An oral antisense oligonucleotide for PCSK9 inhibition

Abstract

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.

PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology

“…Initially, antisense oligonucleotides (ASOs) were first used in murine and monkey models to inhibit the translation of the PCSK9 mRNA, but studies were terminated due to unknown reasons [160]. Nevertheless recently, a group has developed a highly potent ASO to be orally administered and it was observed that repeated daily dosing in rats, dogs or monkeys reduces dyslipidaemia with great efficacy [161]. Another way to suppress the mRNA is to silence them using small interfering RNA (siRNA) that can be administered via lipoid nanoparticles, for which clinical trials have been successfully carried out.…”

RNA Silencing in the Management of Dyslipidemias

“…Further promising RNA silencing technologies directed at a variety of biological targets have the potential to improve the management of dyslipidaemias. Preclinical studies [52]…”

“…Other proteins associated with plasma lipid homeostasis, particularly if they are functional in the liver, are therefore likely to be included in research and development programmes using this technology. An orally available antisense oligonucleotide for PCSK9 has recently demonstrated promise in preclinical studies [52], and RNA silencing is currently under investigation to target a range of proteins implicated in the pathophysiology of atherosclerosis (Table 2).…”

Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

“…They are also being widely investigated for oral delivery with the goal to protect gene vectors from gastric acid degradation and to facilitate its transport across the intestinal epithelium [ 109 ]. Despite the fact that oral administration of gene therapies has not yet reached the clinic, multiple studies have validated its potential in preclinical studies [ 109 , 110 , 111 , 112 , 113 ].…”

“…They have advanced an oral antisense molecule (ISIS 104838) into phase I using a sodium caprate-based tablet, achieving somewhat higher oral bioavailability values than peptides—an average of 9.5% plasma bioavailability across four formulations tested [ 135 ]. More recently, Ionis Pharmaceuticals published, together with AstraZeneca, the oral delivery of an oligonucleotide conjugated to GalNAc (AZD8233, also known as ION-863633) for targeting of PCSK9 in the liver, also using a sodium caprate-based tablet [ 112 ]. The exposure was measured in cynomolgus monkeys, and a bioavailability of 7% in the liver was achieved, which was 5-fold higher than measured in plasma.…”