MSD’s oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has reduced low-density lipoprotein cholesterol (LDL-C) levels when combined with background therapies in a Phase III trial.
In the CORALreef AddOn study (NCT06450366), MSD compared enlicitide decanoate to other oral non-statin therapies, such as bempedoic acid, ezetimibe or bempedoic acid with ezetimibe, when added to background statins in adults with hypercholesterolemia who have a history of or are at risk for atherosclerotic cardiovascular disease (ASCVD).
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In the study, the once-daily tablet led to a statistically significant and clinically meaningful 64.6% reduction in LDL-C from baseline. The reduction compared to bempedoic acid was 56.7%, 36% compared to ezetimibe and 28.1% compared to bempedoic acid with ezetimibe at eight weeks (day 56) of treatment.
Enlicitide also demonstrated statistically significant reductions at eight weeks across key secondary endpoints, including a 54.6% reduction in apolipoprotein B (ApoB) compared to baseline. This is compared to a 5.4% reduction from baseline with bempedoic acid, a 20.2% reduction from baseline with ezetimibe and a 27.7% reduction from baseline with bempedoic acid with ezetimibe.
Additionally, treatment with enlicitide significantly reduced non-high-density lipoprotein cholesterol (non-HDL-C) by 58% compared to a 5.2% reduction with bempedoic acid, 25.1% with ezetimibe and 31.8% with bempedoic acid plus ezetimibe.
The late-breaking data was presented on 30 March at the American College of Cardiology’s Annual Scientific Session and Expo (ACC.26) and published simultaneously in JACC.
The overall safety profile was consistent with that observed in the other two Phase III trials, CORALreef Lipids (NCT05952856) and CORALreef HeFH (NCT05952869). High adherence with study intervention (98%) and dosing instructions (≥96%) were observed across treatment groups.
This data comes after the US Food and Drug Administration (FDA) selected enlicitide to receive the Commissioner’s National Priority Voucher (CNPV) in December 2025. Enlicitide is a novel small molecule macrocyclic peptide that binds to PCSK9 and inhibits the interaction of PCSK9 with LDL receptors. If approved, enlicitide would be the first oral PCSK9 inhibitor on the market, providing a more favourable administration than current injectable medicines.
MSD, which is known as Merck in the US, said the scheme puts enlicitide in a position to potentially become the first approved oral PCSK9 inhibitor for patients with hypercholesterolemia.
If approved, GlobalData, parent company of Clinical Trials Arena, predicts the drug will reach blockbuster status in 2031, generating $1.13bn in dyslipidemia alone.
The lipid-modifying agent market is set to rise to $23bn in 2030, GlobalData predicts, primarily driven by Novartis’ Leqvio (inclisiran) and Amgen’s Repatha (evolocumab). Both therapies target PCSK9, similar to enlicitide decanoate; however, they are both injectables.
