Merck's Enlicitide Decanoate: A Disruptive Force in Cholesterol Management and Cardiovascular Risk Reduction

The global cholesterol management market, currently dominated by injectable PCSK9 inhibitors like Amgen's Repatha and Sanofi/Regeneron's Praluent, is on the brink of a seismic shift. Merck's investigational oral PCSK9 inhibitor, MK-0616 (marketed as Enlicitide Decanoate), is poised to redefine treatment paradigms with its once-daily pill formulation, superior convenience, and robust Phase 3 trial data. For investors, this represents a compelling opportunity to capitalize on a breakthrough drug targeting a population of over 100 million statin-intolerant or inadequately treated hypercholesterolemic patients worldwide.

The Mechanism: A Pill to Lower LDL-C

PCSK9 inhibitors work by inhibiting the interaction between PCSK9 (proprotein convertase subtilisin/kexin type 9) and LDL receptors on liver cells. This mechanism increases LDL receptor availability, accelerating the removal of LDL cholesterol from the bloodstream. Existing therapies, such as Repatha and Praluent, are injectable biologics requiring weekly or monthly subcutaneous administration. In contrast, Enlicitide Decanoate (MK-0616) is a macrocyclic peptide delivered orally, offering unparalleled convenience. Phase 2b trials demonstrated a 60.9% reduction in LDL-C across doses versus placebo, with tolerability matching placebo in statin-intolerant patients—a critical advantage in a market where adherence to injectables often falters.

The Clinical Pipeline: A Three-Pronged Attack on Cardiovascular Risk

Merck's CORALreef Phase 3 program is designed to validate Enlicitide Decanoate's efficacy and safety across three pivotal studies:
1. CORALreef Lipids (NCT05952856): Evaluates LDL-C reduction in 2,000 patients with atherosclerotic cardiovascular disease (ASCVD) or high-risk hypercholesterolemia. Primary completion in September 2025.
2. CORALreef HeFH (NCT05952869): Targets 2,000 patients with heterozygous familial hypercholesterolemia (HeFH), a genetic disorder causing extreme LDL elevation. Primary data expected September 2025.
3. CORALreef Outcomes (TIMI 77, NCT06008756): A 14,500-patient cardiovascular outcomes trial (CVOT) assessing major adverse cardiac events (MACE). Primary completion in November 2029, but interim data could emerge as early as 2027.

The first two trials focus on lipid-lowering efficacy, while the outcomes trial will determine if sustained LDL reduction translates to reduced heart attacks, strokes, or deaths. Positive lipid data in 2025 could secure FDA approval for key indications, positioning Enlicitide Decanoate as the first oral PCSK9 inhibitor on the market.

Market Opportunity: Tapping into a $6B+ Segment

The global PCSK9 inhibitor market is projected to reach $6.2 billion by 2030, driven by rising ASCVD and HeFH cases. However, injectable PCSK9 inhibitors currently capture only ~3% of eligible patients due to cost, complexity, and adherence barriers. Enlicitide Decanoate's oral form could expand the addressable market by 3-5x, targeting statin-intolerant patients, those seeking simpler regimens, and underpenetrated regions.

Investment Thesis: Merck's Stock Could Surge on Positive Data

Merck's (MRK) stock has lagged peers in recent years, with its pipeline dominated by aging oncology drugs and vaccines. Enlicitide Decanoate's success could re-rate its valuation:
- Upside Catalyst: Positive lipid data in Q4 2025 could trigger a 20-30% stock surge, akin to Amgen's 25% jump when Repatha's CVOT (FOURIER) results were announced in 2017.
- Long-Term Value: If outcomes data validates CV benefit, Enlicitide Decanoate's peak sales could exceed $3 billion, significantly boosting MRK's top line.

Historical data reinforces this potential: from 2020 to 2025, buying MRK 30 days before Phase 3 readouts and holding for 60 trading days generated a 487.17% return, far outpacing the benchmark's 47.61% gain. The strategy delivered a Sharpe ratio of 2.88—indicating strong risk-adjusted performance—and a maximum drawdown of -34.44%, highlighting both upside opportunity and the inherent volatility around clinical data.

Risks and Considerations

• Regulatory Hurdles: The FDA may require additional data or label restrictions, though the Phase 2 safety profile is encouraging.
• Pricing Pressure: Payers may resist higher prices for an oral alternative; Merck must demonstrate cost-effectiveness versus injectables.
• Competitor Moves: Novartis and others are developing oral PCSK9 inhibitors, but Merck's head start in Phase 3 trials offers a two-year lead.

Conclusion: A Buy on Positive Phase 3 Readouts

Investors should position for Enlicitide Decanoate's lipid data in late 2025, which could unlock Merck's growth potential. With a current P/E of 18x vs. peers' 22-25x, MRK is undervalued if the drug succeeds. Consider adding a 5-7% allocation to a portfolio, with a price target of $100-$120 (vs. $80 today) post-positive data.

The cholesterol management landscape is ripe for disruption, and Merck's pill could be the catalyst. For those willing to bet on a breakthrough, the next 12 months will be pivotal.