linafexor (CS0159) / Cascade Pharma - LARVOL DELTA

Pulsatile FXR activation for liver diseases. (PubMed, Cell Metab) - "Sustained receptor activation is often prioritized in drug development. Zang and colleagues challenge this paradigm with linafexor, a rapidly cleared farnesoid X receptor agonist that produces pulsatile activation, preserves receptor responsiveness, reduces broad transcriptional disruption, and improves efficacy and safety, highlighting temporal alignment as a design principle for metabolic therapeutics."

Journal • Hepatology

Discovery of Novel Isoxazole-Based FXR Agonists Containing a 1,2,4-Oxadiazol-5(4H)-one Ring. (PubMed, J Med Chem) - "In particular, compound 34 (Linafexor) is a potent FXR agonist with favorable pharmacokinetic properties, high liver distribution, and ideal in vivo efficacy. It has completed Phase II clinical trial for patients with MASH and is currently undergoing a Phase III clinical trial for patients with primary biliary cholangitis (PBC). This article discusses the synthesis and biological properties of this type of new molecules."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis

Myeloid mas orchestrates chenodeoxycholic acid-driven gut-liver polyamine rheostat to govern MASLD (IDDF 2026) - "Conclusions This study reveals the key mechanism by which myeloid Mas regulates macrophage-epithelial crosstalk through the CDCA-FXR-EP300-Raptor-polyamine axis and demonstrates that myeloid-derived polyamines act as central mediators of gut-liver immunometabolic dialogue. Targeting this pathway, particularly through intervention with the FXR agonist CS0159, provides a novel therapeutic strategy and potential target for MASLD."

Hepatology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • CD36 • EP300 • MRC1 • SCARB1 • TYROBP

A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases. (PubMed, Nature) - P1 | "In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF1912-14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C415, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid-related liver diseases."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis

Drug Interaction and Food Effect Study of CS0159 (clinicaltrials.gov) - P1 | N=32 | Completed | Sponsor: Cascade Pharmaceuticals, Inc | Trial primary completion date: Feb 2027 ➔ Mar 2026 | Not yet recruiting ➔ Completed | Trial completion date: Feb 2027 ➔ Apr 2026

Trial completion • Trial completion date • Trial primary completion date

Linafexor in UDCA-inadequate PBC: A phase 2 trial of a pulsatile FXR agonist (EASL 2026) - "Background and aims: Up to 40% of patients with primary biliary cholangitis (PBC) have an inadequate response to ursodeoxycholic acid (UDCA), highlighting an unmet medical need. Linafexor, a novel pulsatile FXR agonist, demonstrated significant and durable improvements in biochemical markers with a manageable safety profile in patients with PBC. Based on these phase 2 findings, phase 3 clinical trials are now underway."

Late-breaking abstract • P2 data • Hepatology • Liver Failure • Primary Biliary Cholangitis • Pruritus

Efficacy, Safety, and Tolerability of CS0159 Combined With Semaglutide in MAFLD Patients With Obesity and T2DM (clinicaltrials.gov) - P=N/A | N=30 | Not yet recruiting | Sponsor: Shanghai Jiao Tong University School of Medicine

New trial • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

CS0159 in Chinese Patients With PBC (Primary Biliary Cholangitis) (clinicaltrials.gov) - P2 | N=75 | Active, not recruiting | Sponsor: Cascade Pharmaceuticals, Inc | Trial completion date: Jul 2025 ➔ Mar 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Hepatology • Immunology • Primary Biliary Cholangitis

CS0159 in Chinese Patients With PSC (Primary Sclerosing Cholangitis) (clinicaltrials.gov) - P2 | N=50 | Active, not recruiting | Sponsor: Cascade Pharmaceuticals, Inc | Recruiting ➔ Active, not recruiting | Trial completion date: Nov 2025 ➔ May 2026

Enrollment closed • Trial completion date

Drug Interaction and Food Effect Study of CS0159 (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Cascade Pharmaceuticals, Inc

New P1 trial

A Study of CS0159 in Patients With PBC With Inadequate Response or Intolerance to UDCA (clinicaltrials.gov) - P3 | N=135 | Recruiting | Sponsor: Cascade Pharmaceuticals, Inc | Active, not recruiting ➔ Recruiting

Enrollment open • Hepatology • Immunology • Primary Biliary Cholangitis

A Study of CS0159 in Patients With PBC With Inadequate Response or Intolerance to UDCA (clinicaltrials.gov) - P3 | N=135 | Active, not recruiting | Sponsor: Cascade Pharmaceuticals, Inc | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Immunology • Primary Biliary Cholangitis

A Study of CS0159 in Patients With PBC With Inadequate Response or Intolerance to UDCA (clinicaltrials.gov) - P3 | N=135 | Not yet recruiting | Sponsor: Cascade Pharmaceuticals, Inc

