Gilead’s Livdelzi (Seladelpar) Demonstrated a Sustained Efficacy and Long-Term Safety Profile in Management of Primary Biliary Cholangitis

FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced data from a two-and-a-half-year interim analysis from the ongoing Phase 3 ASSURE study, which showed that 81% (30 out of 37) of participants with primary biliary cholangitis (PBC) treated with Livdelzi ^® (seladelpar) achieved a composite biochemical response (CBR), demonstrating significant improvements in a key measures of PBC progression. Additionally, 41% (15 out of 37) of participants achieved normalization of alkaline phosphatase (ALP) levels, a critical biomarker of liver function. These findings were unveiled as a late-breaker presentation at The Liver Meeting ^® 2024 hosted by the American Association for the Study of Liver Diseases (AASLD) in San Diego, California from November 15-19.

ASSURE (NCT03301506) is an ongoing, open-label, study evaluating the long-term efficacy and safety of Livdelzi. ASSURE is enrolling adults with PBC who previously participated in a study of Livdelzi where a key eligibility criterion includes having an inadequate response or intolerance to ursodeoxycholic acid (UDCA). Using a data cutoff of January 31, 2024, the interim analysis represented all participants in the ASSURE study, including those who participated in prior clinical studies of Livdelzi (legacy studies) and participants from the pivotal Phase 3 RESPONSE study. Results demonstrate the safety profile of Livdelzi remains robust, with no treatment-related serious adverse events (SAEs) reported throughout the study duration. The exposure-adjusted incidence of adverse events decreased over time, with 86, 70, and 63 participants per 100 patient-years observed in years 1, 2 and 3 of treatment, respectively. Livdelzi continues to appear generally well tolerated, with no new safety signals or change in frequency of adverse events (AEs) with up to three years of exposure. These results are consistent with the results presented at the European Association for the Study of the Liver (EASL) Congress earlier this year.

"These data support what we've already observed with seladelpar. The long-term data from the ASSURE study reinforce that seladelpar consistently lowers ALP, offering a promising and much-needed option for patients living with this chronic liver condition," said Eric J. Lawitz, MD, principal investigator and Medical Director of the Texas Liver Institute and a Clinical Professor of Medicine at University of Texas Health San Antonio, Texas, USA. "ALP levels are recognized as an important surrogate marker of disease progression in PBC, and providers are shifting to view ALP normalization as a treatment goal. ALP levels are critical markers in assessing liver health, and for people with PBC who are not adequately responding to first-line therapies, reducing, or even normalizing these levels, can make a significant difference in the management of this disease."

In addition to the ASSURE data, Gilead showcased findings from two oral presentations highlighting additional analyses from the Phase 3 RESPONSE trial (NCT04620733):

• A prespecified subgroup analysis underscored the efficacy and safety profile of Livdelzi in people living with PBC and compensated cirrhosis. At Month 12, the adjusted mean change from baseline in ALP for participants with cirrhosis on Livdelzi was -121.4 U/L (a decrease of approximately 35% from baseline) versus 23.2 U/L (an increase of approximately 6.6%) on placebo, and -134.8 U/L (a decrease of approximately 43.5%) for Livdelzi versus -18.0 U/L (a decrease of approximately 5.8%) for placebo in participants without cirrhosis. In Livdelzi participants, AEs were reported in 89% and 86% of participants with and without cirrhosis, respectively, versus 89% and 84% in placebo participants.
• A secondary analysis of pruritus in RESPONSE showed that among participants with a numerical rating score (NRS) of ≥4 and NRS ≥7 at baseline, Livdelzi led to near resolution (NRS of 0 or 1) of itch at Month 12 in 26.5% and 18.8% of participants, respectively, versus 0% of participants on placebo. In Livdelzi participants, AEs were reported in 87.8% and 86.1% of participants with baseline NRS ≥4 and NRS <4, respectively, versus 91.3% and 81% in placebo participants. Overall, the proportion of participants with AEs was similar for Livdelzi and placebo regardless of baseline itch severity.

