New Frontiers in the Treatment of Hypercholesterolaemia: Oral Inhibition of PCSK9

Abstract PCSK9 inhibitors represent a cornerstone of lipid-lowering therapy; however, the need for cost containment and simplified routes of administration has stimulated the development of oral small molecules and peptidomimetics capable of modulating or blocking the PCSK9–LDL receptor (LDL-R) interaction, inhibiting PCSK9 mRNA transcription, or preventing lysosomal degradation of the LDL-R. Agents in advanced development include enlicitide (MK-0616) and laroprovstat (AZD0780), while DC371739, NNC0385-0434 (development currently suspended), and CVI-LM001 should also be considered. Enlicitide decanoate, owing to improved intestinal permeability, significantly reduces free PCSK9 (>90%) and LDL cholesterol (≈60%) in phase I–II studies, with excellent tolerability. Phase III trials (CORALreef-Lipids and CORALreef-HeFH) have confirmed LDL-C reductions of 55–60%, along with favourable effects on non-HDL cholesterol, apoB, and Lp(a), comparable to those achieved with monoclonal antibodies. AZD0780 demonstrates dose-dependent reductions in LDL-C (up to 50%) and potential synergism with rosuvastatin, whereas NNC0385-0434—despite documenting significant decreases in LDL-C and Lp(a)—has been discontinued. DC371739 (a dual PCSK9/ANGPTL3 inhibitor) and CVI-LM001 (a transcriptional modulator) may represent additional therapeutic perspectives. Overall, oral PCSK9 inhibitors show consistent efficacy and favourable safety profiles, positioning them as next-generation lipid-lowering therapies, pending cardiovascular outcome data from ongoing studies. Lipid-lowering therapy with monoclonal antibodies (evolocumab, alirocumab) or siRNA (inclisiran) targeting PCSK9 has enabled patients at high or very high cardiovascular (CV) risk to achieve plasma cholesterol levels previously unattainable, with a consequent reduction in CV risk [1]. However, the need for cost containment and simpler routes of administration has stimulated research into orally administered small molecules and peptidomimetics targeting PCSK9, with the aim of improving accessibility to therapy [1]. Several targets may be exploited to inhibit the effects of PCSK9, including disruption of the PCSK9–LDL receptor (LDL-R) interaction, inhibition of lysosomal degradation of the LDL-R, and induction of allosteric conformational changes in PCSK9 [1]. Below, we discuss the most promising oral agents, noting that none has yet reached the commercial stage.