AHA: MSD's oral PCSK9 matches injectables

MSD has fleshed out the results of phase 3 trials of its cholesterol-lowering, oral PCSK9 inhibitor, enlicitide decanoate, showing its efficacy was comparable to that of injectable alternatives.

The CORALreef Lipids trial in patients with hypercholesterolaemia who could not meet their treatment targets using standard statin therapy – or could not tolerate statins – showed that enlicitide reduced LDL-cholesterol (LDL-C) levels by 59.7% compared to placebo after 24 weeks. It was reported at the AHA congress in New Orleans.

The study enrolled around 2,900 patients who had or were at risk of atherosclerotic cardiovascular disease (ASCVD), and also showed significant reductions with enlicitide on a range of secondary risk markers for heart disease, including non-HDL-C, ApoB, and Lp(a) and a tolerability that was pretty close to placebo.

Lead investigator Ann Marie Navar of UT Southwestern Medical Centre said that, if approved, enlicitide "has the potential to help close gaps in achievement of lipid goals in patients with and at risk for cardiovascular events and ultimately help address the ongoing [cardiovascular disease] epidemic."

Also presented at the AHA were the results of CORALreef HeFH, which recruited around 300 people living with the inherited disorder heterogeneous familial hypercholesterolaemia (HeFH), which leads to high cholesterol levels that are hard to bring down with current therapies.

In that study, enlicitide was similarly effective at reducing LDL-C, slashing it by 59.4% compared to placebo. Almost all (97%) of the patients in the study were already taking statin therapy.

The LDL-C reductions seen with enlicitide in both studies are in the same ballpark as those seen with injectable PCSK9-targeting drugs, which include Amgen's Repatha (evolocumab) and Regeneron's Praluent (alirocumab) – both antibodies dosed once a month – and Novartis' oligonucleotide Leqvio (inclisiran) that can be given by injection twice a year.

The results suggest that enlicitide could be a more convenient alternative to the injectables, easier distribution and storage, and – potentially at least – lower pricing. MSD has said it will use the data from these two studies and a third, already-completed study called CORALreef AddOn as the basis for regulatory filings in the coming months.

CORALreef AddOn has generated topline results showing that enlicitide reduced LDL-C compared to non-statin cholesterol medicines ezetimibe or bempedoic acid in a broad group of patients, including those who had been treated with stable cholesterol-lowering therapies, including at least a statin, or who had documented statin intolerance.

The near-term filing puts MSD ahead of its rivals in the oral PCSK9 category, led by AstraZeneca, whose AZD0780 started phase 3 testing earlier this year.

Analysts have previously suggested that enlicitide could generate peak sales of up to $5 billion per year, which would be a step up from Repatha and Praluent, which made $2.2 billion and $765 million last year, respectively.

Leqvio has struggled to gain momentum, making $754 million in 2024, although there are signs it is picking up speed, with sales tipped to breach the $1 billion threshold this year.

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