Merck’s enlicitide shows major LDL-C reduction in Phase 3 trials, raising hopes for first oral PCSK9 approval

Merck & Co., Inc. (NYSE: MRK) has announced statistically significant topline results from the first two pivotal Phase 3 trials in its CORALreef clinical development program evaluating enlicitide decanoate, a novel oral PCSK9 inhibitor. The trials—CORALreef HeFH and CORALreef AddOn—demonstrated meaningful LDL-C reductions in patients with hyperlipidemia already on statin therapy, reinforcing enlicitide’s potential to become the first approved oral PCSK9 inhibitor in the United States.

The pharmaceutical company confirmed that both studies met their primary and all key secondary endpoints, without reporting any clinically meaningful differences in adverse events between treatment and control groups. If enlicitide advances through the final stages of the clinical program and gains regulatory approval, it could reshape lipid management by replacing injectable PCSK9 therapies with a more accessible, daily oral alternative.

What were the CORALreef HeFH and AddOn trial results?

The CORALreef HeFH trial enrolled patients with heterozygous familial hypercholesterolemia (HeFH) who had either a prior history of or were at elevated risk for atherosclerotic cardiovascular disease (ASCVD). Participants were already receiving moderate- to high-intensity statin therapy. Enlicitide achieved statistically significant reductions in low-density lipoprotein cholesterol (LDL-C) at week 24, with the benefits extending through secondary endpoints at week 52.

The CORALreef AddOn trial assessed enlicitide in adults with hyperlipidemia who were also at risk for ASCVD and were being treated with statins. In this trial, enlicitide was tested against three oral non-statin comparators—ezetimibe, bempedoic acid, and their combination. Across all arms, enlicitide showed statistically superior LDL-C lowering performance by week 8, further validating its efficacy.

Safety outcomes across both studies were encouraging, with adverse events and serious adverse events showing no clinically relevant difference from the placebo or comparator arms. These outcomes underscore enlicitide’s potential to deliver injectable-like results in a more convenient oral form.

How does enlicitide work as an oral PCSK9 inhibitor?

Enlicitide is a macrocyclic peptide designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that regulates the number of LDL receptors on cell surfaces. By blocking PCSK9’s interaction with LDL receptors, enlicitide increases the number of receptors available to remove LDL-C from the bloodstream, thereby improving cholesterol clearance.

Currently approved PCSK9 inhibitors like alirocumab and evolocumab are administered via injection. Enlicitide, if approved, would be the first drug to achieve this therapeutic outcome in a daily oral formulation, addressing a critical unmet need for patients reluctant or unable to maintain injectable therapy regimens.

Dr. Dean Y. Li, president of Merck Research Laboratories, emphasized that Merck is moving with urgency to bring enlicitide to market. He described the candidate as combining antibody-like specificity with oral convenience—potentially a game-changer in cardiovascular therapy.

Why LDL-C reduction remains a critical treatment goal

Low-density lipoprotein cholesterol (LDL-C) is a well-established modifiable risk factor for ASCVD events such as myocardial infarction and stroke. While statins remain the first line of therapy, many patients do not reach guideline-recommended LDL-C goals despite optimal statin use.

According to Dr. Christie M. Ballantyne, principal investigator for the CORALreef HeFH trial and Professor of Medicine at Baylor College of Medicine, LDL-C reduction should be prioritized more aggressively, particularly in patients at high cardiovascular risk. He noted that broader adoption of therapies like enlicitide could enable earlier and more effective intervention to prevent ASCVD events.

Globally, cardiovascular disease remains the leading cause of death, with ASCVD accounting for 85 percent of cardiovascular-related mortality. In the United States, one person dies every 36 seconds due to cardiovascular disease. Hyperlipidemia affects approximately 86 million adults in the U.S. alone, highlighting the scale of the treatment gap that enlicitide could help address.

How is the CORALreef clinical program structured?

The CORALreef Phase 3 program comprises three trials: CORALreef HeFH, CORALreef AddOn, and two ongoing studies—CORALreef Lipids and CORALreef Outcomes. Together, these trials are expected to enroll over 17,000 patients across multiple geographies, targeting a range of lipid disorders and risk profiles.

The HeFH trial (NCT05952869) was a double-blind, placebo-controlled study measuring changes in LDL-C at 24 and 52 weeks, as well as other lipid markers like ApoB, non-HDL-C, and lipoprotein(a). The AddOn trial (NCT06450366) evaluated the same lipid endpoints but compared enlicitide against other oral non-statins at an 8-week primary endpoint.

Detailed findings from the first two trials will be presented at a future scientific congress, with regulatory submissions expected after completion of the full clinical program in late 2025 or early 2026.

How has Merck stock performed amid the enlicitide update?

As of June 9, 2025, Merck & Co., Inc. (NYSE: MRK) was trading at approximately $78.89, reflecting a modest intraday decline of 0.1%. Over the past year, MRK has underperformed broader benchmarks, declining between 21% and 29%, compared to a 20% gain in the S&P 500.

Despite the decline, Merck continues to be viewed as a defensive pharmaceutical stock, supported by a low beta of 0.40 and a dividend yield of approximately 4%. The enlicitide data, alongside other late-stage pipeline programs, is seen as a potential inflection point for the American biopharmaceutical company.

What are analysts saying about Merck and enlicitide?

Analyst sentiment remains moderately bullish, with TipRanks reporting 23 Buy and 16 Hold ratings and a consensus target price range between $100 and $114, implying an upside potential of 27–44%. MarketBeat data adds nuance with a broader range of sentiment, including 1 Sell, 12 Hold, 7 Buy, and 2 Strong Buy recommendations, with an average target near $109.

The biggest near-term risk remains the expiration of market exclusivity for blockbuster immunotherapy Keytruda in 2026, as well as recent challenges in China’s Gardasil franchise. These concerns have led to cautious guidance from firms such as Citi and CFRA, which downgraded the stock in early 2025.

Still, the success of enlicitide and other pipeline therapies could restore growth visibility and ease investor concerns about top-line sustainability post-Keytruda.

What do institutional trends suggest?

Although U.S. equities do not disclose FII/DII flow data, institutional activity around Merck has remained stable. The American pharmaceutical company continues to feature prominently in defensive health care portfolios, and mutual funds have maintained exposure due to the combination of yield and innovation.

However, short interest has risen 11% month-over-month, suggesting a more hedged institutional stance, possibly in anticipation of upcoming regulatory catalysts or pipeline volatility. Options market activity reflects a neutral to slightly bullish bias, with implied volatility levels still within historical norms.

What’s next for Merck and the future of PCSK9 inhibition?

With two out of three Phase 3 trials yielding strong results, Merck is poised to complete the remaining studies in the CORALreef program and file for regulatory approval in key global markets. If successful, enlicitide would not only become the first oral PCSK9 inhibitor approved but could also significantly expand treatment access by eliminating the need for injections.

The commercial implications are substantial. Analysts expect oral PCSK9 inhibitors to potentially unlock broader patient segments previously underserved by injectables. Moreover, oral delivery could improve adherence, outcomes, and ultimately, payer interest.

The future of lipid-lowering therapy could pivot significantly if enlicitide enters the market, particularly in combination with emerging digital adherence tools and broader preventive care frameworks.