enlicitide decanoate (MK-0616) / Merck (MSD), UCB - LARVOL DELTA

Overcoming Challenges in the Metabolism of Peptide Therapeutics: Strategies and Case Studies for Clinical Success. (PubMed, J Med Chem) - "Low permeability and bioavailability of peptides are also briefly covered. Case studies, including semaglutide, MK-0616, LUNA18, sulanemadlin, and oxytocin analogs, illustrate successful applications of these strategies, highlighting how rational design and optimization have advanced peptide candidates from discovery to clinical stage."

Journal • Review • Cardiovascular • Diabetes • Metabolic Disorders • Oncology

Lipid-Lowering Efficacy and Safety of Oral Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Systematic Review and Meta-Analysis. (PubMed, Adv Ther) - "Oral PCSK9 inhibitors demonstrate lipid-lowering efficacy and safety comparable to that of currently approved injectable PCSK9 therapies. These findings support their potential as a convenient and effective alternative, although current evidence remains limited to early-phase studies."

Clinical • Journal • Retrospective data • Dyslipidemia • APOB

A Clinical Study of Enlicitide in Participants With High Cholesterol (MK-0616-037) (clinicaltrials.gov) - P3 | N=975 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Dyslipidemia • APOB

Merck’s oral PCSK9 inhibitor shows 59% LDL-C reduction in HeFH trial (Investing.com) - "The study showed that enlicitide maintained efficacy through one year, with a 61.5% LDL-C reduction compared to placebo at 52 weeks. The drug also significantly reduced non-HDL cholesterol by 53%, apolipoprotein B by 49.1%, and lipoprotein(a) by 27.5% at week 24...According to the data, 67.3% of patients treated with enlicitide achieved at least a 50% reduction in LDL-C along with an LDL-C below 55 mg/dL, compared to 1% in the placebo group."

P3 data • Heterozygous Familial Hypercholesterolemia

Enlicitide decanoate, an oral PCSK9 inhibitor, in participants with heterozygous familial hypercholesterolemia: a Phase 3, double-blind, randomized placebo-controlled trial (AHA 2025) - "Mean baseline LDL-C was 119.0 (SD, ±41.0) mg/dL, 100% were on statins (81.5% high-intensity statin) and 64.4% were on ezetimibe. Among adults with HeFH, treatment with enlicitide, an oral, once-daily PCSK9 inhibitor, was well tolerated and significantly reduced LDL-C, ApoB, non-HDL-C, and Lp(a)."

Clinical • P3 data • Atherosclerosis • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • APOB

Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial. (PubMed, JAMA) - P3 | "To evaluate the efficacy of enlicitide decanoate (an oral proprotein convertase subtilisin/kexin type 9 inhibitor) vs placebo in adults with HeFH requiring further lowering of LDL-C levels despite use of statin therapy...The mean LDL-C level was 119.0 mg/dL (SD, 41.0 mg/dL) at baseline, all had statin current use (81.5% were taking a high-intensity statin), and 64.4% were taking ezetimibe...Among adults with HeFH, treatment with enlicitide was well tolerated and significantly reduced levels of LDL-C, apolipoprotein B, non-HDL-C, and lipoprotein(a). ClinicalTrials.gov Identifier: NCT05952869."

Clinical • Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • APOB

Oral PCSK9 Inhibitors for Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Trials (AHA 2025) - "MK-0616 achieved the greatest LDL-C reduction (–53.69%; 95% CI, –61.05% to –46.34%), followed by NNC0385-0434 (–46.23%; 95% CI, –63.15% to –29.31%) and AZD0780 (–38.18%; 95% CI, –45.06% to –31.29%). Oral PCSK9 inhibitors significantly reduced LDL-C, lipoprotein(a), apolipoprotein B, and total cholesterol compared to placebo, with no significant reduction in triglycerides. Among the agents studied, MK-0616 demonstrated the greatest overall LDL-C lowering effect."

Retrospective data • Review • Dyslipidemia • Metabolic Disorders • APOB

A Clinical Study of Enlicitide in Participants With High Cholesterol (MK-0616-037) (clinicaltrials.gov) - P3 | N=975 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P3 trial • Dyslipidemia • APOB

The evolving landscape of targets for lipid lowering: from molecular mechanisms to translational implications. (PubMed, Eur Heart J) - "Bempedoic acid inhibits ATP citrate lyase, the enzyme upstream of HMG-CoA reductase in the mevalonate pathway, offering an alternative to statins by selectively acting in the liver, minimizing muscle-related side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide decanoate (MK0616)] prevent LDLR degradation, while ezetimibe limits intestinal cholesterol absorption...Ongoing research into strategies to reduce Lp(a), primarily but not exclusively through antisense therapies, aims to demonstrate the cardiovascular benefits of targeting this lipoprotein. In summary, the field of targets for lipid and lipoprotein lowering is constantly evolving and offers new strategies for patients resistant to current therapies or with specific lipid profile abnormalities."

