Aug 2026· Drug Discoveries & Therapeutics· 0 citations· 7 references
Medicine
TL;DR
The ongoing CORALreef Outcomes trial will determine whether enlicitide-mediated LDL-C reduction translates into fewer major cardiovascular events and will help define its long-term clinical role.
Abstract
Hypercholesterolemia, and particularly elevated low-density lipoprotein cholesterol (LDL-C), is a major causal factor in atherosclerotic cardiovascular disease (ASCVD) and contributes substantially to coronary heart disease, ischemic stroke, and peripheral artery disease. Statins remain the cornerstone of lipid-lowering therapy, while ezetimibe and injectable proprotein convertase subtilisin/kexin 9 (PCSK9) targeted agents are added when further LDL-C reduction is required. However, concerns about injections, cost, accessibility, and treatment inertia have limited the use of existing PCSK9 therapies, creating a need for potent oral alternatives. Enlicitide, approved by the US Food and Drug Administration in July 2026, is the first approved oral PCSK9 inhibitor. This macrocyclic peptide blocks the interaction between circulating PCSK9 and hepatic LDL receptors, thereby increasing receptor recycling and LDL-C clearance. In the phase III CORALreef Lipids and CORALreef HeFH trials, once-daily enlicitide reduced LDL-C by approximately 60%, and the effect was maintained for up to 52 weeks. Adverse event rates were generally similar to those observed with a placebo. Nevertheless, those trials primarily evaluated LDL-C reduction rather than cardiovascular outcomes, and their duration was insufficient to establish long-term safety. The ongoing CORALreef Outcomes trial will determine whether enlicitide-mediated LDL-C reduction translates into fewer major cardiovascular events and will help define its long-term clinical role.
A substantial proportion of patients with hypercholesterolaemia, particularly those with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolaemia (HeFH), do not achieve recommended LDL-cholesterol (LDL-C) targets despite statins, ezetimibe, and injectable PCSK9 inhibitors. The parenteral route of the latter remains a well-recognised barrier to their wider use. Objective of the study was to review the discovery, pharmacology, clinical evidence, and therapeutic positioning of enlicitide (Lipfendra), the first oral PCSK9 inhibitor, approved by the US FDA in July 2026. A structured narrative review of PubMed/MEDLINE, ClinicalTrials.gov, FDA regulatory documents, and the primary CORALreef trial publications, with priority given to original clinical and discovery-chemistry sources over secondary reviews. Enlicitide is an orally bioavailable macrocyclic peptide that binds circulating PCSK9 and preserves hepatic LDL-receptor recycling. Across the CORALreef phase 3 programme, it produced placebo-adjusted LDL-C reductions of approximately 56–60%, with concordant reductions in apolipoprotein B, non-HDL-cholesterol, and lipoprotein(a). Its short-term safety profile was comparable to placebo. Its approval further demonstrates, for the first time, that a large extracellular protein-protein interaction, previously considered accessible only to injectable biologics, can be disrupted through an orally administered peptide. Enlicitide brings potent PCSK9 inhibition within an oral formulation for the first time. Whether this translates into reduced cardiovascular events, how it performs over long-term use, and how accessible it will prove outside the United States - including in India, where familial hypercholesterolaemia remains substantially underdiagnosed - are questions that current evidence cannot yet answer.
D. Malathi, Kumaravel Janakiraman, Sathiya Vinotha Ariyur Thangavelu et al.· International Journal of Bas...· 0 citations
Enlicitide (Lipfendra – Merck), an oral proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, has been approved by the FDA to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). It is the first oral PCSK9 inhibitor to be approved in the US; the other FDA-approved PCSK9 inhibitors (alirocumab [Praluent], evolocumab [Repatha], and lerodalcibep [Lerochol]) and the PCSK9-directed small interfering RNA inclisiran (Leqvio) are injected subcutaneously.1 Lipfendra was approved under the Commissioner's National Priority Voucher program, which accelerates the FDA review process for drugs that align with critical national health priorities.
