An oral antisense oligonucleotide for PCSK9 inhibition

Abstract

A highly potent, chemically modified PCSK9 antisense oligonucleotide formulated with a permeation enhancer was developed for oral administration. An oral ASO to lower LDL Strategies to decrease low-density lipoprotein (LDL) cholesterol could help treat atherosclerosis. Here, Gennemark et al. developed an antisense oligonucleotide (ASO) that can be delivered orally, is taken up by the liver, and targets PCSK9, which regulates the LDL receptor. Subcutaneous administration of the ASO showed high potency in mice overexpressing PCSK9, a liver half-life of 18 days in monkeys, and reduced circulating PCSK9 in humans. The oral formulation showed 5 to 7% liver bioavailability compared to subcutaneous administration in rats and dogs, and it reduced LDL cholesterol in healthy monkeys. Results support the potential of this ASO for PCSK9 inhibition while avoiding the need for injections. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.