"Gilead has a legacy of bringing groundbreaking treatments to people in need and Livdelzi is the first and only treatment to demonstrate statistically significant and durable improvements in both pruritus and markers of cholestasis related to the risk of disease progression," said Timothy Watkins, MD, MSc, Vice President, Clinical Development, Inflammation Therapeutics, Gilead Sciences. "With Livdelzi, we've introduced an effective and well tolerated option for people living with PBC, offering an important novel treatment option. We remain committed to advancing innovative therapies that provide real hope and improved outcomes for people facing this challenging liver disease."

In a separate analysis, which spans the Livdelzi program in PBC, Gilead highlighted findings from a large safety database of people treated with Livdelzi for up to five years, which demonstrated that Livdelzi was generally well tolerated considering cumulative use across studies. A total of 486 participants received Livdelzi 10 mg and 152 participants received placebo. The exposure-adjusted subject incidence (per 100 patient-years) for Livdelzi was 48.3 for AEs, 8.0 for SAEs, and 6.1 for liver-related AEs, as compared to 132 for AEs (rate reflective of shorter exposure time for placebo participants), 7.8 for SAEs, and 13.3 for liver-related AEs in placebo participants. There were no treatment-related SAEs.

For more information on the AASLD Annual Meeting and Gilead's presentations, please visit the AASLD website.

Please see below for U.S. Indication and Important Safety Information for Livdelzi.

About ASSURE (NCT03301506)

ASSURE is an open label study to evaluate the long-term safety and tolerability of seladelpar in people with primary biliary cholangitis (PBC) who have already participated in other PBC clinical trials of seladelpar. The study is currently enrolling up to 500 people living with PBC from across 160 sites around the world.

Participants enrolled in ASSURE at the time of this interim data analysis include participants from previous studies of seladelpar in PBC, including the Phase 3 registrational RESPONSE study and legacy clinical trials. Legacy studies include the open label Phase 2 dose-ranging study (2 mg, 5 mg, or 10 mg seladelpar), the open label Phase 3/4 long-term safety study (5 mg or 10 mg seladelpar), the Phase 3 placebo-controlled ENHANCE study (5 mg or 10 mg seladelpar vs placebo), and the ongoing open label study in people with PBC and hepatic impairment. ENHANCE and the long-term study were both terminated early.

About RESPONSE (NCT04620733)

RESPONSE is the pivotal Phase 3, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of seladelpar in adults with primary biliary cholangitis (PBC) who have shown inadequate response or intolerance to ursodeoxycholic acid (UDCA). The trial enrolled 193 participants across multiple sites worldwide. RESPONSE assessed the key biomarker of cholestasis alkaline phosphatase (ALP) and other parameters of liver function, as well as secondary endpoints including pruritus and other patient quality of life measurements.

Participants in the RESPONSE trial received a daily oral dose of 10 mg of seladelpar for 12 months. The trial also aims to address the high unmet need for effective second-line therapies for individuals with PBC.

About Livdelzi

Livdelzi ^® (seladelpar) is an oral PPAR-delta agonist, or delpar, for the treatment of primary biliary cholangitis (PBC). PPAR-delta has been shown to regulate critical metabolic and liver disease pathways. Preclinical and clinical data indicate Livdelzi has anticholestatic, anti-inflammatory, antipruritic, and antifibrotic effects.

Livdelzi has potential to help meet the current unmet need of people living with PBC, as the first and only treatment that achieved statistically significant reduction across biochemical response, alkaline phosphatase (ALP) normalization, and pruritus versus placebo. Pruritus is a common symptom that can significantly impair quality of life in people with PBC.

Livdelzi (10 mg capsule) was granted accelerated approval for the treatment of PBC by the U.S. Food and Drug Administration (FDA) in August 2024. Livdelzi received FDA Breakthrough Therapy Designation, as well as Orphan Drug Designation for the treatment of people living with PBC. Seladelpar has also been accepted for review by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA).

As part of the FDA accelerated approval, Gilead has committed to a confirmatory long-term outcomes study called AFFIRM, which has already been initiated in people with compensated cirrhosis. Continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s).

The Gilead Support Path ^® Program offers information and resources to help patients who are prescribed Livdelzi understand coverage and financial options.