Unknown authors· The Medical letter on drugs...· 0 citations
Dyslipidemia is a major contributor to atherosclerotic cardiovascular disease (ASCVD), the leading cause of morbidity and mortality worldwide. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes hepatic low-density lipoprotein receptor (LDLR) degradation, elevating plasma low-density lipoprotein cholesterol (LDL-C) and contributing to plaque initiation, progression, and destabilization via lipid-dependent and -independent pathways (e.g., inflammation, endothelial dysfunction, thrombosis). PCSK9 inhibition is a validated target for intensive lipid management Beyond statins, monoclonal antibodies (evolocumab, alirocumab) and siRNA-based therapy (inclisiran) achieve reductions in LDL-C of >50%. Large outcome trials (FOURIER, ODYSSEY OUTCOMES, ORION series) have demonstrated reduced major adverse cardiovascular events (MACE) and favorable safety in high-risk populations including acute coronary syndrome, familial hypercholesterolemia, and statin intolerance. Newer approaches include oral small molecule inhibitors (e.g., MK-0616, AZD0780), therapeutic vaccines (e.g., AT04A), and gene-editing (e.g., VERVE-101) with improved adherence, durability or potential cure. For patients with very-high-risk or high-risk ASCVD who do not achieve LDL-C targets with traditional therapies, clinical guidelines, including China-specific recommendations, support the use of PCSK9 inhibitors to lower LDL-C and further reduce CV risk.
Yu-Jie Fang· International Journal of Bio...· 0 citations
Cardiovascular events are a common occurrence in patients with diabetes mellitus. Multiple pharmacological interventions have been developed to reduce cardiovascular risk in this population; however, in this review, we focus on the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in improving cardiovascular outcomes among diabetic patients. We provide an updated and comprehensive overview covering efficacy, safety, tolerability, and cost-effectiveness, while comparing these agents to the current standard of care, i.e., statins. Elevated low-density lipoprotein cholesterol (LDL-C) levels are strongly associated with adverse cardiovascular outcomes. By inhibiting LDL receptor degradation, PCSK9 inhibitors significantly enhance LDL-C clearance, leading to improved cardiovascular profiles. Evidence from large clinical trials such as FOURIER and ODYSSEY demonstrates consistent and promising reductions in major adverse cardiovascular events, even in diabetic subgroups. While the high cost and requirement for parenteral administration remain limitations, PCSK9 inhibitors represent a promising therapy for high-risk diabetic patients who fail to achieve lipid goals with conventional therapy and/or fail to adhere to the mainstay therapy due to adverse events.
Abu-Baker Khalid Sharafeldin, Noor Elhuda Taher Aljundi, Abdullah Hussain et al.· Frontiers in Pharmacology· 0 citations
Enlicitide (MK-0616) is an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the treatment of hypercholesterolemia. We conducted the first systematic review and meta-analysis evaluating the efficacy and safety of enlicitide across randomized controlled trials enrolling adults with hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). The primary outcome was the baseline-to-endpoint percentage change in low-density lipoprotein cholesterol (LDL-C); secondary outcomes included apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) [Lp(a)], and safety. Four randomized controlled trials involving 3894 participants were included. Enlicitide achieved a substantial reduction in LDL-C (mean difference [MD]: −55.78 percentage points; 95% confidence interval [CI]: −61.15 to −50.42; p < 0.0001; I2 = 99.58%), with sustained efficacy demonstrated in the newly available 52-week Phase 3 CORALreef data. Significant reductions were also observed in ApoB (MD: −47.95 pp; 95% CI: −51.22 to −44.67), non-HDL-C (MD: −49.42 pp; 95% CI: −54.23 to −44.60), and Lp(a) (MD: −22.70 pp; 95% CI: −28.62 to −16.78). The pooled incidence of any adverse event was not statistically significant (event rate: 0.21; p = 0.087), and treatment discontinuation due to adverse events was uncommon (event rate: 0.007). Enlicitide demonstrated substantial lipid-lowering efficacy with an acceptable safety profile. The ongoing CORALreef Outcomes trial will determine whether these lipid improvements translate into reductions in major adverse cardiovascular events.
B. Yağmur, E. Cekirdekci· Journal of Cardiovascular De...· 0 citations
These agents have expanded treatment options for patients with familial dyslipidaemia, severe hypertriglyceridaemia, and persistent residual cardiovascular risk while paving the way for precision medicine.
Aryan Arora· Beyond the Pill – The Future...· 0 citations
