AZD2693
Preclinical pharmacology
Murine PNPLA3 tool ASO has been shown to reduce liver steatosis, inflammation and fibrosis in homozygous PNPLA3 148M knock-in mice.
Safety and tolerability
AZD2693 has been evaluated in 3-month repeat dose subcutaneous toxicity studies in preclinical species. Findings were consistent with typical class effects of ASOs, including histiocytic infiltration in multiple tissues and evidence of ASO accumulation in liver and spleen. No effects were attributed to the reduction in PNPLA3.
Preclinical safety pharmacology studies have been conducted with no effects on the respiratory, cardiovascular, central and peripheral nervous systems.
Clinical pharmacology
AZD2693 lowers the mRNA expression of PNPLA3 in patients that are homozygotes for the 148M risk allele thereby reducing an important disease driver for NASH. SAD and MAD studies with AZD2693 are currently ongoing.
Suitable for and exclusions
AZD2693 is suitable for studies requiring knock-down of PNPLA3 in the liver. Women of child-bearing potential and patients with increased risk of bleeding should be excluded from any study (ASO-platform risk)
Mechanism of Action
Patatin-like phospholipase domain containing 3 (PNPLA3) antisense oligonucleotide
Original Therapeutic Area
Cardiovascular, Renal & Metabolism
CNS Penetrant
Low
Route of administration
Subcutaneous
Modality
Antisense oligonucleotide