Journal • Cardiovascular • Dyslipidemia • Metabolic Disorders • ANGPTL3 • APOB • LPL

A Study of Enlicitide Decanoate (MK-0616, an Oral PCSK9 Inhibitor) in Children and Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0616-029) (clinicaltrials.gov) - P2/3 | N=153 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • Pediatrics • APOB

A Clinical Study of How Coffee and Tea Affect Enlicitide in Healthy Volunteers (MK-0616-040) (clinicaltrials.gov) - P1 | N=60 | Completed | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Completed

Trial completion

A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids (clinicaltrials.gov) - P3 | N=2912 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • APOB

Merck’s Investigational Oral PCSK9 Inhibitor Enlicitide Decanoate Met All Primary and Key Secondary Endpoints in Adults with Hypercholesterolemia in Pivotal CORALreef Lipids Study (Merck (MSD) Press Release) - "Treatment with enlicitide resulted in statistically significant and clinically meaningful reduction in low-density lipoprotein cholesterol (LDL-C) compared to placebo at Week 24. Statistically and clinically significant reductions were also seen for enlicitide versus placebo across all key secondary endpoints including in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) [Lp(a)]. There were no clinically meaningful differences in proportions of participants with adverse events (AE), including serious adverse events (SAE), between treatment groups."

P3 data: top line • Familial Hypercholesterolemia

Open-label Extension Study of Enlicitide Decanoate (MK-0616/Enlicitide Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-019) CORALreef Extension (clinicaltrials.gov) - P3 | N=3000 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Dyslipidemia • Metabolic Disorders • APOB

A Study of Enlicitide Decanoate (MK-0616, an Oral PCSK9 Inhibitor) in Children and Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0616-029) (clinicaltrials.gov) - P2/3 | N=153 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P2/3 trial • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • Pediatrics • APOB

Commerical process development for enlicitide decanoate eastern fragment (ACS-Fall 2025) - "We will highlight the challenges encountered during scale-up and the strategies employed to overcome them. By sharing insights from this case study, we aim to contribute to the broader discourse on the commercial process for enlicitide decanoate."

Dyslipidemia

Development of an efficient, robust process for oral PCSK9 inhibitor MK-0616 (ACS-Fall 2025) - "Enlicitide decanoate (MK-0616) is a novel macrocyclic peptide that has demonstrated oral bioavailability and significant reductions in LDL-C in Phase 2b trials in line with the approved therapies; Phase 3 trials are underway. This talk will highlight how our team is inventing new methods to build an efficient, scalable route for MK-0616, an unprecedentedly large "small" molecule."

Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) Cardiovascular Outcomes Study (MK-0616-015) CORALreef Outcomes (clinicaltrials.gov) - P3 | N=14550 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Adverse events • Enrollment closed • Atherosclerosis • Cardiovascular • Dyslipidemia • APOB

Overcoming low organic solubility profiles of peptide intermediates in the commercial process for enlicitide decanoate (MK-0616) (ACS-Fall 2025) - "The peptide intermediate is synthesized via amidation of a non-canonical amino acid residue featured in an upstream compound. The process is robust and has been successfully demonstrated on multikilogram scale to produce the key commercial intermediate in high yield and purity."

Developmental Disorders • Dyslipidemia • Metabolic Disorders

A Clinical Study of Enlicitide in Participants With Severe Renal Impairment (MK-0616-032) (clinicaltrials.gov) - P1 | N=27 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Renal Disease

A Clinical Study of How Coffee and Tea Affect Enlicitide in Healthy Volunteers (MK-0616-040) (clinicaltrials.gov) - P1 | N=60 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

A Clinical Study to Evaluate Enlicitide (MK-0616) Formulations in Healthy Adult Participants (MK-0616-035) (clinicaltrials.gov) - P1 | N=40 | Completed | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Completed

Trial completion

Key takeaways from CORALreef AddOn (Merck (MSD) Press Release) - P3 | N=301 | CORALreef AddOn (NCT06450366) | Sponsor: Merck Sharp & Dohme LLC | "CORALreef AddOn: statistically significant and clinically meaningful reductions in LDL-C for enlicitide versus ezetimibe, versus bempedoic acid and versus ezetimibe and bempedoic acid in adults with hyperlipidemia who have a history of or are at risk for ASCVD and are treated with a statin."

P3 data: top line • Dyslipidemia

Key takeaways from CORALreef HeFH (Merck (MSD) Press Release) - P3 | N=303 | CORALreef HeFH (NCT05952869) | Sponsor: Merck Sharp & Dohme LLC | "CORALreef HeFH: statistically significant and clinically meaningful reductions in LDL-C for enlicitide versus placebo in adults with heterozygous familial hypercholesterolemia (HeFH) who have a history of or are at risk for atherosclerotic cardiovascular disease (ASCVD) and are treated with a statin."

P3 data: top line • Heterozygous Familial Hypercholesterolemia

A Clinical Study of Enlicitide in Participants With Severe Renal Impairment (MK-0616-032) (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Renal Disease