Oral PCSK9 Inhibitors: Will They Work?

Lowering low-density lipoprotein cholesterol (LDL-C) is a crucial step in reducing the risk of atherosclerotic cardiovascular disease. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), an important regulator of circulating LDL-C levels, represent a modern approach for the treatment of hypercholesterolaemia. Approved approaches targeting PCSK9 to date include injectable biologics. Here, we provide an overview of the current state of research on the development of oral PCSK9 inhibitors.

Several small molecules have been developed in recent years. Enlicitide decanoate (formerly known as MK-0616) has been shown to significantly reduce LDL-C levels by a maximum of 66% from baseline with a good safety and tolerability profile. Its formulation with sodium caprate enabled a higher bioavailability. Several clinical trials are currently underway to evaluate the efficacy and safety of this drug, including an outcome trial. AZD0780 is another oral small molecule that lowers LDL-C levels by 52% and can be administered on top of a statin. Several other small molecules with the potential to inhibit PCSK9 have been identified, some of which have stopped the development. Oral PCSK9 inhibitors are showing promising results in early studies. If the results of the outcome studies will be positive, we will have a safe, effective and easy-to-use oral therapy. Oral PCSK9 inhibitors could provide a convenient alternative to injectable PCSK9 inhibitors and result in a greater number of patients receiving an effective LDL-C-lowering therapy.