New P3 trial • Hepatology • Immunology • Primary Biliary Cholangitis

A Study of the Pharmacokinetics and Safety of CS0159 in Subjects With Hepatic Injury (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Cascade Pharmaceuticals, Inc | Recruiting ➔ Completed

Trial completion • Hepatology • Immunology • Liver Failure • Primary Biliary Cholangitis

A new agonist drug receives both orphan drug designation and breakthrough therapy designation [Google translation] (Sina Corp) - "This newspaper...reported that recently, the new farnesoid X receptor (FXR) agonist CS0159, jointly developed by the teams of Xu Huaqiang and Li Jia, researchers at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, has been granted both orphan drug designation and breakthrough therapy designation by the U.S. Food and Drug Administration. It is intended for the treatment of patients with primary biliary cholangitis (PBC)....CS0159 has demonstrated excellent efficacy and safety potential in a Phase II clinical trial for PBC. A Phase III clinical trial is planned to initiate in the second half of 2025 to further validate CS0159's efficacy and safety in a larger patient population, paving the way for its rapid market entry." "

Breakthrough therapy • New P3 trial • Orphan drug • Primary Biliary Cholangitis

Efficacy and Safety of CS0159 Combined With Semaglutide in MASH Patients With Obesity and T2DM (clinicaltrials.gov) - P=N/A | N=62 | Completed | Sponsor: Shanghai Jiao Tong University School of Medicine | Active, not recruiting ➔ Completed

Trial completion • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

A Study of the Pharmacokinetics and Safety of CS0159 in Subjects With Hepatic Injury (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Cascade Pharmaceuticals, Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology • Immunology • Liver Failure • Primary Biliary Cholangitis

Phase I Studies of a Novel Pulsatile FXR Ligand for Treating Cholestatic Liver Diseases (APASL 2025) - "Linafexor (CS0159) demonstrates an exceptional safety and tolerability profile in Phase 1 studies, with no adverse events reported and clear evidence of pharmacodynamic saturation at higher doses. These findings underscore the advantages of a pulse FXR ligand designed to synchronize with circadian bile acid metabolism, supporting its continued development as a promising therapy for cholestatic liver diseases, including MASH, PSC, and PBC."

P1 data • Cholestasis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis

Phase I Studies of a Novel Pulsatile FXR Ligand for Treating Cholestatic Liver Diseases (APASL 2025) - "Linafexor (CS0159), a pulse FXR ligand with a short half-life, demonstrated significant efficacy in treating Cholestatic liver diseases, including MASH, by modulating the metabolic cycle of bile acids in accordance with the fundamental principles of animal physiology. The circadian-dependent effects on bile acid metabolism may contribute to its enhanced efficacy and safety profile."

P1 data • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis

Phase 2 Studies of a Novel Pulsatile FXR Ligand for MASH (APASL 2025) - "Linafexor (CS0159) demonstrates robust efficacy and a remarkable safety profile in patients with MASH, with dose-dependent improvements in liver histology and metabolic markers. The alignment of Linafexor's pharmacokinetics with circadian bile acid rhythms underscores its potential as a new class therapeutic for MASH. Further studies are warranted to confirm these promising findings."

P2 data • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis

Phase II Studies of a Novel Pulsatile FXR Ligand for PBC and PSC (APASL 2025) - "The Phase 2 study results for Linafexor in PBC and PSC will be reported at the APASL 2025 meeting. Drawing from earlier studies, Linafexor is expected to offer a promising therapeutic option for these diseases, with efficacy and safety outcomes consistent with its novel mechanism of action and pharmacological profile."

P2 data • Cholestasis • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis

A Study of the Pharmacokinetics and Safety of CS0159 in Subjects With Hepatic Injury (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Cascade Pharmaceuticals, Inc

New P1 trial • Hepatology • Immunology • Liver Failure • Primary Biliary Cholangitis

CS0159 in Chinese Patients With PSC (Primary Sclerosing Cholangitis) (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Cascade Pharmaceuticals, Inc | Trial completion date: Dec 2024 ➔ Nov 2025 | Trial primary completion date: Dec 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Hepatology

Efficacy and Safety of CS0159 Combined With Semaglutide in MASH Patients With Obesity and T2DM (clinicaltrials.gov) - P=N/A | N=60 | Active, not recruiting | Sponsor: Shanghai Jiao Tong University School of Medicine | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

CS0159 in Chinese Patients With PBC (Primary Biliary Cholangitis) (clinicaltrials.gov) - P2 | N=75 | Active, not recruiting | Sponsor: Cascade Pharmaceuticals, Inc | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2024 ➔ Jul 2025

Enrollment closed • Trial completion date • Hepatology • Immunology • Primary Biliary Cholangitis