate include a favorable effect on the lipid panel and better tolerability, due to mitigation of itching.
HCPLive Hepatology: Can you break down the study’s results? What is the clinical significance of these findings?
Levy: Results from the two studies show that the combination of OCA + bezafibrate achieved biochemical remission in 40-44% of patients in the first 12 weeks, with normalization of all liver tests. Furthermore, OCA 5 or 5-10 mg + bezafibrate 400 mg cohorts in both studies showed a >60% reduction from baseline in serum ALP. Interestingly, the depth of response appears to be greater than we would have expected with each agent used alone. From a safety and tolerability standpoint, the frequency of treatment-emergent adverse events was generally balanced across all arms in both studies. Two severe TEAEs occurred in Study 213; one severe TEAE occurred in Study 214. As expected, we saw less itching with the combination OCA5-10/bezafibrate 400 mg SR. In totality, these results illustrate the combination’s potential to deliver biochemical responses across a range of biomarkers that predict improved clinical outcomes in PBC. These results are really impressive and should be investigated further in a phase 3 trial with the sustained release formulation of bezafibrate and low doses of OCA.
HCPLive Hepatology: What’s next in the development program for OCA-bezafibrate combination?
Levy: The two Phase 2 studies remain ongoing and are continuing to explore a range of therapeutic doses and formulations for the combination of OCA and bezafibrate. Looking ahead, the results presented at The Liver Meeting support progression to Phase 3 trials with sustained release formulation of bezafibrate and low doses of OCA. This is an exciting time for people living with PBC, as the possibility of achieving complete normalization of all liver chemistries with a tolerable therapy became more palpable. We are looking forward to confirming the synergistic effect of this potent drug combination, as each of them has been suggested to improve survival free of liver transplantation based on real world data.
Brooks, A. Phase 2 Studies Show OCA-Bezafibrate Achieves Biochemical Remission, ALP Reduction. HCPLive. November 15, 2023. Accessed November 20, 2023. https://www.hcplive.com/view/phase-2-studies-show-oca-bezafibrate-achieves-biochemical-remission-alp-reduction