Merck’s LIPFENDRA — first FDA‑approved once‑daily oral PCSK9 inhibitor
- FDA approved LIPFENDRA (enlicitide) 20 mg tablets once daily as an adjunct to diet and exercise to reduce LDL‑C in adults with hypercholesterolemia, including HeFH.
- CORALreef Lipids showed a placebo‑adjusted LDL‑C reduction of 56% at week 24 (60% in a post‑hoc analysis); CORALreef HeFH showed a 59% reduction at week 24.
- Selected safety: in HeFH the most common adverse reactions more frequent vs placebo were diarrhea (7% vs 2%) and dizziness (9% vs 4%); discontinuation rates were similar to placebo.
- The CORALreef program includes >19,000 participants; the large outcomes trial has completed enrollment with >14,500 — cardiovascular benefit of LIPFENDRA is not yet established.
Approval and mechanism
The U.S. FDA has approved LIPFENDRA (enlicitide) 20 mg tablets, administered once daily as an adjunct to diet and exercise, to reduce low‑density lipoprotein cholesterol (LDL‑C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). LIPFENDRA is a novel macrocyclic peptide that binds PCSK9 and inhibits its interaction with LDL receptors; it is the first oral PCSK9 inhibitor approved in the U.S.
Phase 3 efficacy
Approval was based on two pivotal CORALreef Phase 3 trials. In CORALreef Lipids (n=2,904; randomized 2:1) LIPFENDRA produced a placebo‑adjusted LDL‑C reduction of 56% at week 24 (60% in a post‑hoc analysis excluding biologically impossible baseline values). In CORALreef HeFH (n=303; randomized 2:1) the placebo‑adjusted reduction was 59% at week 24. Treatment also produced significant reductions in non‑HDL‑C and apolipoprotein B (ApoB).
Safety
In CORALreef Lipids adverse reaction rates were similar between LIPFENDRA and placebo and discontinuations for adverse reactions were comparable. In CORALreef HeFH the adverse reactions observed more frequently with LIPFENDRA were diarrhea (7% vs 2%) and dizziness (9% vs 4%); otherwise the safety profile was generally consistent across trials.
Trials and next steps
The broader CORALreef program is evaluating LIPFENDRA in over 19,000 participants and includes a cardiovascular outcomes trial that completed enrollment with more than 14,500 participants. It is not yet known whether LIPFENDRA reduces cardiovascular morbidity and mortality; the outcomes trial will address that question.
Source: Merck
