AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials

作     者：Armisen, Javier Rauschecker, Mitra Sarv, Janeli Liljeblad, Mathias Wernevik, Linda Niazi, Mohammad Knöchel, Jane Eklund, Olof Sandell, Therése Sherwood, James Bergenholm, Linnéa Hallén, Stefan Wang, Shan Kamble, Prasad Bhat, Maria Maxvall, Ingela Wang, Yixin Lee, Richard G. Bhanot, Sanjay Guo, Shuling Romeo, Stefano Lawitz, Eric Fjellström, Ola Lindén, Daniel Blau, Jenny E. Loomba, Rohit 

作者机构：Research and Early Development Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Cambridge United Kingdom Research and Early Development Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gaithersburg MD United States Late Stage Development Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden Translational Science and Experimental Medicine Research and Early Development Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden Clinical Operations Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden Clinical Pharmacology and Quantitative Pharmacology Clinical Pharmacology & Safety Sciences R&D AstraZeneca Gothenburg Sweden Global Patient Safety Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden Precision Medicine and Biosamples Diagnostic and HBS Science Biopharma Diagnostics Oncology R&D AstraZeneca Cambridge United Kingdom Drug Metabolism and Pharmacokinetics Research and Early Development Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden Bioscience Metabolism Research and Early Development Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden Image Analysis & Platform Pathology Clinical Pharmacology and Safety Sciences BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden Ionis Pharmaceuticals Inc. Carlsbad CA United States Department of Molecular and Clinical Medicine Institute of Medicine The Sahlgrenska Academy Wallenberg Laboratory University of Gothenburg Gothenburg Sweden Department of Cardiology Sahlgrenska University Hospital Gothenburg Sweden Department of Medical and Surgical Sciences University Magna Graecia Catanzaro Italy Texas Liver Institute University of Texas Health San Antonio San Antonio TX United States Research and Early Development Cardiovascular Renal and Metabolism BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden MASLD Research Center Division of Gastroenterology and Hepatology University of California at San Diego La Jolla CA United States 

出 版 物：《Journal of Hepatology》 (J. Hepatol.)

年 卷 期：2025年第83卷第1期

页      面：31-42页

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：AstraZeneca  AZ 

主　　题：antisense oligonucleotide (ASO) clinical trial Liver disease metabolic dysfunction-associated steatohepatitis (MASH) metabolic dysfunction-associated steatotic liver disease (MASLD) non-alcoholic fatty liver disease (NAFLD) non-alcoholic steatohepatitis (NASH) patatin-like phospholipase domain-containing protein 3 (PNPLA3) precision medicine 

摘      要：Background & Aims: A common genetic variant (rs738409) encoding an isoleucine to methionine substitution at position 148 in the PNPLA3 protein is a determinant of hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver-related mortality. AZD2693 is a liver-targeted antisense oligonucleotide against PNPLA3 mRNA. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics in single and multiple ascending dose studies. Methods: AZD2693 was assessed in 3D cultures of homozygous PNPLA3 148M primary human hepatocytes and mice expressing human PNPLA3. The single ascending dose study investigated 2–110 mg doses in overweight/mildly obese but otherwise healthy volunteers. The multiple ascending dose study investigated three monthly doses (25 mg, 50 mg and 80 mg) in participants with MRI-proton density fat fraction (MRI-PDFF) ≥7%. Changes in liver fat content were assessed at baseline, weeks 8 and 12 by MRI-PDFF. PNPLA3 mRNA and protein knockdown levels were evaluated for the 80 mg dose. Results: AZD2693 potently reduced PNPLA3 expression in human hepatocytes and livers of mice. Clinically, AZD2693 was generally well tolerated (no adverse events leading to discontinuation or treatment-related serious adverse events). Half-life was 14–33 days across investigated doses. A least-square mean liver PNPLA3 mRNA knockdown of 89% and reduction of protein levels demonstrated target engagement. Changes in hepatic steatosis at week 12 were −7.6% and −12.2% (placebo-corrected least-square means) for the 25 mg and 50 mg doses, respectively. There was a dose-dependent increase of polyunsaturated fatty acids in serum triglycerides and decreases vs. placebo in high-sensitivity C-reactive protein and interleukin 6. Conclusions: AZD2693 reduced liver PNPLA3 with an acceptable safety and tolerability profile. These findings support the continued development of AZD2693. Impact and implications: Clinical treatment options for metabolic dysfunction-associated steatohepati