Seladelpar

FOSTER CITY, Calif.--( BUSINESS WIRE )--Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending seladelpar for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA alone, or as monotherapy in those unable to tolerate UDCA. The final European Commission decision is anticipated in the first quarter of 2025. This follows the accelerated approval by the U.S. Food and Drug Administration (FDA) in August 2024. PBC is a rare, chronic, autoimmune disease of the bile ducts that affects approximately 15 per 100,000 people in Europe, primarily women, and can cause liver damage and possible liver failure if untreated. The most common symptoms of PBC are pruritus (chronic itch) and fatigue, which can be debilitating for some people. The disease currently has no cure and treatment goals for people living with PBC include suppressing liver damage and reducing the symptoms related to cholestasis. The effect of treatment on slowing disease progression is primarily measured by an improvement in liver biochemical tests, including the normalization of alkaline phosphatase (ALP) levels, an important marker of disease progression in PBC. “ This positive opinion from the Committee confirms promising clinical benefit and value of seladelpar, which has been underscored by its differentiated body of data,” said Palak Trivedi, MD, BSc (Hons), MBBS, MRCP (UK), ESEGH, PhD, Associate Professor and Consultant Hepatologist at the Queen Elizabeth Hospital in Birmingham. “ After many years of treating people with PBC, I have seen the critical unmet need for additional effective and symptom-directed treatment options. Today’s recommendation of a potential new therapy that can help treat both the disease and improve symptoms that impact quality of life is a significant milestone for the PBC community.” The positive opinion was supported primarily by data from the pivotal placebo-controlled Phase 3 RESPONSE study. In the study, 62% of participants taking seladelpar achieved the primary endpoint of composite biochemical response at month 12 compared with 20% of participants taking placebo. Treatment with seladelpar led to normalization of ALP values in 25% of trial participants at month 12. This change was not seen in any trial participants receiving placebo. ALP is a cholestatic marker that is a predictor of risk for liver transplant and death. Change from baseline pruritus score at month 6 was a key secondary endpoint; treatment with seladelpar led to a statistically significant reduction in pruritus compared with placebo. Participants entering the study with moderate to severe itch experienced a 3.2-point improvement on a pruritus scale of 0-10 after six months of treatment with seladelpar, compared to a decrease of 1.7 points with placebo. “ We are encouraged by the CHMP’s positive opinion as we are one step closer to providing seladelpar to people living with PBC in Europe,” said Timothy Watkins, MD, MSc, Vice President, Clinical Development of Inflammation Therapeutics, Gilead Sciences. “ There are still people living with PBC who do not have an adequate response to current medicines or who are still experiencing symptoms, such as debilitating itch. As a leader in liver disease, Gilead is committed to bringing forth therapies that not only improve markers of disease progression but also help alleviate symptoms which impact the lives of people living with this rare liver condition.” In addition to Europe, Gilead is working with regulatory authorities on marketing applications for seladelpar in other parts of the world. In August 2024, the FDA granted accelerated approval for seladelpar for the treatment of PBC in combination with (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. Continued approval of seladelpar for the approved indication may be contingent on verification and description of clinical benefit in confirmatory trial(s). About RESPONSE (NCT04620733) RESPONSE is a Phase 3, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of seladelpar in adults with PBC who have shown inadequate response or intolerance to first-line treatment with UDCA. The trial enrolled 193 participants across multiple sites worldwide. RESPONSE assessed key biomarkers of cholestasis, including ALP levels, as well as secondary endpoints related to liver function and patient quality of life. Participants in the RESPONSE trial received a daily oral dose of 10 mg of seladelpar or placebo for 12 months, with a focus on measuring changes in ALP and other relevant liver function tests. The trial aimed to address the high unmet need for effective second-line therapies for individuals with PBC, providing important insights into the long-term management of this chronic liver disease. 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 110,000 people in Europe). 