AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: two randomized phase I trials
Journal of Hepatology, 2025
Armisen J., Rauschecker M., Sarv J., Liljeblad M., Wernevik L., Niazi M., Knöchel J., Eklund O., Sandell T., Sherwood J., Bergenholm L., Hallén S., Wang S., Kamble P., Bhat M., Maxvall I., Wang Y., Lee R., Bhanot S., Guo S., Romeo S., Lawitz E., Fjellström O., Lindén D., Blau J., Loomba R.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases Hepatology | Pathophysiology | Plasma | O Olink Target 96 |
Abstract
Background & Aims
A common genetic variant (rs738409) encoding isoleucine to methionine 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 ascending dose (SAD) and multiple ascending dose (MAD) studies.
Methods
AZD2693 was assessed in 3D cultures of homozygous PNPLA3 148M primary human hepatocytes and mice expressing human PNPLA3. The SAD study investigated 2–110 mg doses in overweight/mildly obese but otherwise healthy volunteers. The MAD study investigated three monthly doses (25 mg, 50 mg and 80 mg) in participants with magnetic resonance imaging 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 (LS) 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 LS 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.