U.S. Indication for Livdelzi

Livdelzi is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction of ALP. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Limitations of Use: Use of Livdelzi is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

U.S. Important Safety Information for Livdelzi

Warnings and Precautions

• Fractures: Fractures occurred in 4% of LIVDELZI-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with LIVDELZI and monitor bone health according to current standards of care.
• Liver Test Abnormalities: LIVDELZI has been associated with dose-related increases in serum transaminase (AST and ALT) levels > 3 x ULN in patients receiving 50 mg and 200 mg once daily (5x and 20x higher than the recommended dosage of 10 mg once daily). Perform baseline clinical and laboratory testing when starting LIVDELZI and monitor thereafter according to routine patient management. Interrupt treatment if the liver tests (ALT, AST, total bilirubin, and/or ALP) worsen, or if the patient develops signs and symptoms of clinical hepatitis (eg, jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting LIVDELZI.
• Biliary Obstruction: Avoid use of LIVDELZI in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated.

Adverse Reactions

• The most common adverse reactions (≥5%) with LIVDELZI were headache (8%), abdominal pain (7%), nausea (6%), abdominal distension (6%), and dizziness (5%).

Drug Interactions

• OAT3 Inhibitors and Strong CYP2C9 Inhibitors: Avoid coadministration with LIVDELZI due to increased LIVDELZI exposure.
• Rifampin: Monitor biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during LIVDELZI treatment. Coadministration may result in delayed or suboptimal biochemical response of LIVDELZI.
• Dual Moderate CYP2C9 and Moderate-to-Strong CYP3A4 Inhibitors and BCRP Inhibitors (eg, cyclosporine): Monitor closely for adverse effects. Concomitant administration with LIVDELZI may increase LIVDELZI exposure.
• CYP2C9 Poor Metabolizers Using Moderate-to-Strong CYP3A4 Inhibitors: Monitor more frequently for adverse reactions as concomitant use of a moderate-to-strong CYP3A4 inhibitor in patients who are CYP2C9 poor metabolizers may increase LIVDELZI exposure and risk of LIVDELZI adverse reactions.
• Bile Acid Sequestrants: Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible.

Pregnancy and Lactation

• Pregnancy: There are insufficient data from human pregnancies exposed to LIVDELZI to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Gilead Sciences, Inc., at 1-800-445-3235.
• Lactation: There are no data on the presence of LIVDELZI in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI.

About PBC

PBC is a rare, chronic inflammatory liver disease primarily affecting women (1 in 1,000 women over the age of 40 or about 130,000 total people in the U.S.). PBC is characterized by impaired bile flow (known as cholestasis) and the accumulation of toxic bile acids in the liver, leading to inflammation and destruction of the bile ducts within the liver and causing increased levels of alkaline phosphatase (ALP), alanine transaminase (ALT) and gamma-glutamyl transferase (GGT), enzymes found primarily in the liver, as well as total bilirubin. The most common symptoms of PBC are pruritus and fatigue, which can be debilitating for some people. Progression of PBC is associated with an increased risk of liver-related mortality.

About Gilead Sciences in Liver Disease

For decades, Gilead has pioneered the way forward to improve the lives of people living with liver disease around the world. We have helped to transform hepatitis C from a chronic condition into one that can be cured for millions of people. For people living with hepatitis B or D, our focus on advancing our medicines drives hope that today's research will turn into tomorrow's cures. Beyond viral hepatitis, we're working to deliver advanced treatments for people living with PBC. But our commitment doesn't stop there. Through our ground-breaking science and collaborative partnerships, we strive to create healthier futures for everyone living with liver disease. We are committed to a future without liver disease.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead's ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials, including those involving Livdelzi (seladelpar) (such as the RESPONSE, ENHANCE, ASSURE and any confirmatory studies); uncertainties relating to regulatory applications and related filing and approval timelines, including MHRA and EMA reviews of seladelpar for the treatment of PBC; the risk that any regulatory approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements.

Livdelzi, Support Path, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies.

U.S. full Prescribing Information for Livdelzi is available at www.gilead.com .

For more information about Gilead, please visit the company's website at www.gilead.com , follow Gilead on X/Twitter (@Gilead Sciences) and LinkedIn (@Gilead-Sciences).

Source: Gilead Sciences, Inc.

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