A Proof-of-Concept, Open-Label Study Evaluating the Safety and Tolerability of Cilofexor in Subjects With Primary Sclerosing Cholangitis (PSC) and Compensated Cirrhosis

The primary objective of this study is to assess the safety and tolerability of escalating doses of cilofexor (CILO) in participants with primary sclerosing cholangitis (PSC) and compensated cirrhosis.

Start Date17 Oct 2019

Sponsor / Collaborator

Gilead Sciences, Inc.

NCT03987074 / CompletedPhase 2

A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)

The primary objective of this study is to evaluate the safety and tolerability of study drug(s) in participants with nonalcoholic steatohepatitis (NASH).

Start Date29 Jul 2019

Sponsor / Collaborator

Gilead Sciences, Inc.

[+1]

ACTRN12619000655145 / CompletedPhase 1

A Phase 1 Open-Label, Parallel-Group, Two-Treatment, Single-Dose Study to Evaluate the Pharmacokinetics of GS-9674 and GS-0976 in Subjects with Normal Renal Function and Severe Renal Impairment

Start Date24 Jul 2019

Sponsor / Collaborator

Gilead Sciences, Inc.

100 Clinical Results associated with Cilofexor tromethamine

100 Translational Medicine associated with Cilofexor tromethamine

100 Patents (Medical) associated with Cilofexor tromethamine

Literatures (Medical) associated with Cilofexor tromethamine

01 Dec 2024·American Journal of Physiology-Gastrointestinal and Liver Physiology

Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition

Article

Author: Luedde, Tom ; Dawson, Paul A. ; Bennett, Ashley L. ; Karpen, Saul J. ; Ebert, Matthias ; Herebian, Diran ; Klindt, Caroline ; Mayatepek, Ertan ; Truong, Jennifer K. ; Pachura, Kimberly J.

Bile acids are implicated as a common contributor to the pathogenesis and progression of cholestatic liver disease. Using a mouse model with a humanized bile acid composition, we demonstrated that mono and combination therapy using an IBAT inhibitor and FXR nonsteroidal agonist were effective at reducing hepatic bile acid accretion and reversing liver injury, without reducing hepatic bile acid hydrophobicity. The findings support the concept of a therapeutically tractable threshold for bile acid-induced liver injury.

01 Jul 2024·European Journal of Pharmacology

Novel insights into gut health: Cilostazol strengthens gut integrity by adjusting TLR-2/NF-κB/IL-23 and CD44/AKT/GSK-3β/cyclin-D1 trajectories in methotrexate-induced mucositis model

Article

Author: Sabra, Omar ; El-Komy, Fatma ; El-Abhar, Hanan ; Mansour, Suzan M ; Ahmed, Kawkab

Methotrexate (MTX)-induced gastrointestinal mucositis is a common adverse effect characterized by redox imbalance and overproduction of inflammatory mediators that perturb intestinal integrity. Currently, there is no definitive treatment for this condition and its prevention is still far beyond comprehension. Because of its pleiotropic pharmacological actions, we aimed to explore the potential mechanisms through which cilostazol (CILO) can protect against MTX-induced intestinal mucositis. Wistar rats were allocated into 4 groups, control, CILO (100 mg/kg, p.o for 14 days), MTX (7.5 mg/kg for 4 successive days), and CILO + MTX. The improving effect of CILO on the morphological structure was confirmed by an upturn in the histopathological and transition electron microscope examinations evidenced by the increased jejunal villus height/width and the crypt depth besides the maintenance of tight junctions. These findings were verified biochemically; on the molecular level, CILO reduced the MTX-induced lipid peroxidation, cleaved caspase-3, p53, and the inflammatory parameters (TLR-2, NF-κB, IL-23, TNF-α, IL-1β), while increasing the anti-inflammatory marker IL-10 and the antioxidant enzyme SOD. Moreover, CILO decreased the injurious axis AKT/GSK-3β/cyclin-D1, and CD44⁺, but increased the immunoexpression of the cell proliferating marker PCNA. CILO also upheld the intestinal barrier by enhancing the tight junction molecules (ZO-1, claudin-4) and the E-cadherin/β-catenin complex while abating the mesenchymal marker vimentin. In conclusion, CILO protected gut integrity by reducing the epithelial-mesenchymal transition process, the MTX-induced oxidative, apoptotic, and inflammatory mediators, and turning off the CD44/AKT/GSK-3β/cyclin D1 trajectory and intensifying the expression of PCNA.

