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 a financial earthquake that will drop drug prices by 80% or more, change how doctors prescribe, and put billions back into patients’ pockets. The blockbuster patent expirations starting in 2025 aren’t scattered events. They’re a coordinated wave, and the drugs at the center of it are the ones millions rely on every day.

What’s Expanding 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. This heart failure drug generated $7.8 billion in global sales in 2024. For patients, that means a monthly cost that’s been $150-$300 could drop to $20-$40 within months. Hospitals and pharmacies are already preparing. Over 87% of hospital pharmacy directors surveyed by ASHP in October 2024 are updating formularies and training staff for the switch. The FDA even approved the first generic version of sacubitril ahead of schedule in October 2024-unusually fast, signaling how heavily the industry is gearing up.

Why does this matter? Entresto isn’t a minor drug. It’s become the new standard of care for heart failure with reduced ejection fraction. When generics hit, doctors won’t just prescribe them-they’ll be encouraged to. Patient advocacy groups like the American Heart Association found that 68% of heart failure patients would switch immediately if cost dropped. That’s not just savings-it’s better access.

2026: Eliquis Falls-And the Anticoagulant Market Shifts

November 2026 is when Bristol Myers Squibb and Pfizer’s Eliquis (apixaban) loses its key crystalline form patent. In 2024, Eliquis raked in $13.2 billion globally. That’s more than the entire annual revenue of many mid-sized pharma companies. Once generics arrive, expect prices to plummet fast. Small-molecule drugs like Eliquis typically see 80-90% price drops within a year of generic entry, with generics capturing over 90% of the market within two years.

But here’s the twist: Eliquis isn’t alone. Other blood thinners like Xarelto and Pradaxa already have generics. So when Eliquis goes generic, it won’t just be competing with the brand-it’ll be in a crowded, price-war zone. Pharmacists are already watching supply chains closely. After Humira biosimilars caused initial shortages in 2023, many pharmacies are now building buffer stocks. One pharmacy technician on a major Facebook group noted: “We’re seeing multiple manufacturers ramping up, but I’m nervous about the first few months.”

2028: The Giant Falls-Keytruda’s $30 Billion Cliff

By far the biggest single event on this timeline is Merck’s Keytruda (pembrolizumab), which loses its core patent in 2028. In 2024, it brought in $29.3 billion-more than any other drug in history. It’s used to treat melanoma, lung cancer, Hodgkin’s lymphoma, and more. Unlike Entresto or Eliquis, Keytruda is a biologic. That means generics can’t just copy it. They have to make biosimilars, which are far harder to develop and get approved.

That’s why the impact won’t be immediate. Biosimilars take 18-24 months longer to reach market than regular generics. But when they do, the effect will be massive. JPMorgan analyst Christopher Schott predicts Merck could lose $15 billion in annual revenue within 18 months of biosimilar entry. That’s more than the entire market cap of many tech startups.

Merck isn’t sitting still. In November 2024, they announced a $12 billion investment in next-generation cancer therapies to replace Keytruda’s revenue. They’re betting on new immunotherapies, targeted drugs, and combination treatments. But even with innovation, the loss of Keytruda will reshape oncology. No other drug in history has had such a dominant position in cancer care. When biosimilars arrive, oncologists will have to decide: stick with the brand, or switch to a cheaper version that’s just as effective? The answer will depend on insurance coverage, hospital protocols, and patient trust.

Why This Wave Is Different: It’s Not Just One Drug-It’s 65 of Them

The 2025-2030 period isn’t just about Entresto, Eliquis, and Keytruda. According to IQVIA, 65 drugs with annual sales over $100 million will lose patent protection during this window. Together, they represent $187 billion in global sales at risk. That’s nearly 30% of the entire blockbuster drug market.

Here’s the breakdown by therapeutic area:

• Oncology (32%): Keytruda, Ibrance, Tecentriq, Opdivo
• Cardiovascular (25%): Entresto, Eliquis, Farxiga
• Immunology (20%): Humira (already started), Stelara, Rinvoq
• Diabetes (10%): Trulicity, Ozempic (patents later, but looming)

Each of these drugs has its own timeline, legal battles, and market dynamics. For example, Humira’s patent battles dragged on for years, delaying biosimilars until 2023. Now, those biosimilars are capturing over 40% of the market. That’s the blueprint for what’s coming next.

The Hidden Players: Generic Manufacturers Are Already in Position

Behind every patent expiration is a team of scientists, regulators, and business teams working for years to get ready. Generic drugmakers like Teva, Mylan, and Sandoz have been preparing since 2020. Teva alone has 37 products in development targeting these expirations. Mylan has 29. These companies spend an average of $2.6 million and 3-4 years to get each generic approved.

The FDA has received 127 applications for drugs expiring in 2025 alone-up 27% from last year. That’s not just a coincidence. It’s a race. The first generic to market often captures 80% of sales in the first month. After that, it’s a price war. That’s why companies are filing early, even before the patent expires, to get that first-mover advantage.

And it’s not just the U.S. The European Union, Canada, and Australia are also preparing. But the U.S. market is where the biggest money is. It accounts for 63% of the $187 billion in at-risk sales-even though it only has 20% of the world’s patients. Why? Because drug prices here are unregulated. A pill that costs $5 in Germany can cost $150 here. When patents expire, the drop is dramatic.

What This Means for Patients, Doctors, and Pharmacies

For patients, this is good news. The Congressional Budget Office estimates these expirations will save the U.S. healthcare system $312 billion over the next decade. $198 billion of that will happen between 2025 and 2027. For a heart failure patient on Entresto, that could mean $1,500-$3,000 saved per year. For a cancer patient on Keytruda, it could mean thousands less out of pocket.

But it’s not all smooth sailing. Doctors need to learn how to switch patients safely. Pharmacists need to manage inventory and substitution rules. In 63% of states, pharmacists can automatically substitute biosimilars-but only 28% have similar rules for complex generics like Entresto. That means confusion. A patient might get a different pill than expected. A doctor might not realize the switch happened.

That’s why organizations like ASHP and the American Medical Association are releasing toolkits. They’re training staff on therapeutic interchange, updating electronic records, and preparing patient education materials. One hospital system in California already negotiated 60% price reductions with pharmacy benefit managers before the generic even hit. They didn’t wait-they acted.

The Bigger Picture: Innovation, Consolidation, and the Future

Pharma companies aren’t just losing money-they’re being forced to change. Merck, BMS, and others are investing billions into new therapies: gene editing, RNA drugs, personalized cancer vaccines. Some analysts say innovation will replace 65-75% of lost revenue by 2030. Others think consolidation is inevitable. Goldman Sachs predicts 30% more mergers in pharma through 2026. By 2035, the top 10 drugmakers might shrink to 6 or 7.

Regulators are watching too. The FTC has seen a 23% jump in investigations into “pay-for-delay” deals-where brand companies pay generics to delay entry. Those deals are now illegal, but they still happen. The government is cracking down harder than ever.

One thing is clear: the era of sky-high prices for blockbuster drugs is ending. The tools to make cheaper versions exist. The demand is there. The patents are expiring. And for the first time in decades, patients-not just shareholders-are winning.