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 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 Seladelpar Seladelpar is an oral PPAR-delta agonist, or delpar, for the treatment of PBC. PPAR-delta has been shown to regulate critical metabolic and liver disease pathways. Preclinical and clinical data indicate seladelpar has anticholestatic, anti-inflammatory, antipruritic, and antifibrotic effects. Seladelpar has potential to help meet the current unmet need of people living with PBC, as the first and only treatment that achieved statistically significant improvements across biochemical response, ALP normalization, and pruritus versus placebo. Pruritus is a common symptom that can significantly impair quality of life in people with PBC. Livdelzi ® (seladelpar) was granted accelerated approval for the treatment of PBC by the U.S. Food and Drug Administration (FDA) in August 2024. Seladelpar received FDA Breakthrough Therapy Designation, as well as Orphan Drug Designation for the treatment of people living with PBC. Seladelpar has Priority Medicine (PRIME) designation in the EU, which is assigned to optimize the development of novel medicines that target conditions with an unmet medical need for which no treatment options exists or where they can offer a major therapeutic advantage over existing treatments. Seladelpar is also under review by the UK Medicines and Healthcare products Regulatory Agency (MHRA). 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 U.S. approval may be contingent upon verification of clinical benefit in confirmatory trial(s). U.S. Indication for Livdelzi (seladelpar) 10mg capsules 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 (e.g., 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 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. The company has helped to transform hepatitis C from a chronic condition into one that can be cured for millions of people. For individuals living with hepatitis B or D, Gilead's focus on advancing medicines drives hope that today’s research will turn into tomorrow’s cures. Beyond viral hepatitis, Gilead is working to deliver advanced treatments for people living with PBC. The commitment of Gilead doesn’t stop there. Through ground-breaking science and collaborative partnerships, the company strives to create healthier futures for everyone living with liver disease. Gilead remains devoted 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 and any confirmatory studies); uncertainties relating to regulatory applications and related filing and approval timelines, including European Commission and MHRA 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.

The Food and Drug Administration has identified additional safety concerns associated with use of a drug used to treat a rare liver condition in the latest sign of trouble for a medicine once seen as a future blockbuster.The agency on Thursday said its found cases of serious liver injury among patients with the rare disease primary biliary cholangitis and treated with a drug called Ocaliva, U.S. rights to which are currently owned by Italian pharmaceutical company Alfasigma. The findings were uncovered in a review of post-approval clinical trial data, and notably indicated these events occurred in patients who didnt yet have cirrhosis, or scarring of the liver. The agency three years ago restricted use of Ocaliva in those who already have advanced cirrhosis.According to the FDA, since curtailing Ocalivas use in 2021, the agency identified 20 more instances of liver transplants, listings for liver transplants, or liver-related deaths among people who received treatment. In its statement, the FDA cautioned that frequent liver test monitoring is necessary to catch a decline in organ function early in someone taking Ocaliva and to ensure appropriate discontinuation of treatment.The regulator advised doctors to stop use if patients have any evidence of disease progression or if Ocaliva isnt clearly effective. It will continue watching Ocalivas safety profile and follow up if new information arises.The announcement is another setback for Ocaliva, a drug that was once among the most closely watched medicines in the biotechnology industry.Known scientifically as obeticholic acid, Ocaliva was originally developed by biotech company Intercept Pharmaceuticals, which in 2016 secured for the drug the first FDA approval for PBC in two decades. Intercept had broader ambitions, aiming to make the drug the first available therapy for a far more common liver disease now known as metabolic dysfunction associated steatohepatitis, or MASH.Early clinical data caused Intercepts value to soar and made MASH, a leading cause of liver transplants, a top target for drugmakers. But further results made the drugs benefits less clear, and safety risks chiefly the potential for drug-induced injury more apparent. The FDA twice, in 2020 and again in 2023, rejected Ocalivas use in MASH, forcing Intercept to lay off staff and abandon development. Intercept sold to Alfasigma months after the second rejection.Since then, use of Ocaliva has been curtailed further. European regulators this year revoked its marketing authorization in the EU, where Ocaliva rights were owned by Advanz Pharma following a 2022 deal with Intercept. The FDA also declined to convert Ocalivas accelerated approval in 2016 into a standard clearance, though the agency still allowed the company to market the drug under its original OK.New competitors have emerged, too, as the FDA approved Ipsens Iqirvo in June and Gilead Sciences Livdelzi two months later.PBC is estimated to affect about 100,000 people in the U.S. The disease causes progressive organ damage and cirrhosis, and is often associated with severe itching and fatigue. '