AstraZeneca's cholesterol drug to face off with Merck's in oral PCSK9 market

AstraZeneca has recently unveiled promising early results for its new oral PCSK9 inhibitor, AZD0780. This development sets the stage for a potential competition with Merck & Co.'s similar oral drug, MK-0616, as both pharmaceutical giants strive to introduce the first convenient pill form of potent cholesterol-lowering medications. The findings were showcased at the annual meeting of the European Atherosclerosis Society (EAS).

The Phase I trial for AZD0780 involved two dosage levels, 30mg and 60mg, administered orally once daily over a 28-day period to separate groups of 15 participants each. These groups were compared to a placebo-controlled group of the same size. Additionally, another cohort of 35 participants with LDL cholesterol levels ranging from 100 to 190mg/dL were pre-treated with the statin Crestor (rosuvastatin) for three weeks. Following this period, they received either 30mg of AZD0780 or a placebo for four weeks.

The results revealed that AZD0780 led to a substantial 52% reduction in LDL cholesterol in treatment-naive hypercholesterolaemic patients after the Crestor pre-treatment phase, compared to Crestor alone. This equates to a total LDL cholesterol reduction of 78% when compared to baseline levels. As a standalone treatment, the 30mg and 60mg doses of AZD0780 reduced cholesterol levels by 30% and 38% respectively, relative to baseline. Initial data also indicated that food intake increased total drug exposure by approximately 30% compared to fasting. Importantly, no serious adverse events were reported during the study.

Regina Fritsche Danielson, Global Head of Research and Early Development for Cardiovascular, Renal, and Metabolic Diseases at AstraZeneca, highlighted the benefits of an oral PCSK9 inhibitor over current injectable monoclonal antibodies such as Sanofi and Regeneron Pharmaceuticals' Praluent (alirocumab) and Amgen's Repatha (evolocumab). Danielson noted that many patients are reluctant to use injectable medications, and physicians are hesitant to prescribe them. The availability of a simple oral tablet could offer a more acceptable alternative for patients needing to manage their LDL cholesterol levels. Danielson mentioned that achieving a 50% greater reduction in cholesterol on top of statin treatment could enable more than 90% of patients to reach their target cholesterol levels, which is crucial for reducing cardiovascular risk.

Although Merck’s MK-0616 has previously shown around a 60% reduction in LDL cholesterol at the highest dose during Phase II trials, analysts at Jefferies suggest that AstraZeneca's AZD0780 might have an edge. Unlike Merck’s macrocyclic peptide, which requires a gastrointestinal absorption enhancer, AZD0780 is a true small molecule, originating from AstraZeneca's acquisition of Dogma Therapeutics, and is not significantly affected by food intake.

Merck commenced a Phase III programme for MK-0616 last year, with studies evaluating LDL cholesterol reduction and cardiovascular outcomes, aiming for a 2029 readout. In contrast, AstraZeneca has laid out an ambitious plan to nearly double its revenue to $80 billion by 2030. During a recent investor day, AstraZeneca's management suggested that AZD0780 could be part of a combination therapy with its next-generation oral GLP-1 agonist, AZD5004.

Currently, the focus for AZD0780 remains on reducing LDL cholesterol. AstraZeneca began a Phase II dyslipidaemia study in January, which is progressing well. Danielson expressed optimism about having data by the end of this year. Following the conclusion of the study, AstraZeneca plans to discuss the design for Phase III trials. While exact market timelines for AZD0780 remain undisclosed, Danielson emphasized the program is being fast-tracked.