Can Merck rebuild its cardiovascular empire post-Keytruda? A closer look at its next decade of drug growth

Merck & Co., Inc. (NYSE: MRK), long regarded as a global oncology leader due to its blockbuster immunotherapy Keytruda, is now staring down one of the most consequential patent cliffs in pharmaceutical history. With Keytruda expected to lose exclusivity by 2028, the American biopharmaceutical major is moving aggressively to reassert itself in cardiovascular and immunology markets—areas it once dominated. Its recent topline results from the Phase 3 CORALreef program for enlicitide, a first-in-class oral PCSK9 inhibitor, alongside strategic acquisitions and sotatercept‘s commercial debut, reflect a deliberate pivot. The question now is whether these bets are enough to build a post-Keytruda empire.

What is Merck’s strategy after the Keytruda patent expiry in 2028?

Keytruda generated over $25 billion in global sales in 2024, accounting for more than 40% of Merck’s total revenue. That concentration is precisely what analysts say Merck must address as biosimilar competition looms in the next three years. The drug’s market exclusivity in the U.S. is expected to lapse around 2028, and although Merck is actively pursuing subcutaneous formulations and label expansions, these may not be sufficient to stave off erosion.

To mitigate this, Merck has laid out a roadmap centered on advancing late-stage pipeline assets in cardiometabolic and immunology, executing value-creating M&A such as the 2021 Acceleron deal for sotatercept and the 2023 acquisition of Prometheus Biosciences, and expanding vaccine and infectious disease franchises while doubling down on digital health partnerships and real-world evidence frameworks. CEO Robert Davis has repeatedly emphasized that the company’s capital deployment strategy is focused on internal innovation, targeted business development, and shareholder return continuity—a signal that Merck intends to use Keytruda’s cash flow to seed the next era.

Can Merck’s cardiovascular pipeline replace Keytruda’s lost revenue?

Merck’s cardiovascular ambitions rest on several pillars, but enlicitide and sotatercept (branded Winrevair) are at the forefront. Enlicitide recently delivered positive topline data from the CORALreef HeFH and AddOn Phase 3 trials. The oral macrocyclic peptide PCSK9 inhibitor significantly reduced LDL-C in statin-treated adults and could, if approved, become the first oral PCSK9 therapy globally. Analysts project peak annual sales of $4–6 billion, contingent on payer uptake, pricing parity with injectables, and guideline inclusion by 2027.

Sotatercept, acquired through Merck’s $11.5 billion Acceleron Pharma deal in 2021, was recently approved in the U.S. and U.K. for pulmonary arterial hypertension (PAH). Marketed as Winrevair, the drug is a first-in-class activin signaling inhibitor with potential to alter the disease course in PAH patients. Analysts expect $2–4 billion in peak sales, with broader label expansion in heart failure and other pulmonary indications under evaluation. Together, enlicitide and Winrevair could form a dual anchor in Merck’s cardiovascular resurgence.

What role does enlicitide play in Merck’s post-Keytruda portfolio?

Enlicitide’s significance goes beyond cholesterol control. It marks Merck’s return to lipid leadership—a space it once ruled through drugs like Zocor and Vytorin. The therapy’s oral format makes it a potential disruptor in a market dominated by injectables like Amgen’s Repatha and Regeneron–Sanofi’s Praluent. Unlike monoclonal antibodies, enlicitide is a macrocyclic peptide, giving it antibody-like specificity but with oral bioavailability. That convenience factor could be a key commercial differentiator, especially if Merck can price it competitively while securing broad payer access.

The full CORALreef data will be unveiled at an upcoming scientific congress. Regulatory filings in the U.S., Europe, and Japan are expected by early 2026.

How is Merck repositioning in cardiometabolic diseases?

In addition to PCSK9 inhibition and PAH, Merck is building out a broader cardiometabolic portfolio. Notably, its investigational SGLT2 inhibitor MK-5475 and collaborations in digital therapeutics for hypertension signal interest in chronic disease management. Its Prometheus Biosciences acquisition, while primarily focused on immunology, also gives it a platform for genetically informed drug development that could translate into personalized cardiometabolic solutions. This represents a thematic convergence with payer preferences in value-based care and population health. In sum, Merck isn’t just building products—it’s crafting disease platforms that integrate biologics, AI diagnostics, and biomarker-driven strategies.

What are analysts and institutions saying about Merck’s pivot?

As of June 2025, Merck stock (NYSE: MRK) is trading near $79, down over 20% year-to-date, significantly lagging the S&P 500. While investor sentiment was buoyed by enlicitide’s recent trial success, the stock remains pressured by broader uncertainty around Keytruda’s durability and vaccine market headwinds.

According to TipRanks, Merck has a consensus Moderate Buy rating, with 23 Buy and 16 Hold recommendations. The average 12-month price target ranges from $100 to $114, implying a 27–44% upside from current levels. MarketBeat’s ratings show 1 Sell, 12 Hold, 7 Buy, and 2 Strong Buy. Short interest has increased by 11% month-over-month, indicating growing hedge fund caution. However, Merck continues to see strong institutional holding levels, with top asset managers rotating exposure toward pipeline-based valuation rather than current revenue.

What risks still shadow Merck’s transformation strategy?

Despite pipeline progress, over 40% of revenue still comes from Keytruda. Regulatory or pricing hurdles in launching replacements could widen the gap post-2028. Merck’s Gardasil franchise, another key growth driver, saw a steep revenue decline in Q1 2025 due to vaccination policy shifts in China, where the company faces more intense local competition. Additionally, enlicitide must navigate FDA approval, market access, and physician adoption. Meanwhile, Winrevair’s launch requires building commercial infrastructure in a rare disease category with specialist gatekeepers. Still, many analysts believe Merck is better positioned than peers like Bristol Myers Squibb or Gilead, which also face post-blockbuster transitions but with fewer diversified platforms.

What’s the long-term outlook for Merck’s cardiovascular ambitions?

If Merck successfully commercializes both enlicitide and sotatercept, analysts believe it could generate $6–10 billion in annual cardiovascular revenue by the early 2030s. Add in incremental contributions from digital health and other cardiometabolic programs, and the business could serve as a core revenue pillar beyond oncology. This would not only rebalance the portfolio but reposition Merck as a dual-force in oncology and cardiovascular care—reminiscent of its diversified stature in the early 2000s.

As CEO Robert Davis stated in a recent investor call, Merck’s goal is not just to defend but to redefine its growth trajectory. With the right execution, its cardiovascular pivot could make that ambition a reality.