By mid-2025, the pharmaceutical industry will hit a turning point unlike anything seen in the last 30 years. Dozens of top-selling drugs - some bringing in billions each year - will lose patent protection. This isn’t a slow fade. It’s a cliff. And it’s starting now.
What’s Actually Expiring in 2025?
The first major hit comes in July 2025: Entresto (sacubitril/valsartan), Novartis’ $7.8 billion heart failure drug. Its core combination patent (US8329752) expires, opening the door for generic versions. This isn’t just another drug. It’s one of the most prescribed treatments for chronic heart failure, used by millions. Patients currently pay $150-$300 a month. Generics could drop that to $20-$40. Hospitals and pharmacies are already preparing - formularies are being rewritten, stockpiles adjusted, and patient education programs launched.
Entresto isn’t alone. The FDA has already approved the first generic version of sacubitril ahead of schedule, signaling how aggressively generic manufacturers are moving. By the end of 2025, at least six other drugs with over $1 billion in annual sales will face patent cliffs, including key diabetes and autoimmune treatments.
The Big Three: Keytruda, Eliquis, and the $187 Billion Wave
The real earthquake hits later. In 2026, Eliquis (apixaban) - the $13.2 billion blood thinner co-marketed by Bristol Myers Squibb and Pfizer - loses protection for its key crystalline form patent. With multiple generic competitors already lined up, prices will likely plummet 85% within a year. Market share will shift to generics faster than almost any drug in history.
Then comes Keytruda (pembrolizumab), Merck’s $29.3 billion cancer immunotherapy. Its core composition patent expires in 2028. This is the single largest patent expiration ever. No small-molecule drug comes close. Keytruda is used in over 15 cancer types, from melanoma to lung cancer. It’s not just a drug - it’s become standard of care. And there’s no direct substitute. Biosimilars will take years to catch up, but even then, doctors may hesitate. Oncology is slow to change. Still, Merck is already investing $12 billion into next-gen cancer therapies to offset the coming revenue loss.
Together, these three drugs alone account for over $50 billion in annual sales. Add in others like Ibrance, Trulicity, and Humira’s follow-ons, and you get to $187 billion in global sales at risk between 2025 and 2030. That’s nearly 30% of the entire blockbuster drug market.
Why This Isn’t Just About Price
Most people think patent expirations mean cheaper pills. That’s true - but it’s only half the story.
Small-molecule drugs like Entresto and Eliquis are relatively easy to copy. Generics hit fast, prices crash, and market share flips in under a year. But biologics - like Keytruda - are complex proteins made in living cells. Copying them isn’t like copying aspirin. These are called biosimilars, and they take 3-5 years to get approved. Even after approval, doctors don’t switch easily. They worry about safety, dosing, and long-term outcomes.
That’s why biosimilars only capture 50-60% of the market after five years, while generics for small molecules take over 90%. The difference isn’t just technical - it’s cultural. Oncologists trust the brand. Nurses are trained on the original. Pharmacies stock the branded version. Changing that takes time, education, and policy.
Who’s Preparing - and How
It’s not just patients and pharmacies getting ready. The entire system is retooling.
- Generic companies like Teva, Mylan, and Sandoz have over 140 products in development targeting the 2025-2030 wave. Each one costs $2.6 million and takes 3-4 years to develop.
- Hospitals are already negotiating 60% price cuts with pharmacy benefit managers (PBMs) for drugs like Entresto. Eighty-seven percent of hospital pharmacists surveyed in 2024 are training staff on the transition.
- Pharmacies are stockpiling generics ahead of approval. But they’re also worried about shortages - just like what happened with Humira biosimilars in 2023.
- Drugmakers like Merck and BMS aren’t waiting. They’re buying smaller biotechs. BMS spent $4.1 billion on Karuna Therapeutics to build a new pipeline in neuroscience, ahead of Eliquis’ 2026 expiration.
The FDA has received 127 generic applications for drugs expiring in 2025 - a 27% jump from last year. The agency’s Orange Book now lists over 1,200 products with upcoming patent cliffs. This isn’t a rumor. It’s happening.
The Real Winner: Patients and the Healthcare System
Behind all the corporate strategy and patent litigation, there’s a human story.