01 Jun 2024·Clinical Pharmacology in Drug Development

Evaluation of the Effects of Meal Type and Acid‐Reducing Agents on the Pharmacokinetics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist

Article

Author: Wang, Lulu ; Barchuk, William T ; Othman, Ahmed A ; Xiao, Deqing ; Weber, Elijah J ; Younis, Islam R

AbstractCilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated the effects of food and acid‐reducing agents (ARAs) on the pharmacokinetics of cilofexor (100‐ or 30‐mg fixed‐dose combination with firsocostat) in healthy participants. Cohorts 1 (n = 20, 100 mg) and 2 (n = 30, 30 mg) followed a 3‐period, 2‐sequence crossover design and evaluated effects of light‐fat and high‐fat meals. Cohort 3 (n = 30, 100 mg fasting) followed a 2‐period, 2‐sequence crossover design and evaluated the effects of a 40‐mg single dose of famotidine. Cohort 4 (n = 18, 100 mg) followed a 3‐period, 2‐sequence crossover design and evaluated the effects of a 40‐mg once‐daily regimen of omeprazole administered under fasting conditions or following a light‐fat meal. Administration with light‐fat or high‐fat meals resulted in no change and an ∼35% reduction in cilofexor AUC, respectively, relative to the fasting conditions. Under fasting conditions, famotidine increased cilofexor AUC by 3.2‐fold and Cmax by 6.1‐fold, while omeprazole increased cilofexor AUC by 3.1‐fold and Cmax by 4.8‐fold. With a low‐fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5‐fold, AUC 2.1‐fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30 mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations.

News (Medical) associated with Cilofexor tromethamine

22 Oct 2024

·www.biospace.com

Gilead to Present Latest Research Across Key Liver Disease Indication at the American Association for the Study of Liver Disease (AASLD) Meeting 2024

