Cynthia Levy, MD: Interim ASSURE Data Suggest Seladelpar Could Be “Transformative” in PBC

New data from the ongoing, phase 3 ASSURE study were presented at Digestive Disease Week (DDW) 2024 in Washington, DC, this weekend and showed seladelpar was associated with clinically meaningful improvements in markers of cholestasis and liver injury in patients with primary biliary cholangitis (PBC).

Results showed the selective PPAR-delta agonist demonstrated a strong signal of safety and tolerability through month 12 of the study, leading to clinically meaningful improvements in markers of cholestasis and liver injury, including high rates of alkaline phosphatase (ALP) normalization.

At the data cutoff in June 2023, 148 (85%) patients reached the 12-month treatment mark, 70.3% of whom achieved the composite response endpoint of ALP 1.67 times the upper limit of the normal range (ULN), an ALP decrease of ≥15% from baseline, and total bilirubin levels at 12 months with seladelpar 10 mg. ALP normalization was also confirmed in 37.2% of patients who received seladelpar. Additionally, no treatment-related serious adverse events were observed, although treatment discontinuation due to adverse events occurred in 4.0% of the study population.

For further insight into the treatment of PBC, seladelpar’s potential for these patients, and the clinical significance of the interim ASSURE data, the editorial team of HCPLive Hepatology spoke with Cynthia Levy, MD, professor of medicine in the division of digestive health and liver diseases and associate director of the Schiff Center for Liver Diseases at the University of Miami.

HCPLive: What is the current treatment landscape for PBC? Where does an unmet need remain?

Levy: At this time, there is no cure for PBC. However, early treatment may slow liver damage. Currently, ursodeoxycholic acid (UDCA) is the only approved first-line therapy for PBC. UDCA dilutes the bile acid pool, resulting in reduced cholestasis. However, UCDA fails to provide an adequate response in approximately 40% of people with PBC, and is not tolerated in 5-10% of people due to weight gain, hair loss or GI side effects.

Obeticholic acid is a second-line therapy and agonist for the farnesoid X receptor (FXR), a key regulator of bile acid. However, it may worsen pruritus (itching), provide an inadequate response in a significant number of people with PBC, or cause intolerable side effects, therefore causing treatment discontinuation.

Up to 40% of people with PBC do not have an adequate response to first line treatment, and up to 50% do not have an adequate response to second line treatment, or struggle with exacerbated symptoms. This leads to continued disease progression, potentially requiring liver transplantation. There remains a significant unmet need for treatments that are effective, tolerable and minimize symptoms to improve quality of life for people living with PBC.

HCPLive: Can you explain seladelpar’s mechanism of action and what makes it a viable agent for PBC?

Levy: Seladelpar, an investigational treatment for people with PBC, is a potential best-in-class oral, selective PPAR-delta agonist, or delpar, that targets multiple cell types and processes in PBC progression to help reduce inflammation, bile acids and pruritus. Preclinical and clinical data support its ability to regulate genes involved in bile acid synthesis, inflammation, fibrosis, and lipid metabolism, storage, and transport, as well as patient-reported pruritis (itch).

HCPLive: What do these findings from ASSURE add to our knowledge about its safety and efficacy for PBC?

Levy: Interim data from the ASSURE study show that treatment with seladelpar led to improvements in markers of cholestasis and reduced inflammation. 70.3% of participants achieved the clinically meaningful composite endpoint of alkaline phosphatase (ALP) and bilirubin reduction at 12 months, and 37.2% achieved ALP normalization. In the initial participants that reached 24 months of treatment (n=20), 70% achieved the composite endpoint of alkaline phosphatase (ALP) and bilirubin reduction and 25% saw sustained ALP normalization.

Reduction in patient-reported pruritus – or itching – was rapid (within one month) and durable (patient-reported mean reduction at Month 6 was sustained through Month 12) in participants with moderate to severe symptoms. These new data expand on our growing understanding of the clinical profile of seladelpar as we work to bring safe and effective treatments to those in need.

HCPLive: What is the clinical significance of this data in combination with findings from other Phase 3 studies of seladelpar?

Levy: The interim data results are highly consistent with results from the Phase 3 RESPONSE study of seladelpar, which demonstrate that seladelpar can help patients achieve ALP normalization and a reduction in pruritus in people living with PBC. These data continue to support the clinical, efficacy, and safety data observed across the robust development program and continue to indicate that seladelpar has the potential to be a transformative new treatment option for PBC, if approved. Treatments that effectively address the debilitating pruritis and slow the disease progression could greatly improve the quality of life for those living with PBC.

HCPLive: Looking ahead, what might seladelpar eventually bring to our available armamentarium for cholestatic disease?

Levy: Robust, long-term data from current and ongoing clinical trials indicate that seladelpar has the potential to become a transformative therapy if approved for use in people living with PBC, bringing us closer to addressing the needs of patients living with this rare disease.

Reference:

^{Iapoce, C. ASSURE: Seladelpar Achieves Clinical Improvement in Primary Biliary Cholangitis. HCPLive. May 18, 2024. Accessed May 18, 2024. https://www.hcplive.com/view/assure-seladelapr-achieves-clinical-improvement-primary-biliary-cholangitis}