Patients with heart failure, diabetes, or cancer are paying hundreds of dollars a month for drugs that could soon cost less than a coffee. A 2024 survey by the American Heart Association found 68% of heart failure patients would switch to generic Entresto immediately if it were available. That’s not just savings - that’s access.
Over the next decade, these expirations could save the U.S. healthcare system $182 billion, according to the Association for Accessible Medicines. The Congressional Budget Office estimates total savings of $312 billion by 2035. That’s money that can go to more screenings, better care, or lower premiums.
But it’s not automatic. Pharmacists need training. Doctors need guidelines. Patients need to know their options. Without preparation, the transition could be messy - delays, confusion, even temporary shortages.
What Comes After the Cliff?
By 2030, the landscape will look very different.
Big pharma won’t disappear - but it will shrink. Goldman Sachs predicts 30% more mergers through 2026. The top 10 drug companies could consolidate into 6 or 7 by 2035. Innovation won’t stop. Companies are pouring money into gene therapy, mRNA treatments, and AI-driven drug discovery. But the era of billion-dollar blockbusters with 20-year monopolies is ending.
The future belongs to companies that can innovate faster than their patents expire. And to patients who finally get access to life-saving drugs without bankrupting themselves.
2025 isn’t just another year. It’s the start of a new chapter in medicine - one where affordability finally catches up to innovation.
What drugs are losing patent protection in 2025?
The biggest drug losing patent protection in 2025 is Entresto (sacubitril/valsartan), a heart failure medication with $7.8 billion in global sales. Its core combination patent expires in July 2025. Other drugs with 2025 expirations include several diabetes and autoimmune treatments, though none match Entresto’s scale. The FDA has already approved the first generic version of sacubitril ahead of schedule, signaling strong market readiness.
Why is Keytruda’s patent expiration such a big deal?
Keytruda (pembrolizumab) generated $29.3 billion in sales in 2024 - the highest of any drug in history. It’s used across more than 15 cancer types and has become the standard treatment for many. Unlike small-molecule drugs, it’s a biologic - meaning biosimilars are harder and slower to develop. Its patent expires in 2028, and analysts predict Merck could lose $15 billion in annual revenue within 18 months of generic entry. This is the largest single revenue drop the pharmaceutical industry has ever faced.
Will generic Entresto be as effective as the brand?
Yes. Generic drugs are required by the FDA to have the same active ingredients, strength, dosage form, and route of administration as the brand. They must also prove they’re bioequivalent - meaning they work the same way in the body. For Entresto, generics will contain the exact same combination of sacubitril and valsartan. Thousands of patients have already switched to generics for similar drugs like Lipitor and Nexium with no loss in effectiveness.
How long does it take for generics to replace brand-name drugs?
For small-molecule drugs like Entresto and Eliquis, generics typically capture 45% of the market in the first month, 75% by six months, and over 90% within a year. For biologics like Keytruda, it’s slower. Biosimilars may only reach 25% market share in the first year, 50% by year three, and 75% by year five due to physician hesitation and complex manufacturing. Hospitals adopt generics faster than retail pharmacies - often within 3 months vs. 6 months.
What’s the difference between a generic and a biosimilar?
Generics are exact copies of small-molecule drugs - like aspirin or metformin - made from chemical compounds. Biosimilars are highly similar but not identical copies of biologic drugs - complex proteins made from living cells, like Keytruda or Humira. Biosimilars require more testing, take longer to approve (3-5 years vs. 1-2 for generics), and cost more to produce. They’re also less likely to be automatically substituted by pharmacists without a doctor’s approval.
How will this affect my prescription costs?
If you’re taking a drug like Entresto, Eliquis, or eventually Keytruda, your out-of-pocket cost could drop by 80-90% within a year of generic or biosimilar entry. For example, Entresto currently costs $150-$300 a month. Generics could bring that down to $20-$40. Even with insurance, copays will shrink significantly. Patients with high-deductible plans will benefit the most. Always check with your pharmacist or insurer - some plans may require you to switch to the generic to maintain coverage.
Are there any risks with switching to generics?
For small-molecule drugs, the risks are extremely low. The FDA requires generics to meet the same strict standards as brand-name drugs. For biologics like Keytruda, biosimilars are closely monitored, but some doctors may prefer to wait for more real-world data before switching. In rare cases, patients may respond differently to a new formulation - but this is uncommon. Always consult your doctor before switching, especially if you’re on a complex regimen like cancer treatment.