- Key Insights from Viral Hepatitis, PBC, and MASH/Fibrosis Studies Highlight Gilead’s Ongoing Commitment to Advancing Life-Changing Liver Disease Research - FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced new research to be presented at The Liver Meeting ® 2024, hosted by the American Association for the Study of Liver Diseases (AASLD) from November 15-19 in San Diego, Calif. More than 40 abstracts will be presented with key data, including 11 abstracts reporting new data on primary biliary cholangitis (PBC). The data will include findings from the RESPONSE trial that demonstrate the efficacy and safety pro Livdelzi ® (seladelpar) in people living with PBC and compensated cirrhosis. Additionally, data will be presented on the effects of Livdelzi on pruritus (chronic itching), a symptom that has significant impact on the quality of life of people living with PBC, along with interim long-term efficacy and safety results from the ongoing ASSURE study. Beyond PBC, Gilead will be presenting an interim analysis of the Phase 3 MYR301 study, which is evaluating people living with hepatitis Delta virus (HDV) who received bulevirtide monotherapy (2 mg for 144 weeks; 10 mg for 144 weeks; or 10 mg for 96 weeks) for chronic HDV and have been off treatment for 48 weeks. The study is evaluating whether or not patients treated with bulevirtide monotherapy for 2-3 years maintained virological and biochemical responses one year after stopping treatment. An additional 144-week analysis of patient-reported outcomes for individuals treated with bulevirtide 2 mg will also be presented, adding to the wealth of long-term data for the treatment for chronic HDV. “We’re excited to share our latest research at The Liver Meeting, as we push the boundaries of what’s possible in liver disease treatment. The breadth of this research reflects Gilead’s unwavering dedication to advancing life-changing science and shaping healthier futures for people living with liver disease,” said Anu Osinusi, Vice President of Clinical Development for Hepatitis, Respiratory and Emerging Viruses, Gilead Sciences. “The depth and range of our data, spanning both viral and inflammatory liver diseases, underscores our commitment to making a meaningful impact at every stage of a person’s journey in liver disease. Our goals go far beyond treatment alone—our work spans awareness, education, screening, diagnosis, and long-term care, all intending to address unmet needs and enhance treatment outcomes.” Gilead will also present hepatitis C virus (HCV) data which will include safety and tolerability outcomes for Epclusa ® (velpatasvir/sofosbuvir) in pregnant individuals with chronic HCV (the STORC study). As a special population that is often excluded from clinical research, these results may help clinicians better support pregnant people living with HCV, which in turn may reduce the risk of transmission to infants. Furthermore, real-world findings from the SVR10K study on HCV will be showcased, demonstrating the effects of direct-acting antivirals against all HCV genotypes across diverse regions. Late-breaking data from a Phase 2a open-label study assessing the safety and efficacy of novel combination therapies for chronic hepatitis B virus (HBV) will also be presented by Gilead. Key Abstracts at AASLD 2024: ID Abstract Title PBC 164 Efficacy and Safety of Seladelpar in Patients with PBC and Compensated Cirrhosis in the Phase 3 Placebo-controlled RESPONSE Trial 167 Attenuation, Near Resolution, and Prevention of Pruritis in Patients with PBC Treated with Seladelpar: A Secondary Analysis of Patterns of Pruritis Change in the RESPONSE Trial 4339 Alkaline Phosphatase Changes with Seladelpar Across Subgroups of Primary Biliary Cholangitis Patients in the RESPONSE Trial 4342 Seladelpar and Reductions in Lipids in Patients with Primary Biliary Cholangitis with and without Statin use in the Phase 3 Placebo-controlled RESPONSE Study 4341 Long-term Safety of Seladelpar 10 mg with up to 5 Years of Treatment in Patients with Primary Biliary Cholangitis Primary sclerosing cholangitis (PSC) 151 Associations Between Biomarkers and Magnetic Resonance Imaging-derived ANALI Score in Patients with Primary Sclerosing Cholangitis: Analysis from the Phase 3 PRIMIS Study HDV 1147 Efficacy and Safety of BLV Monotherapy for Chronic Hepatitis Delta: Post Treatment Results through 48 Weeks after the End of Treatment from an Interim Analysis of a Randomized Phase 3 Study MYR301 1193 Patient-reported Outcomes among Patients with Chronic Hepatitis Delta Treated with Bulevirtide 2 mg: A Long-term Analysis of the Phase 3 MYR301 Trial at 144 Weeks 139 Long-term Bulevirtide Monotherapy in Patients with HDV-related Compensated Cirrhosis: Effectiveness, Safety and Clinical Outcomes from the Retrospective Multicenter European Study (SAVE-D) HCV 222 Safety, Tolerability, and Outcomes of Velpatasvir/Sofosbuvir in Treatment of Chronic Hepatitis C Virus during Pregnancy (STORC) 1455 The SVR10K Study: A Real-world Data with Pangenotypic Direct-acting Antivirals across Multiple Diverse Regions 1476 Hepatitis C Treatment Uptake Differs by Gender among a Commercially Insured Population in the United States HBV 1380 Results from a Phase 2a, Open-label Study to Evaluate the Safety and Efficacy of Novel Combination Therapies Containing VIR-2218, Selgantolimod, and