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AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two
Javier Armisen1, Mitra Rauschecker2, Janeli Sarv3
1Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca, Cambridge, UK.
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 steatohepatitis (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 I single and multiple ascending dose 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 IIb FORTUNA study is now ongoing.
Clinical Trial Number:
NCT04142424, NCT04483947.
Insights
AZD2693, an antisense oligonucleotide, effectively reduced liver fat and PNPLA3 expression in a Phase 1 study. These findings support its continued development for metabolic dysfunction-associated steatohepatitis (MASH).
Area of Science:
- Hepatology
- Pharmacology
- Genetics
Background:
- The PNPLA3 rs738409 variant (I148M) is a major genetic determinant of hepatic steatosis and advanced liver disease.
- Metabolic dysfunction-associated steatohepatitis (MASH) has limited treatment options.
- AZD2693 is a novel liver-targeted antisense oligonucleotide designed to reduce PNPLA3 expression.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2693.
- To assess the effect of AZD2693 on liver fat content and PNPLA3 expression in humans.
Main Methods:
- Phase 1, single and multiple ascending dose studies of AZD2693 were conducted.
- Participants included healthy volunteers and individuals with elevated liver fat (MRI-PDFF ≥7%).
- Liver fat content, PNPLA3 mRNA, and protein levels were assessed.
Main Results:
- AZD2693 was generally well tolerated with no serious adverse events.
- Significant reduction in liver PNPLA3 mRNA (89%) and protein levels was observed, demonstrating target engagement.
- Dose-dependent reduction in liver fat content (up to -12.2% placebo-corrected) was achieved.
Conclusions:
- AZD2693 demonstrated potent reduction of liver PNPLA3 expression.
- The drug was safe and well-tolerated, supporting its further development.
- AZD2693 shows promise as a precision medicine for MASH patients with the PNPLA3 148M variant.
