By 2028, the biggest drug in the world could lose its patent protection-and with it, the chance for patients and insurers to save billions. That drug is Keytruda, Merck’s cancer immunotherapy that brought in $25.5 billion in sales in 2024 alone. But it’s not alone. A wave of blockbuster biologics, from Humira to Eylea, are hitting patent cliffs over the next five years, opening the door for biosimilars to enter the market in ways we’ve never seen before.
What Exactly Are Biosimilars?
Biosimilars aren’t generics. That’s the first thing to understand. Generics are exact copies of small-molecule drugs like aspirin or metformin. Biosimilars are highly similar versions of complex biological drugs-proteins made from living cells. Think monoclonal antibodies, vaccines, or hormone therapies. These aren’t made in a lab with chemicals; they’re grown in bioreactors using human or animal cells. Even tiny changes in the process-temperature, pH, cell line-can alter the final product. The FDA requires biosimilars to show no clinically meaningful differences in safety, purity, or potency compared to the original. That means extensive testing: thousands of analytical tests, animal studies, and often clinical trials. It’s not a shortcut. It’s a marathon. And it costs $150-250 million per product to get there.The Patent Cliff: $200 Billion at Stake
Between 2025 and 2030, over $200 billion in annual global sales for biologics will lose patent protection. That’s not a guess. It’s from Clival’s 2024 analysis. The biggest names are falling one by one:- Eylea (aflibercept) - $5.9 billion in U.S. sales in 2023. Patents expired in 2025. Three biosimilars-Yesafili, Opuviz, and Enzeevu-were approved in 2024. By Q1 2025, they already held 12% of the market.
- Enbrel (etanercept) - Patent expired in 2023. Sandoz’s biosimilar launched at a 35% discount. Now it’s the most prescribed version in many U.S. hospitals.
- Humira (adalimumab) - Once the world’s top-selling drug. Its patents expired in 2023. Twelve biosimilars are now approved. In 18 months, they captured 80% of new prescriptions.
- Keytruda (pembrolizumab) - The giant. Patents expire in 2028. Fourteen companies are already in Phase 3 trials. This could be the biggest biosimilar entry in history.
Why Is Keytruda Such a Big Deal?
Keytruda treats more than 20 types of cancer. It’s used in lung, melanoma, breast, and head and neck cancers. It’s not just a drug-it’s part of standard care for millions. That’s why its biosimilar entry in 2028 will be watched like a stock market crash. But here’s the catch: Merck didn’t make it easy. They built a patent thicket-237 patents, some stretching to 2035. Some are for delivery methods, others for dosing schedules. The FDA has to sort through them. That’s why, even though the core patent expires in 2028, some biosimilars might still face legal delays. Meanwhile, companies like Coherus BioSciences and Alvotech are racing to get their versions approved. Regeneron even partnered with Alvotech in January 2025 to co-develop biosimilars for Eylea. Big pharma is no longer just defending its turf-it’s getting into the biosimilar game too.
Market Entry Is Not the Same Everywhere
Europe adopted biosimilars fast. Why? Because payers forced the issue. In the EU, reimbursement rules favor lower-cost options. For some drugs, biosimilar use exceeds 70%. In the U.S., it’s slower. Only 30-40% for most products. The reason? Money flows backward. Medicare Part B pays providers based on the drug’s average sales price (ASP). If a doctor gives a $10,000 reference drug, they get reimbursed more than if they give a $7,000 biosimilar. That creates a financial incentive to stick with the original-even if the biosimilar is just as safe. Hospitals are fighting back. Kaiser Permanente now mandates biosimilar substitution for all new filgrastim prescriptions. Mass General Brigham saw biosimilar use jump from 12% to 68% after implementing similar rules. Payers like Cigna and Centene now offer $0 copays for biosimilars versus $50 for the brand. That’s changing behavior fast.Manufacturing Is the Hidden Hurdle
You can’t just copy a biologic like you copy a pill. These drugs are made from living cells. Even a slight shift in temperature during fermentation can change the sugar chains (glycosylation) attached to the protein. For Keytruda, those sugar chains are critical for how the immune system responds. If they’re off-even a little-the drug might not work as well. That’s why Samsung Bioepis spent $450 million on a single facility in Incheon, South Korea, built just for biosimilar production. Every step is tracked, validated, and documented. The FDA inspects these facilities like they’re nuclear plants. One misstep, and the whole batch is scrapped. And it’s not just the drug. Packaging, storage, labeling-all have to match. Biosimilars can’t be stored at room temperature if the original can’t. They need the same syringe type, same needle size, same shelf life.Real-World Outcomes: Are They Really the Same?
