AstraZeneca and Ionis Announce Breakthrough with Oral-Enabled PCSK9 Antisense Therapy AZD8233

PCSK9 (proprotein convertase subtilisin/kexin type 9) is involved in regulating the lifecycle of hepatic low-density lipoprotein (LDL) receptors. Research has shown that gain-of-function mutations in PCSK9 in humans are associated with familial hypercholesterolemia, whereas loss-of-function mutations lead to reduced LDL cholesterol levels and can prevent coronary heart disease, making PCSK9 a highly attractive therapeutic target for the treatment of atherosclerotic cardiovascular disease.

Currently, the two approved monoclonal antibodies (evolocumab and alirocumab) and one siRNA therapy (inclisiran) targeting PCSK9 are all administered via subcutaneous injection.

On May 12, researchers from AstraZeneca and Ionis Pharmaceuticals published data on AZD8233, an antisense oligonucleotide (ASO) therapy targeting PCSK9, in Science Translational Medicine. The study showed that in individuals with elevated LDL cholesterol, a single injection of AZD8233 reduced PCSK9 levels by over 90%, achieving a maximum mean reduction in LDL cholesterol of nearly 70%. Furthermore, the feasibility of oral administration of AZD8233 was also demonstrated.

Source: Science Translational Medicine

AZD8233 is a GalNAc (N-acetylgalactosamine) ASO designed to selectively inhibit the translation and protein synthesis of PCSK9 mRNA in hepatocytes.

In transgenic mice overexpressing human PCSK9, researchers observed a dose-dependent reduction in plasma PCSK9 and LDL cholesterol following weekly subcutaneous injection of AZD8233.

4-Week Dose-Response Study of AZD8233 (Source: Science Translational Medicine)

In patients with elevated LDL cholesterol, a single subcutaneous injection of AZD8233 (12, 30, and 90 mg) effectively and dose-dependently reduced plasma PCSK9 concentrations. Notably, for at least 1 month following injection, the 90 mg dose of AZD8233 reduced PCSK9 levels by more than 90%, with a maximum mean reduction in LDL cholesterol of 68%.

Plasma PCSK9 Levels Following Subcutaneous Administration of AZD8233 in Subjects with Elevated LDL Cholesterol (Source: Science Translational Medicine)

Next, the researchers investigated the feasibility of oral administration of AZD8233. Oral delivery presents a significant challenge in ASO development, as ASOs are highly charged, hydrophilic macromolecules with poor intestinal permeability, resulting in negligible bioavailability following oral administration.

Building on previous findings, researchers formulated AZD8233 into tablets with sodium caprate (a transient permeation enhancer), demonstrating the feasibility of oral AZD8233 through three studies conducted in rats, dogs, and monkeys.

The bioavailability of AZD8233 in the liver (target organ) of laboratory dogs was 7%, approximately 5-fold higher than its plasma bioavailability. Furthermore, oral administration of AZD8233 reduced plasma PCSK9 (>50%) and LDL cholesterol (45%–50%) in healthy monkeys.

Oral Administration Study of AZD8233 Tablets in Rats, Dogs, and Monkeys (Source: Science Translational Medicine)

Notably, oral administration enhances the delivery of AZD8233 to hepatocytes by fully leveraging the hepatic first-pass effect following intestinal absorption, and the low bioavailability of AZD8233 in plasma and the kidneys indicates that oral administration reduces drug exposure to extrahepatic organs/tissues.

Overall, AZD8233 is a highly potent PCSK9-targeted inhibitor, and the demonstration of its oral feasibility has opened new opportunities for the development of PCSK9 inhibitors. This convenient, non-invasive alternative approach has the potential to improve patient adherence and therapeutic outcomes.

References:

[1] Peter Gennemark et al. An oral antisense oligonucleotide for PCSK9 inhibition. Science Translational Medicine (2021)