Nivolumab for the Treatment of Chronic Hepatitis B 1252 Effectiveness and Safety of Tenofovir Alafenamide in Chronic Hepatitis B Patients with Suboptimal Response to Antiviral Therapy 1337 Characterization of Changes in Noninvasive Fibrosis Markers over 8 Years of Tenofovir-based Treatment in Chronic Hepatitis B Patients Enrolled in Two Phase 3 Trials Nonalcoholic steatohepatitis (NASH)/Fibrosis 1520 Prospective Validation of the Mediterranean Diet Adherence Screener (MEDAS) for Point-of-care Assessment of Diet Quality in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease For more information, including a complete list of abstract titles being presented at the meeting, please visit the AASLD website . In July 2023, the European Commission (EC) granted full Marketing Authorization (MA) for bulevirtide 2 mg for the treatment of adults with chronic HDV and compensated liver disease. Bulevirtide’s conditional MA license in Great Britain was converted to a full MA in August 2023 and a full MA was granted in Switzerland and Australia in 2024. In regions where it is not approved, including the U.S., bulevirtide 2 mg is an investigational product. In these regions, health authorities have not established the safety and efficacy of bulevirtide. Bulevirtide 10 mg is an investigational product and has not been approved anywhere. Cilofexor and selgantolimod are investigational compounds and are not approved by the FDA or any other regulatory authority; their safety and efficacy have not been established. Please see below for the U.S. Indications and Important Safety Information, including BOXED WARNINGS, for Epclusa and Livdelzi. U.S. Important Safety Information And Indication for EPCLUSA BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. Contraindications If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information. Warnings and Precautions Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with EPCLUSA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers and/or Moderate to Strong Inducers of CYP2B6, CYP2C8 or CYP3A4 : Rifampin, St. John’s wort and carbamazepine are not recommended for use with EPCLUSA as they may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations. Adverse Reactions The most common adverse reactions (≥10%, all grades) with EPCLUSA in adults and pediatric patients 6 years of age and older were headache and fatigue; and when used with RBV in adults with decompensated cirrhosis were fatigue, anemia, nausea, headache, insomnia and diarrhea. The most common adverse reactions (≥10%, grade 1 or 2) in pediatric patients less than 6 years of age were vomiting and spitting up the drug. Drug Interactions Coadministration of EPCLUSA is not recommended with topotecan due to increased concentrations of topotecan. Coadministration of EPCLUSA is not recommended with proton-pump inhibitors, phenobarbital, phenytoin, rifabutin, rifapentine, efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir. Consult the full Prescribing Information for EPCLUSA for more information on potentially significant drug interactions, including clinical comments. Indication EPCLUSA is indicated for the treatment of adult and pediatric patients 3 years of age and older with chronic hepatitis C virus genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis. 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. Indication LIVDELZI is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have 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). About HDV HDV is considered the most aggressive or severe form of viral hepatitis, associated with more rapid progression towards liver-related death and liver cancer in people with HBV. On average, HDV progresses to cirrhosis within 5 years and to liver cancer within 10 years. Nearly 5% of people who have a chronic infection with HBV are estimated to have HDV, equating to 12-15 million people worldwide. The prevalence of HDV infection is largely underestimated due to lack of universal testing of HBV-positive individuals for HDV. 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 or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials or studies, including those involving Epclusa, Hepcludex (bulevirtide), Livdelzi (seladelpar), cilofexor and selgantolimod (such as the ASSURE, RESPONSE, MYR301, STORC and SVR10K studies); uncertainties relating to regulatory applications and related filing and approval timelines, including the risk that the FDA and other regulatory authorities may not approve bulevirtide for the treatment of HDV, and the risk that any such approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; the possibility that Gilead may make a strategic decision to discontinue development of investigational programs for indications that are currently under evaluation and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; 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 June 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. Epclusa, Hepcludex, Livdelzi, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. For more information about Gilead, please visit the company’s website at , follow Gilead on Twitter (@Gilead Sciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. Contacts Meaghan Smith, Media public_affairs@gilead.com Jacquie Ross, Investors investor_relations@gilead.com

