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

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.

Clinical trial number

NCT04142424, NCT04483947

Impact and implications

Clinical treatment options for MASH are limited. The genetic risk factor with the largest effect size for progressing to poor liver-related outcomes in MASH is a single-nucleotide polymorphism in the gene PNPLA3 (p.I148M). In Phase 1 SAD and MAD studies, AZD2693, a liver-targeted antisense oligonucleotide was well tolerated, reduced liver PNPLA3 mRNA and protein levels, and dose dependently reduced liver fat content in homozygous PNPLA3 148M risk allele carriers. These data support continued development of AZD2693 as a potential precision medicine treatment for MASH. The Phase 2b FORTUNA study is now ongoing.