FDA Approves Enlicitide, First Oral PCSK9 for High Cholesterol

[DaoMa]

FDA Approves Enlicitide, First Oral PCSK9 for High Cholesterol | AJMC


www.ajmc.com

July 16, 2026

The FDA approved enlicitide (Lipfendra; Merck), the first oral PCSK9 inhibitor for lowering low-density lipoprotein cholesterol (LDL-C) in combination with diet and exercise, giving patients and prescribers a daily pill alternative to injectables.1 The pills are approved for adults with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH).

Enlicitide uses the same mechanism as injectable monoclonal antibodies like evolocumab (Repatha; Amgen) and alirocumab (Praluent; Regeneron and Sanofi) but is delivered as a 20-mg tablet rather than a subcutaneous injection.

“By harnessing the innovative science of PCSK9 inhibitors and novel macrocyclic peptide technology, Lipfendra was designed to significantly lower LDL-C in the form of a convenient once-daily pill,” Dean Y. Li, MD, PhD, president of Merck Research Laboratories, said in a statement.2 “This is a pivotal moment as we bring the first U.S. FDA-approved oral PCSK9 inhibitor to adults with high LDL-C, offering patients an important new option.”

Trial Data Behind the Approval​

The approval rests on 2 phase 3 trials from Merck’s CORALreef program: CORALreef Lipids and CORALreef HeFH.

CORALreef Lipids randomized 2912 adults with hypercholesterolemia and a history of, or elevated risk for, a major atherosclerotic cardiovascular disease (ASCVD) event, with 2904 ultimately receiving treatment and being included in the analysis. Enlicitide reduced LDL-C by 55.8% compared with placebo at 24 weeks (95% CI, –61 to –51; P < .001), representing a 57.1% mean reduction from baseline vs a 3% increase for placebo. The trial, published in the New England Journal of Medicine earlier this year, also found the LDL-C–lowering effect held up over time, with the placebo-adjusted reduction at 47.6 percentage points at week 52.3

CORALreef HeFH was a smaller 303-patient trial in patients with the inherited condition. Enlicitide cut LDL-C by 59% compared with placebo at 24 weeks (95% CI, –66 to –53; P < .001). Both trials also showed significant reductions in non-HDL cholesterol and apolipoprotein B, additional markers of ASCVD risk.

On safety, the profile in CORALreef Lipids was similar to placebo, and treatment discontinuation rates due to adverse events were comparable between arms in both trials. In CORALreef HeFH, diarrhea (7% vs 2%) and dizziness (9% vs 4%) occurred more often with enlicitide than placebo.

An ongoing cardiovascular outcomes trial, CORALreef Outcomes, has completed enrollment of more than 14,500 participants and will determine whether the drug’s LDL-lowering effect translates into fewer heart attacks, strokes, and cardiovascular deaths.

Pill Efficacy Comparable to Injectable Alternatives​

Ann Marie Navar, MD, PhD, a lead investigator on CORALreef Lipids and associate professor of medicine at UT Southwestern Medical Center, first presented the trial’s topline results at the American Heart Association 2025 Scientific Sessions, where she called the magnitude of LDL-C lowering not just statistically but also clinically significant.4,5 In an interview with The American Journal of Managed Care®, Navar said the reanalyzed 24-week data showing a 60% reduction in LDL-C compared with placebo amounted to “a remarkable reduction,” with more than two-thirds of patients achieving at least a 50% LDL-C reduction also reaching an on-treatment LDL-C level below 55 mg/dL.5

What struck her most, she said, was how closely enlicitide’s effects tracked those of the injectable PCSK9 monoclonal antibodies already on the market.

“It’s almost remarkable, in fact, how numerically similar the reductions in LDL cholesterol, non-HDL [high-density lipoprotein] cholesterol, apo B [apolipoprotein B], and lipoprotein(a) are between enlicitide, an oral PCSK9 inhibitor, and evolocumab and alirocumab, which are injectables,” Navar said. “But it’s actually not surprising, because the way that enlicitide works is very similar to how the monoclonals work. Both of these therapies bind to the PCSK9 protein and prevent it from interacting with the LDL receptor. So, pharmacologically, it’s not surprising to see almost the exact same numbers in terms of cholesterol lowering.”

Adherence in the trial was notably high: 97% of participants reported taking all, or nearly all, of their prescribed doses.3 Navar said that consistency showed up in the durability of the results.

“The fact that we saw such dramatic LDL lowering at week 24 that was sustained through week 52 tells us that participants were really good at being able to take the drug and stay on it,” she said.

While the trial wasn’t designed to directly compare patient preference between pills and injections, Navar said the choice matters in daily practice.

“There are definitely patients who would prefer to take a pill instead of an injection, and I’m really excited about the possibility of being able to offer my patients different options for LDL lowering that work similarly in terms of their magnitude of benefit, but one is an injection and one is a pill and letting patients decide for themselves what they want to do,” she said.

Enlicitide’s Implications for Health Care Access and Equity​

Beyond patient preference, Navar framed the oral formulation as a potential fix for a prescribing gap that has kept many eligible patients off non-statin therapy altogether. Prior research from her group found that a substantial share of cardiologists have never prescribed an injectable PCSK9 inhibitor and that the vast majority of primary care physicians have never prescribed one at all.

Katherine Wilemon, CEO of the Family Heart Foundation, framed the approval in similar terms, calling timely identification and treatment of risk factors like elevated LDL-C “one of the greatest opportunities” to reduce ASCVD risk.