Phase 2Clinical ResultDrug ApprovalPhase 3

12 Feb 2024

·medcitynews.com

Gilead’s $4.3B CymaBay Acquisition Adds Liver Disease Drug Under FDA Review

Gilead Sciences is acquiring biotech company CymaBay Therapeutics in a $4.3 billion deal that comes with a drug candidate currently under FDA review in a rare liver disease with few treatments. According to deal terms announced Monday, Gilead will pay $32.50 cash for each share of CymaBay. That price is a 27% premium to CymaBay’s closing stock price on Friday. The acquisition marks a comeback for the company and its drug, which just a few years ago faced an uncertain future amid safety questions. The main asset of CymaBay is seladelpar, a drug that the Newark, California-based company has developed for treating primary biliary cholangitis (PBC), a rare and progressive autoimmune condition that destroys the bile ducts of the liver. But this small molecule was at one time among the leading drug candidates for nonalcoholic steatohepatitis (NASH), a fatty liver disease that has no FDA-approved treatments. In 2019, a safety signal led CymaBay to stop a mid-stage test of seladelpar in NASH as well as a recently started study in primary sclerosing cholangitis, another chronic liver disorder. The FDA subsequently placed a formal clinical hold on the drug. The hold also stalled the development of the drug in PBC. The FDA cleared the company to resume testing of the drug in 2020, but CymaBay elected to continue development only in PBC. PBC is a chronic disorder that mainly affects women over the age of 40, impairing liver function. Common early symptoms include severe pruritus (itching) and fatigue. PBC can progress to cirrhosis and liver failure. The first-line drug treatment for PBC is ursodeoxycholic acid, or ursodiol, an old drug for dissolving gallstones that in 1996 won an additional approval as a treatment for PBC. The Intercept Pharmaceuticals drug Ocaliva was approved in 2016 as a second-line therapy for PBC. Intercept, which was acquired late last year by Italian company Alfasigma, reported $240.4 million in sales for the drug in the nine months ended Sept. 30, 2023. CymaBay’s seladelpar is a small molecule designed to bind to and activate peroxisome proliferator activated receptor delta (PPAR delta), a receptor that regulates genes involved in the synthesis of bile acids, metabolism, inflammation, and fibrosis. In its placebo-controlled Phase 3 clinical trial, results showed treatment with the drug led to statistically significant normalization of enzymes indicative of liver disease as well as improvement in pruritus. Late last year, CymaBay submitted a new drug application seeking approval of seladelpar as a treatment for patients who are inadequate responders to or intolerant of ursodiol. CymaBay announced Monday that the FDA will evaluate the application under priority review, setting an Aug. 14 target date for a regulatory decision. Gilead’s portfolio of liver disease drugs include the hepatitis B drugs Vemlidy and Viread as well as hepatitis C drug Harvoni. The Foster City, California-based drugmaker is also in the chase for NASH (now also called MASH, for metabolic associated steatohepatitis) with cilofexor and firsocostat, which are in Phase 2 testing as part of a combination treatment with Novo Nordisk’s semaglutide. “Building on the strong research and development work by the CymaBay team to date, we have the potential to address a significant unmet need for people living with PBC and expand on our existing broad range of transformational therapies,” Gilead Chairman and CEO Daniel O’Day said in a prepared statement. CymaBay licensed seladelpar from Johnson & Johnson in a 2006 deal. If it’s approved, J&J is in line to receive royalties from sales. The CymaBay pipeline also includes MBX-2982, a molecule in Phase 2a testing for treating hypoglycemia in patients with type 1 diabetes. In a note sent to investors, William Blair analyst Andy Hsieh wrote that the CymaBay acquisition validates the clinical performance and commercial potential of seladelpar in PBC. He called the acquisition “poetic closure” for the company following the molecule’s previous clinical trial setbacks “We commend management’s resilience and persistence that ultimately led to seladelpar demonstrating the best-in-class clinical profile in PBC, and we expect the drug to benefit thousands of patients living with PBC as soon as later this year,” Hsieh said. Hsieh said the Gilead offer is fair and it is unlikely another bidder will emerge. The transaction requires the majority of CymaBay shareholders to tender their shares. The companies expect to close the transaction in the current quarter.

