AstraZeneca’s cholesterol drug sets up oral PCSK9 showdown with Merck & Co.

2024-05-29

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AstraZeneca has taken the wraps off early data for its oral PCSK9 inhibitor AZD0780, setting the stage for a potential rivalry with Merck & Co.'s similar programme, dubbed MK-0616, as the two companies race to bring the first convenient pill form of these potent cholesterol-lowering drugs to market. Findings were presented Wednesday at the annual meeting of the European Atherosclerosis Society (EAS).

The Phase I study evaluated two dose levels of AZD0780, 30mg and 60mg, administered orally once daily for 28 days to separate cohorts of 15 participants each, compared to a placebo group of equal size. Separately, 35 participants with LDL levels ranging from 100 to 190mg/dL took the statin Crestor (rosuvastatin) for 3 weeks, followed by either 30mg of AZD0780 or placebo for another 4 weeks.

Over 50% decline in 'bad' cholesterol

Results demonstrated that AZD0780, when administered to treatment-naive hypercholesterolaemic patients after the Crestor run-in period, achieved a statistically significant 52% reduction in LDL cholesterol versus Crestor alone. The total reduction in LDL was 78% when compared to baseline levels.

As monotherapy, the low and high AZD0780 doses cut cholesterol levels by 30% and 38%, respectively, versus baseline. Preliminary data also suggested that food increased total exposure by about 30% compared to fasting. No serious adverse events were reported.

Advantages over current injectables

Regina Fritsche Danielson, global head of research and early development, cardiovascular, renal and metabolic diseases at AstraZeneca, underscored the advantages an effective oral PCSK9 option could hold over currently marketed monoclonal antibodies like Sanofi and Regeneron Pharmaceuticals' Praluent (alirocumab) and Amgen's Repatha (evolocumab), which are both injected.

"Many patients are not really open to take an injectable, and physicians are not so keen to prescribe the injectable PCSK9, so now we have an alternative and simple small tablet that we can give to these patients to really control the LDL cholesterol," Danielson told FirstWord. Achieving 50% more cholesterol lowering on top of statins could enable over 90% of patients to hit target cholesterol levels, she says, a key goal given the cardiovascular (CV) risk that persists in many people despite existing therapies.

Merck's contender

While Merck's MK-0616 generated excitement earlier by posting around 60% LDL-cholesterol reductions at the highest dose in Phase II testing, analysts at Jefferies suggest AstraZeneca's design could prove advantageous. Unlike Merck's macrocyclic peptide, which requires a GI absorption enhancer, "AZD0780 is a true small molecule, from a prior acquisition of Dogma Therapeutics, and so should not have meaningful food effects," they said.

Merck kicked off a Phase III programme for MK-0616 last year. In addition to a pair of registrational studies to evaluate LDL-cholesterol reduction, the company launched a Phase III CV outcomes study last October, with a planned 2029 readout. See – Spotlight On: Merck & Co.'s oral PCSK9 - why it's so important.

The AZD0780 data come as AstraZeneca has laid out an ambitious plan to nearly double its revenues to $80 billion by 2030. During the company's recent investor day, management hinted that AZD0780 could also be part of a combination with its next-generation oral GLP-1 agonist GLP-1 agonist AZD5004. For more, see Spotlight On: AstraZeneca's bold ambitions - the key takeaways.

Phase II data by year-end

But for now, the focus for AZD0780 is on curbing LDL cholesterol. AstraZeneca started a Phase II dyslipidaemia study in January that is "recruiting extremely well," according to Danielson, "so we actually are very hopeful that we will have the data towards the end of this year." The company is anticipating an end-of-Phase-II meeting when the study wraps up to discuss the Phase III design. Danielson did not want to tease any timelines for when AZD0780 could hit the market, but said that "it's a very accelerated programme."