The U.S. Food and Drug Administration has approved the first once-daily oral PCSK9 inhibitor, Lipfendra (enlicitide), offering a new treatment option for millions of Americans with high cholesterol. The approval, announced Thursday (July 16) by Merck, means adults with hypercholesterolemia—including those with inherited forms—can now access a pill that lowers LDL (“bad”) cholesterol by nearly 60 percent, compared to placebo, over 24 weeks.
According to Merck’s announcement, Lipfendra works by blocking the action of PCSK9, a protein that regulates how the liver removes LDL cholesterol from the blood. Unlike earlier PCSK9 inhibitors, which are only available as injections, Lipfendra is a tablet taken once daily as an add-on to diet and other cholesterol-lowering therapies.
The FDA based its decision on two Phase 3 trials—CORALreef Lipids and CORALreef HeFH—which showed Lipfendra reduced LDL-C by 56 percent and 59 percent, respectively, compared to placebo after 24 weeks. These reductions are roughly double the impact of standard statin therapy, according to trial data and statements from medical experts. The most common side effects reported were diarrhea and dizziness, with overall rates of serious side effects and treatment discontinuations similar to those seen with placebo.
Until now, PCSK9 inhibitors such as Repatha and Praluent have been available only as injections, which some experts believe limited their use. Lipfendra’s oral form is expected to improve access and adherence for patients who need further LDL reduction beyond what statins provide, including people with very high or inherited cholesterol.
The FDA’s approval is part of the Commissioner’s National Priority Voucher program, which fast-tracks drugs that address major public health needs. Lipfendra will be available at a list price of $315 per month, about half the cost of existing PCSK9 drugs.
However, Lipfendra comes with strict administration guidelines: patients must fast for eight hours before taking the pill and wait 30 minutes after taking it before eating. This requirement could affect patient compliance.
A large clinical trial is underway to determine whether Lipfendra also reduces the risk of heart attacks, strokes, and cardiovascular deaths. Results are expected in 2029. Until then, the pill is approved to help lower LDL cholesterol as part of a broader cholesterol management plan.
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