Phase 2AcquisitionClinical ResultPhase 3Drug Approval

12 Feb 2024

·www.fiercebiotech.com

Gilead pays $4.3B for CymaBay, the biotech that never gave up on liver disease med

CymaBay Therapeutics CEO Sujal Shah said its time for Gilead Sciences to apply its regulatory and commercial expertise to advancing liver disease med seladelpar. Gilead Sciences is bolstering its liver disease portfolio with the $4.3 billion acquisition of CymaBay Therapeutics, specifically for the primary biliary cholangitis (PBC) med seladelpar. The deal follows a Big Pharma trend of picking up late-stage, validated assets. Seladelpar was submitted to the FDA to treat PBC with pruritus, or itching, without cirrhosis or with compensated cirrhosis in December 2023. The rare liver disease primarily affects women over 40 and is characterized by impaired bile flow and the accumulation of bile acids in the liver, causing an elevation of liver enzymes that can be dangerous. Seladelpar was granted a priority review for the condition with a due date of Aug. 14 for a decision, according to a separate update from CymaBay this morning. “We are looking forward to advancing seladelpar by leveraging Gilead’s long-standing expertise in treating and curing liver diseases,” said Gilead CEO Daniel O’Day in a Monday statement. “Building on the strong research and development work by the CymaBay team to date, we have the potential to address a significant unmet need for people living with PBC and expand on our existing broad range of transformational therapies.” This will not be new territory for Gilead, which has a deep portfolio of HIV meds and has also previously tested GS-9674 for PBC. The med, now known as cilofexor, was unsuccessful in PBC and the related disease primary sclerosing cholangitis. Gilead is now testing cilofexor in combination with Novo Nordisk’s semaglutide for metabolic dysfunction-associated steatohepatitis (MASH—previously known as nonalcoholic steatohepatitis or NASH). Seladelpar improved levels of serum alkaline phosphatase and bilirubin, as well as reduced itch, in a phase 3 trial that read out in September. The data teed up the regulatory filing. It wasn’t smooth sailing for the med through the clinic, with seladelpar failing in MASH in 2019. But CymaBay pressed on, culminating in today’s deal with Gilead. “Now that seladelpar has achieved priority review with the FDA, we are excited that Gilead, with its long-standing commitment to patients with liver disease, can apply its regulatory and commercial expertise to bring seladelpar as quickly as possible to people with PBC,” CymaBay CEO Sujal Shah said in a statement. The deal has been approved by members of each company’s board and is set to close in the first quarter. CymaBay will become a wholly owned subsidiary of Gilead at close. Gilead is paying $32.50 per share in cash, a 27% premium to CymaBay's closing price as of Feb. 9. CymaBay's shares climbed 24% in premarket trading Monday to $32 apiece, compared to $25.69 at close Friday. William Blair analysts said the Gilead deal validates the clinical performance and potential of seladelpar. "The acquisition by Gilead represents a poetic closure to the CymaBay story," the firm wrote, noting the company's difficult decision to cut the MASH indication after adverse events cropped up. "We commend management’s resilience and persistence that ultimately led to seladelpar demonstrating the best-in-class clinical profile in PBC, and we expect the drug to benefit thousands of patients living with PBC as soon as later this year." William Blair had previously assumed an acquisition price of $2.9 billion, calling the Gilead offer fair. The firm assumes that no other bidder will emerge with a better offer, and the deal will close as planned.

AcquisitionPhase 3Priority ReviewClinical Result

100 Deals associated with Cilofexor tromethamine

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cholangitis, Sclerosing	Phase 3	BE	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 3	FI	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 3	AU	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 3	AT	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 3	ES	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 3	FR	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 2	JP	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 1	DK	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Phase 1	DE	Gilead Sciences, Inc.	27 Mar 2019
Cholangitis, Sclerosing	Preclinical	IL	Gilead Sciences, Inc.	27 Mar 2019

