In late-stage studies, Merck & Co.’s PCSK9-targeted pill achieved low-density lipoprotein cholesterol (LDL-C) reductions similar to those observed with existing injectables.
The results from two phase 3 trials give Merck’s once-daily drug, enlicitide, a “significant advantage” over injected biologics, given its oral administration, room-temperature storage and likely lower pricing, Leerink Partners analysts said in a Nov. 10 note to clients.
Existing PCSK9 inhibitors have achieved blockbuster status, but they never came close to Wall Street’s initial high expectations of a $40 billion-plus market. By Leerink’s calculation, combined U.S. sales of PCSK9 biologics were only about $1.8 billion in 2024. Adoption of these drugs remains limited, thanks partly to their route of administration and high costs.
Enlicitide, instead, “could see significant uptake in the primary care setting, where injectable hesitation is high,” the Leerink team said.
If Merck's drug wins an FDA approval, patient conversions from injectables to enlicitide could be fueled by the oral med's strong lipid-lowering data, according to the analysts.
In patients with high levels of LDL-C who were already on background lipid-lowering therapies or who couldn't tolerate statins, enlicitide reduced LDL-C levels by 59.7% compared to placebo at week 24. The result, presented at the American Heart Association (AHA) Scientific Sessions 2025 over the weekend, means that the CORALreef Lipids trial met its primary endpoint. The study enrolled more than 2,900 patients who had a history of a major atherosclerotic cardiovascular disease event (ASCVD) or who were at an increased risk for such an episode.
The 59.7% figure came from a post-hoc re-analysis after the rules for handling missing data were revised to correct for five biologically impossible baseline values being included in the original analysis, which yielded a 55.8% result. The intent of the re-analysis was to “provide a more clinically accurate estimate of the treatment,” Merck said in its Nov. 8 announcement.
At AHA 2025, Merck also reported another positive phase 3 readout from a trial dubbed CORALreef HeFH conducted in patients with heterozygous familial hypercholesterolemia, a genetic disorder characterized by elevated LDL-C. In this study, enlicitide showed a similar 59.4% LDL-C reduction versus placebo at week 24. The 303 patients enrolled in the trial were also on background statins.
Enlicitide’s LDL-C reduction power is comparable to reductions seen with PCSK9 injectables, including Amgen’s Repatha, Regeneron’s Praluent and Novartis’ Leqvio, the Leerink team noted. About 97% of patients in the large CORALreef Lipids trial were on background statins, and the control group didn’t see any obvious worsening of LDL-C, which suggests that enlicitide did drive the observed treatment effect, the Leerink analysts added.
Merck recently said that another phase 3 trial, CORALreef AddOn, pitting enlicitide against non-statin cholesterol medicines ezetimibe or bempedoic acid, also met its key endpoint of LDL-C reduction at week 8.
Merck said it plans to share data from all three trials with regulatory authorities worldwide.
Giving Leerink further confidence in enlicitide, Amgen at AHA 2025 shared detailed results from the phase 3 Vesalius-CV trial showing the addition of Repatha to background therapy reduced the risk of death from cardiovascular causes by 21% in patients with high cardiovascular risk but without a history of a prior event.
Repatha’s primary prevention data strongly support the PCSK9 mechanism, which enlicitide leverages, the Leerink team said. Enlicitide’s CORALreef Lipids trial is combined for both primary and secondary prevention, as it involves a mix of patients both with and without a past ASCVD experience.
“[T]hese survival benefits in a relatively lower-risk patient population support earlier, more aggressive use of LDL-C lowering therapies, and could drive updates to global guidelines for therapeutic intervention to help all patients at risk get to the 55 mg/dL LDL-C goal,” the Leerink analysts said of the Repatha data in their note.
Granted, the trials measured different outcomes, as Merck's showed enlicitide's lipid-lowering ability while Amgen's showed Repatha's power to reduce the risk of major cardiovascular events or death. But the Leerink team argued that many doctors may view the Merck pill as interchangeable with the injectables “given equivalent epitopes and lipid-lowering effects.”
Merck is working to get the CV outcomes results from the phase 3 CORALreef Outcomes study, which is fully enrolled with more than 14,700 patients. While the New Jersey pharma is projecting a primary completion in late 2029, the Leerink team figured the readout could come much sooner if enlicitide’s efficacy matches that of the antibodies.
Recent positive readouts from enlicitide, as well as from the pulmonary arterial hypertension drug Winrevair, are giving Leerink analysts increased confidence that Merck can fill the expected revenue hole left by Keytruda’s looming loss of exclusivity.
That is not to say enlicitide will be navigating a completely clear sea. As the Leerink team noted, the PCSK9 field is becoming increasingly crowded. AstraZeneca is also developing an oral PCSK9 drug, coded AZD0780, although that drug is years behind enlicitide.
Any meaningful utilization in the primary prevention setting will take time, a BMO analyst said in a separate note.
One major uncertainty over the potential uptake of enlicitide centers on its dosing instructions. The Merck pill must be taken on an empty stomach after an overnight eight-hour fast and 30 minutes before breakfast, as interactions with food decrease its efficacy. That requirement raises a concern over compliance.
In the two phase 3 trials that have read out, patients self-reported a 97% adherence rate to the doses. However, adherence may deteriorate in the real world outside of a controlled clinical trial setting where patients go on frequent check-ins with physicians, the Leerink team noted.
But at the same time, the Leerink team wondered if compliance will even be such a big issue for the potential launch. That’s because Merck tested enlicitide at a 20-mg daily dose, whereas a 10-mg dose has shown similar impact on LDL-C reduction in earlier trials. The analysts wondered if Merck has already factored in some negative impacts from deviation from the fasting guidelines with its dose selection.