Patients and doctors are watching closely. At the American Society of Clinical Oncology in 2024, Dr. Laura Chow reported no difference in outcomes between Humira and its biosimilars in inflammatory bowel disease patients. That’s reassuring. But Dr. Richard Pazdur from the FDA’s Oncology Center documented cases where patients switching between rituximab biosimilars and the original had unexpected immune reactions. Not common. But enough to make clinicians cautious. Patient surveys show 78% are happy with the cost savings. But 34% are confused about whether they’re getting the biosimilar or the original. Pharmacists at CVS Caremark say prior authorization denials dropped 22% for biosimilars in 2025-proof that insurers are getting better at approving them. But academic medical centers still struggle to track long-term outcomes across multiple biosimilar brands.
The Future: Faster, Cheaper, More Complex
The FDA approved 17 biosimilars in 2024-up from just 5 in 2020. That’s a 240% increase in four years. And the pipeline is crowded: 412 biosimilar candidates are now in development targeting 87 reference products. The next wave won’t just be antibodies. It’ll be antibody-drug conjugates, fusion proteins, and complex cell therapies. The FDA’s 2025 draft guidance on “Analytical Similarity for Highly Complex Biologics” is trying to keep up. It’s not just about matching the molecule anymore. It’s about matching how it behaves in the body. Meanwhile, consolidation is happening. Sandoz bought Biocon’s biosimilars business for $3.9 billion in 2024. Viatris, the joint venture between Pfizer and Mylan, is now a major biosimilar player. The market leader? Sandoz, with 28% share.What This Means for Patients and Providers
If you’re on a biologic today-whether it’s for arthritis, psoriasis, or cancer-your options are about to expand. You may be switched to a biosimilar without asking. That’s legal in many states now, thanks to interchangeability designations. The FDA has approved 12 interchangeable biosimilars as of December 2025. That means pharmacists can swap them without consulting your doctor. But here’s the advice: Don’t panic. The data is clear: for most patients, biosimilars work just as well. Ask your doctor if your drug has a biosimilar. Check the FDA’s Purple Book-it’s updated daily. Ask your insurer what’s covered. You might save hundreds-or thousands-per year. And if you’re a provider? Start preparing now. Update your EHR systems. Train your staff. Know the differences between biosimilars. Track outcomes. This isn’t the future. It’s happening right now.What’s Next?
The next 18 months will be critical. Eylea biosimilars will keep gaining ground. Cosentyx (secukinumab) will enter the EU market in 2026, ahead of the U.S. And in 2028, Keytruda’s patent expires. That’s when the real test begins. Will biosimilars capture 65% of the market, as SVB Leerink predicts? Or will originator companies use legal tricks and rebate deals to hold on, as Evercore ISI warns? One thing’s certain: the era of sky-high prices for biologics is ending. The question isn’t if biosimilars will win. It’s how fast-and how fairly.Are biosimilars the same as generics?
No. Generics are exact chemical copies of small-molecule drugs. Biosimilars are highly similar versions of complex biological drugs made from living cells. They’re not identical, but they’re proven to have no clinically meaningful differences in safety or effectiveness. The approval process for biosimilars is far more complex and expensive than for generics.
Why are biosimilars cheaper than the original biologics?
Biosimilars cost less because they don’t need to repeat all the early clinical trials the original drug did. The manufacturer only needs to prove similarity, not re-prove safety from scratch. That cuts development costs by 50-70%. But they still require $150-250 million in investment and 7-10 years to bring to market. The savings come from reduced R&D, not lower quality.
Can I be switched to a biosimilar without my doctor’s approval?
In many U.S. states, yes-if the biosimilar is designated as “interchangeable” by the FDA. As of December 2025, 12 biosimilars have this status. Pharmacists can substitute them without consulting your doctor, just like with generics. But some states require notification, and some insurers still require prior authorization. Always check your state’s laws and your insurance plan.
What’s the biggest barrier to biosimilar adoption in the U.S.?
The biggest barrier isn’t science-it’s money. Medicare Part B reimburses providers based on the drug’s average sales price. So if a doctor gives a $10,000 brand-name drug, they get paid more than if they give a $7,000 biosimilar. That creates a financial incentive to stick with the original. Payers are trying to fix this with $0 copays for biosimilars, but the system is slow to change.
When will Keytruda biosimilars be available?
Keytruda’s core patent expires in 2028. Fourteen companies are already in Phase 3 trials. The first biosimilars could launch as early as late 2028, but legal challenges and patent disputes may delay some. Don’t expect widespread availability until 2029 or 2030. This will be the largest biosimilar entry in history, potentially saving the U.S. healthcare system tens of billions.
How do I know if I’m getting a biosimilar?
Check your prescription label. Biosimilars have a unique nonproprietary name that ends with a four-letter suffix (e.g., adalimumab-atto for an Humira biosimilar). Your pharmacy will also notify you if a substitution is made. If you’re unsure, ask your pharmacist or check the FDA’s Purple Book database, which lists all approved biosimilars and their interchangeability status.
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