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04060147 (Phase 1B Study, Pubmed)	Phase 1	Cholangitis, Sclerosing alanine transaminase \| alkaline phosphatase \| gamma-glutamyl transferase ... View more	11	Cilofexor 30 mg	liihsyfocv(dwzjsajpne) = fatigue (2/11 [18.2%]) mcirwviccw (kqhghqekri ) View more	Positive	01 Jul 2024
				Cilofexor 60 mg
NCT03890120 (PRIMIS, CTgov)	Phase 3	Cholangitis, Sclerosing	419	Cilofexor (Cilofexor 100 mg (Blinded Phase))	eovnhwdctt(sruigdkolc) = mpjdrryqzp isbxiudlze (zidyxnvyim, gndcaykpuw - fqoklymbbz) View more	-	29 Nov 2023
				Placebo (Placebo (Blinded Phase))	eovnhwdctt(sruigdkolc) = rezcfvoahh isbxiudlze (zidyxnvyim, hpnybsvqms - vezgiczptk) View more
NCT04060147 (Phase 1B Study, CTgov)	Phase 1	Fibrosis \| Cholangitis, Sclerosing \| Compensated cirrhosis	11	Cilofexor	jytcnhblgl(xxavdbipdo) = kinsyylwmc gitmquzrzj (mglfqqxkrb, rguzqvypxh - xdkcremxar) View more	-	27 Jul 2023
PRIMIS (EASL2022)	Not Applicable	Cholangitis, Sclerosing	11	Cilofexor 30 mg	nupzsletss(xtkhpvjfrs) = xvaddwivte hfhwcprghg (twlifcpjhm ) View more	Positive	23 Jun 2022
NCT03987074 (Pubmed \| J Hepatol) Manual	Phase 2	Nonalcoholic Steatohepatitis	108	Semaglutide+Cilofexor tromethamine	(khrqleocco) = Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. cbtryoksqk (zfdbpdmexc ) View more	Positive	16 Apr 2022
				Semaglutide+Firsocostat+Cilofexor tromethamine
NCT02781584 (Pubmed \| Clin Gastroenterol Hepatol) Manual	Phase 2	Hypertriglyceridemia \| Nonalcoholic Steatohepatitis	66	Fenofibrate+Cilofexor tromethamine+FirsocostatFirsocostat	(krkzdxlwbk) = most treatment-emergent adverse events were Grade 1 to 2 severity lhlexdaopz (iygafdlawc ) View more	Positive	06 Jan 2022
				Icosapent Ethyl+Cilofexor tromethamine+Firsocostat
NCT03987074 (CTgov)	Phase 2	Nonalcoholic Steatohepatitis	109	Semaglutide (Semaglutide)	bpmrckkyno(vvirpbfidx) = scqzhnvhnp jgqugpnmom (ufgzxtxagk, wkquribheq - cgcjqzylho) View more	-	15 Jul 2021
				Semaglutide+Firsocostat (Semaglutide + Firsocostat 20 mg)	bpmrckkyno(vvirpbfidx) = ovqjcbcegh jgqugpnmom (ufgzxtxagk, pghyjjndkb - fbjgjajdwz) View more
NCT03449446 (ATLAS, CTgov)	Phase 2	Nonalcoholic Steatohepatitis \| Fibrosis \| Compensated cirrhosis	395	Placebo to match SEL	bfihcswvks(afcukfzmlc) = eguccielna pjkjjtkrbp (ossbftustg, kfivbdhulr - ibbmtzoojq) View more	-	03 Dec 2020
NCT02808312 (CTgov)	Phase 1	Nonalcoholic Steatohepatitis \| Cholangitis, Sclerosing	57	Cilofexor (Cohort 1: Mild Hepatic Impairment)	xqknyakfgn(hrryxvuomc) = mhkxywbxcb zxbikccgfx (mihfmsjwyg, arzzetruka - ussqcxlbcv) View more	-	30 Sep 2020
				Cilofexor (Cohort 1: Normal Hepatic Function)	xqknyakfgn(hrryxvuomc) = sdlcpezmop zxbikccgfx (mihfmsjwyg, wcuphnedhe - ahejerywvx) View more
NCT02854605 (Pubmed \| Hepatology)	Phase 2	Nonalcoholic Steatohepatitis	140	Cilofexor 100 mg	(wkiipksnpr) = przctlbkvz gdczqtdxey (pvwgtlyrdc )	-	01 Jul 2020
				Cilofexor 30 mg	(wkiipksnpr) = yzefgsxutv gdczqtdxey (pvwgtlyrdc )

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