“We are encouraged by the approval of a new oral PCSK9 inhibitor option for adults who need additional LDL-C lowering,” she said in a statement.2

What Comes Next for the First Oral PCSK9​

Existing injectable PCSK9 inhibitors have posted strong LDL-lowering results in trials for years but have seen limited real-world uptake, a gap researchers have tied to prescriber unfamiliarity, prior authorization burdens, and the logistics of self-injection or in-office administration.4 Whether an oral option changes that trajectory—and whether payers extend the same coverage pathways used for existing PCSK9 inhibitors to enlicitide—will likely shape how quickly the drug reaches patients who have gone untreated on statins alone.

Results from the CORALreef Outcomes trial, expected around 2029, will also determine whether the drug’s cholesterol-lowering effect holds up as evidence of reduced cardiovascular events, a benchmark already established for its injectable counterparts.2,3

For Navar, the promise of enlicitide extends past the lab data.

“My real hope is that having an oral therapy that’s not only easy to take but easy to prescribe will actually expand the pool of physicians and clinicians who are comfortable and regularly prescribing non-statin therapy,” she said. “My hope for enlicitide is that as an oral pill that’s very easy to prescribe, we may actually be able to increase the pool of clinicians adding on therapy after statins, and that is going to be a rising tide that lifts all boats and hopefully also helps equalize some of the inequity in access to non-statin lipid-lowering therapy that we’re seeing now.”

References

1. FDA approves first oral therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to lower bad cholesterol in adults with high cholesterol. News release. FDA. July 16, 2026. Accessed July 16, 2026. https://www.fda.gov/drugs/news-even...convertase-subtilisinkexin-type-9-pcsk9-lower
2. Merck’s Lipfendra (enlicitide) is the first and only once-daily oral PCSK9 inhibitor approved by the U.S. FDA to reduce LDL-C in adults with hypercholesterolemia. News release. Merck. July 16, 2026. Accessed July 16, 2026. https://www.merck.com/news/mercks-l...ce-ldl-c-in-adults-with-hypercholesterolemia/
3. Navar AM, Mikhailova E, Catapano AL, et al. A placebo-controlled trial of the oral PCSK9 inhibitor enlicitide. N Engl J Med. 2026;394:529-539. doi:10.1056/NEJMoa2511002
4. Klein HE. Oral PCSK9 inhibitor enlicitide matches injectables in lowering LDL cholesterol. AJMC. November 8, 2025. Accessed July 16, 2026. https://www.ajmc.com/view/oral-pcsk...tches-injectables-in-lowering-ldl-cholesterol
5. Joszt L, Navar AM. Efficacy and equity with oral PCSK9s: Ann Marie Navar, MD, PhD. AJMC. November 8, 2025. Accessed July 16, 2026. https://www.ajmc.com/view/efficacy-and-equity-with-oral-pcsk9s-ann-marie-navar-md-phd

 

[DaoMa]

FDA approves a first-of-its-kind pill to cut cholesterol in high-risk patients​

The logo for Merck appears above a trading post on the floor of the New York Stock Exchange, May 1, 2025.

PHOTO: Associated Press file

PUBLISHED ONJuly 17, 2026 12:59 PM

www.asiaone.com

WASHINGTON — The Food and Drug Administration has approved a first-of-its-kind pill that can drastically reduce cholesterol in a way that's previously only been available with expensive, injectable drugs.

The drug from Merck was OK'd on Thursday (July 16) for patients with artery-clogging cholesterol that persists even after taking statins, the standard medications for cutting heart attack risk. Merck will market its pill under the brand name Lipfendra.

It's the first noninjectable medication that works by blocking a liver protein called PCSK9.

That protein limits the body's ability to clear cholesterol from the blood, and biotech injectables targeting it have been available from Amgen and other drugmakers for more than a decade.

But patient access has been stymied for years by high prices, insurance restrictions and limited prescribing by doctors.

Statins block some of the liver's production of cholesterol and are the cornerstone of treatment. But even at the highest doses, many people need additional help lowering their LDL, or bad, cholesterol enough to meet medical guidelines.

Merck, which has headquarters in Rahway, New Jersey, won approval based on two studies in high-risk patients who added the company's pill to their standard treatment, including statins.

In one study of 3,000 patients, those taking Lipfendra saw their levels of LDL cholesterol drop more than 55 per cent after six months.

In a second study, patients averaged a reduction of 59 per cent compared with patients who received a dummy pill.

That benefit dropped only slightly over a year, and side effects — including dizziness and diarrhoea — were similar between those taking the pill or a placebo, researchers found. One caveat: The pill must be taken on an empty stomach.

The FDA reviewed the drug under its programme that promises ultra-fast reviews for promising medications that serve the public interest.

The pathway was created by then-FDA chief Dr Marty Makary, who resigned from the agency in May after months of pressure from drugmakers, patients and other outside groups.

Heart disease is the nation's leading cause of death, and high LDL cholesterol, which causes plaque to build up in arteries, is a top risk factor for heart attacks and strokes.

While an LDL level of 100 is considered fine for healthy people, doctors recommend lowering it to at least 70 once people develop high cholesterol or heart disease — and even lower for those at very high risk.

Source: Associated Press

 

[DaoMa]

 

[DaoMa]

@glockman
this cardiologist really chio right?

 

[glockman]

@glockman
this cardiologist really chio right?

a chio cardiologist! Not only does she steal your heart, she takes good care of it too.