Blockbuster Patent Expirations 2025 and Beyond: Key Drugs, Timeline, and Market Impact

By mid-2025, the pharmaceutical world will face its biggest shift in decades. Dozens of top-selling drugs, each bringing in billions annually, will lose patent protection. This isn’t just a legal technicality-it’s going to change how patients pay for medicine, how pharmacies stock shelves, and how hospitals manage treatment plans. The blockbuster patent expirations starting in 2025 aren’t a distant forecast-they’re already here, with generics ready to hit the market the moment the patents expire.

What’s Expiring in 2025? Entresto Leads the Way

The first major hit comes in July 2025, when Novartis’ Entresto (sacubitril/valsartan) loses its core patent protection in the U.S. Entresto, a heart failure drug, brought in $7.8 billion globally in 2024. For patients, that means monthly costs could drop from $150-$300 to as low as $20-$40 once generics arrive. Hospitals and pharmacies have been preparing for months. By October 2024, 87% of hospital pharmacy directors surveyed by ASHP had already started formulary changes and staff training to switch patients over.

The FDA approved the first generic version of sacubitril-Entresto’s key component-back in October 2024, signaling that manufacturers were ready to roll out full generics the moment the patent expired. This isn’t unusual for small-molecule drugs. Once a patent expires, generic versions typically capture 90% of the market within a year. But Entresto’s case is special because it’s a combination drug, which makes manufacturing slightly more complex than a single-ingredient pill. Still, with over 120 ANDA applications filed targeting Entresto, competition will be fierce.

2026: Eliquis Goes Generic-The Anticoagulant Giant Falls

Just over a year later, in November 2026, Bristol Myers Squibb and Pfizer’s Eliquis (apixaban) loses its key crystalline form patent. Eliquis generated $13.2 billion in global sales in 2024, making it one of the most profitable drugs ever. Unlike Entresto, Eliquis competes in a crowded space. Already, other blood thinners like Xarelto and Pradaxa have generics available. That means when Eliquis generics hit, prices will crash even faster.

Patients on Eliquis are mostly older adults managing atrial fibrillation or recovering from surgery. Many pay hundreds per month out of pocket. With generics, that could drop by 85% within six months. Pharmacy technicians are already seeing a spike in inquiries. One user on the Pharmacy Technicians United Facebook group noted, “We’re getting calls every day from patients asking if the generic will be cheaper.”

But there’s a catch: Eliquis has multiple patents beyond the core composition. Some secondary patents may still block certain generic versions for a few more months. Still, the main revenue stream ends in late 2026. By early 2027, generic apixaban will likely be the default choice in most U.S. pharmacies.

2028: The $30 Billion Giant-Keytruda’s Turn

Nothing compares to what’s coming in 2028. Merck’s Keytruda (pembrolizumab), a cancer immunotherapy drug, will lose its core composition patent. In 2024, Keytruda brought in over $29 billion-more than any other drug on the planet. It’s used to treat melanoma, lung cancer, and several other deadly cancers. For many patients, it’s the only thing keeping them alive.

Unlike heart or blood pressure drugs, there’s no simple generic version of Keytruda. It’s a biologic-a complex protein made in living cells. That means the competition won’t be “generics” but “biosimilars.” Biosimilars are similar, but not identical, to the original. They take longer to develop, cost more to produce, and face more regulatory hurdles. The FDA has approved only a handful so far, and none target Keytruda yet.

Analysts predict Merck could lose up to $15 billion in annual revenue within 18 months of biosimilar entry. That’s the biggest single-year revenue drop in pharmaceutical history. But here’s the twist: even with biosimilars, Keytruda won’t disappear. Doctors are cautious. Many patients have been on Keytruda for years. Switching isn’t automatic. Biosimilars may only capture 50-60% of the market over three to five years. And Merck isn’t sitting still. In November 2024, they announced a $12 billion investment in next-generation cancer therapies to replace Keytruda’s revenue.

Why Biologics Are Different-The Patent Thicket Problem

Not all blockbuster drugs are created equal. Small-molecule drugs like Eliquis and Entresto have straightforward chemical structures. Generics can copy them exactly. Biologics like Keytruda, Humira, and Enbrel are made from living organisms. Their complexity makes exact copying impossible. That’s why biosimilars take 18-24 months longer to reach the market after patent expiry.

On top of that, biologics are protected by dozens of patents-not just one. Dr. Gary Pisano from Harvard noted that biologics average 132 patents per product, compared to just 14 for small molecules. These aren’t just about the active ingredient. They cover delivery systems, manufacturing methods, even packaging. Companies use these to extend exclusivity, a practice called “patent thickets.”

These patent thickets often lead to lawsuits. Generic manufacturers must fight through legal delays before they can sell. The RAND Corporation found that patent litigation delays biosimilar entry by an average of 2.3 years. That’s why Humira, despite its core patent expiring in 2023, still had limited competition until late 2024.

Who Wins? Who Loses?

The winners are clear: patients, insurers, and government programs like Medicare. The Congressional Budget Office estimates the 2025-2030 patent expirations will save the U.S. healthcare system $312 billion over the decade. That’s $198 billion in savings just from 2025 to 2027.

For patients on Entresto or Eliquis, monthly costs could drop from hundreds to tens of dollars. A 2024 American Heart Association survey found 68% of heart failure patients would switch to generic Entresto immediately if available. That’s not just about money-it’s about access.

Pharmaceutical companies, on the other hand, face massive revenue loss. Merck stands to lose $31.2 billion in potential revenue from expiring patents by 2030. Amgen could lose 52% of its 2024 revenue. That’s why companies are scrambling: Bristol Myers Squibb bought Karuna Therapeutics for $4.1 billion to build a new pipeline. Teva, Mylan, and Sandoz are racing to develop the most generic and biosimilar products. Teva alone has 37 drugs in development targeting the 2025-2030 cliff.

How Are Providers Getting Ready?

Hospitals and pharmacies aren’t waiting for the patents to expire. They’re acting now. ASHP’s 2024 survey showed 76% of hospital pharmacists are taking extra training on the upcoming expirations. Formulary committees are rewriting drug lists. Pharmacists are preparing patient education materials.

One hospital system in Ohio already negotiated a 60% price reduction with its pharmacy benefit manager (PBM) for Entresto, anticipating the generic launch. That’s not uncommon. PBMs, which manage drug coverage for insurers, are pushing hard for lower prices. The Generic Pharmaceutical Association’s “Patent Cliff Navigator” tool is now used by 82% of PBMs to track expiration dates month by month.

But challenges remain. Only 28% of U.S. states have laws allowing pharmacists to automatically substitute complex generics like Entresto. That means doctors may need to write new prescriptions, and patients may face delays. Pharmacists are also worried about supply chain issues. After Humira biosimilars launched, there were shortages. Will the same happen with Entresto or Eliquis generics? No one knows for sure.

What’s Next After 2030?

The patent cliff doesn’t end in 2030. It just slows down. Another wave is already building. Drugs like Trulicity (diabetes), Dupixent (eczema), and Stelara (psoriasis) have patents expiring in the early 2030s. The industry is shifting. Companies are investing less in me-too drugs and more in gene therapies, RNA treatments, and personalized cancer vaccines. The days of billion-dollar blockbusters built on a single chemical are fading.

But for now, the focus is on 2025-2028. These three drugs-Entresto, Eliquis, Keytruda-represent over $50 billion in annual sales. Their transition to generics and biosimilars will reshape how medicine is priced, prescribed, and paid for. Patients will pay less. Pharmacies will stock more generics. Hospitals will save millions. And the pharmaceutical industry will have to adapt-or lose its biggest profits.