Ocaliva shown to reduce markers of liver damage, scarring in PBC trial

Oral therapy conditionally approved in US and Europe for some adult patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A pair of hands, a stethoscope, and a handful of oral medications surround a graph labeled

Treatment with Ocaliva (obeticholic acid) — an oral therapy with conditional approval in both the U.S. and Europe — reduced levels of additional markers of liver damage and scarring in adults with primary biliary cholangitis (PBC), according to new analyses of data from the Phase 3 POISE clinical trial.

These findings add to the trial’s top-line data, which showed that a significantly greater proportion of patients on Ocaliva compared with a placebo — 46% versus 10% — achieved normalization of two other liver damage markers. That data, indicating the study met its main goal, supported the therapy’s conditional approval in both the U.S. and Europe.

The new results were presented by Intercept Pharmaceuticals, Ocaliva’s developer and a wholly owned subsidiary of Alfasigma, at Digestive Disease Week 2024, a forum held earlier this month in Washington, D.C.

“At a time when the field is rapidly evolving, we are pleased to share new analyses from this study that demonstrate the benefits of [Ocaliva] and build on our eight years of real-world experience on the market,” Sangeeta Sawhney, MD, Intercept’s senior vice president and head of U.S. research and development, said in a company press release.

“The Phase 3 POISE study has been instrumental in furthering our collective understanding of the effects of [Ocaliva] in PBC treatment,” Sawhney said.

FDA decision on full regulatory approval of Ocaliva expected in October

PBC is a chronic disorder characterized by inflammation of the bile ducts, which are a series of tubes that normally carry the digestive fluid bile to the intestines from the liver where it’s made. This results in a buildup of bile in the liver, causing liver damage which can progress to scarring, or fibrosis, that interferes with liver function.

Ocaliva, taken once a day, is designed to reduce liver inflammation and lessen liver bile buildup by modulating farnesoid X receptor, a liver protein that helps control the movement of bile.

The therapy was conditionally approved by regulatory agencies in both the U.S. and the European Union in 2016 to treat certain adults with PBC. It may be used in combination with the first-line PBC therapy ursodeoxycholic acid (UDCA, marketed as Urso and Actigall), or it may be given alone in patients who cannot tolerate UDCA.

Conditional, or accelerated, approval is based on early clinical trial evidence showing the therapy’s potential to benefit patients; full approval requires further trial data proving its efficacy. A regulatory application from Intercept seeking Ocaliva’s full approval is now being reviewed in the U.S., with a decision expected in October.

Ocaliva’s accelerated approvals were based mainly on biomarker data from the Phase 3 POISE trial (NCT01473524) that showed the therapy was superior to a placebo at normalizing blood levels of alkaline phosphatase (ALP) and bilirubin, two markers of liver damage.

The one-year study enrolled 217 adults with PBC who were randomly assigned to receive either a placebo, Ocaliva at a dose of 10 mg/day, or Ocaliva at a dose of 5 mg/day (which could be increased up to 10 mg/day after six months).

The newly-presented data concerned the therapy’s effects on two other liver damage markers — alanine aminotransferase (ALT) and aspartate aminotransferase (AST) — and on a non-invasive measure of liver scarring called aminotransferase to platelet ratio index (APRI) score.

“When treating PBC, it’s imperative to assess other biomarkers beyond ALP, such as ALT and AST, as well as potential liver fibrosis, which can be done via non-invasive measures like APRI,” said Robert G. Gish, MD, a professor at Loma Linda University, in California.

“Together, these assessments can better equip clinicians to make informed decisions about their patients’ care,” Gish added.

New analyses focus on different measures of liver damage in PBC

The results of the new analyses showed that, compared with the placebo, Ocaliva led to significantly greater mean reductions in ALT levels (by more than 20 units per liter, or U/L, with either dose vs. 5 U/L) and AST levels (by more than 10 U/L with either dose vs. 1 U/L).

By the end of the trial, about one-third of patients on the higher Ocaliva dose had normalized ALT and/or AST levels, whereas approximately 1 in 10 of those given the placebo achieved normalization of either marker.

The company noted that rates of ALT and/or AST normalization were higher with Ocaliva than the placebo even among patients who did not meet the trial’s main goal of achieving normal or near-normal ALP and bilirubin levels.

Beyond the established effect of [Ocaliva] on alkaline phosphatase (ALP) levels, these new analyses demonstrate the impact of [Ocaliva] on other important indicators of poor clinical outcomes in PBC.

Similarly, Ocaliva treatment reduced APRI scores significantly more than did the placebo, including among patients with a higher risk of liver fibrosis.

“Beyond the established effect of [Ocaliva] on alkaline phosphatase (ALP) levels, these new analyses demonstrate the impact of [Ocaliva] on other important indicators of poor clinical outcomes in PBC,” Gish said.

At the same conference, Intercept also shared new data from a Phase 2 trial (NCT04594694) that is testing Ocaliva in combination with bezafibrate in 75 adults with PBC.

Bezafibrate is a fibrate, a type of medication that lowers fatty molecules in the blood. It exerts its effects by activating PPARs, proteins that regulate gene activity related to processes that contribute to liver damage in PBC, including inflammation and scarring.

Participants were randomly assigned to take 200 or 400 mg of bezafibrate, with or without Ocaliva (starting at a dose of 5 mg/day, and increased up to 10 mg/day), for three months. After completing this treatment period, the dosage of the Ocaliva-bezafibrate combo could be optimized in the study’s long-term safety extension portion.

After six months, patients given the high dose of bezafibrate plus Ocaliva experienced a significantly greater reduction in ALP levels (65.3% vs. 49%), the data showed. The combination therapy also was the only treatment regimen that led to normalization of total mean cholesterol levels.

“The results from this analysis provide important insights on the potential benefits of [Ocaliva]-bezafibrate combination therapy in PBC,” Sawhney said in a separate press release.