AstraZeneca has announced positive Phase 1 clinical data for its oral PCSK9 inhibitor, AZD0780, potentially offering a convenient alternative to injectable cholesterol-lowering medications. The trial results, presented at the European Atherosclerosis Society (EAS) congress, revealed a 52% reduction in LDL cholesterol levels when AZD0780 was added to standard statin therapy in treatment-naive participants with high cholesterol (hypercholesterolemia). This reduction, combined with statin therapy, resulted in a 78% total reduction in LDL-C from baseline.
Efficacy and Comparison to Existing Therapies
The current landscape of PCSK9 inhibitors includes injectable antibodies like Amgen's Repatha (evolocumab) and Sanofi/Regeneron's Praluent (alirocumab), as well as Novartis' small interfering RNA therapy Leqvio (inclisiran). These injectables typically achieve a 50% to 60% reduction in LDL-C when used with statins. AstraZeneca's AZD0780 and MSD's MK-0616, both oral alternatives, have demonstrated efficacy levels within a similar range in early trials.
MSD's MK-0616 achieved LDL-C reductions of 40% to 60% compared to placebo in its main Phase 2 study. While cross-study comparisons should be made cautiously, AZD0780's 52% reduction on top of statins suggests a potentially strong effect. A notable difference is that the bioavailability of MK-0616 is affected by food, requiring administration on an empty stomach, whereas data suggests AZD0780 is not affected by food intake.
Development Plans and Market Context
AstraZeneca is moving forward with a Phase 2 program for AZD0780. MSD is currently conducting three Phase 3 studies for MK-0616, involving approximately 17,000 patients. These studies are evaluating the drug's ability to reduce LDL-C in hypercholesterolemia (CORALreef Lipids), heterozygous familial hypercholesterolemia (CORALreef HeFH), and its impact on cardiovascular outcomes (CORALreef Outcomes).
"The role of PCSK9 in cholesterol management is well-established [and] AZD0780 inhibits PCSK9 via a novel, previously unexplored mode of action that is compatible with traditional oral small molecule drug discovery," said Sharon Barr, AZ’s head of biopharmaceuticals R&D. "We are progressing development of AZD0780 as an innovative, convenient oral option for patients who are currently unable to meet their LDL-C targets with statins alone to reduce their risk of [cardiovascular] events."
The acquisition of AZD0780 from Dogma Therapeutics in 2020 underscores AstraZeneca's commitment to developing oral therapies for cardiovascular disease. The development of oral PCSK9 inhibitors addresses a significant unmet need, as current injectable therapies have not fully met commercial expectations, potentially due to the inconvenience of their administration route.
