Which Blockbuster Drugs Are Losing Patent Protection in 2028?: A Complete Guide for Generic & Biosimilar Sponsors
As four major blockbuster drugs losing patent protection in 2028, the pharmaceutical industry faces one of the most commercially significant exclusivity cliffs in recent years, with more than $56 billion in annual revenue at stake. For generic and biosimilar sponsors, this is not simply a future market event but a present strategic window that demands immediate planning.
As biologics dominate this expiry cycle, development timelines, regulatory shifts, and competitive entry strategies are becoming more complex and more consequential. This article examines which drugs are approaching loss of exclusivity, what their patent expiry means across global markets, and how sponsors should position development programs now to capture the opportunity effectively.
Why 2028 matters?
Four major drugs are expected to lose US exclusivity in 2028. Together, they generated more than $56 billion in global revenue in 2024, according to the originator’s annual reports. Notably, three of these four products are biologics, which is an important distinction that significantly influences how sponsors approach development planning, financing strategies, and overall program execution.
The 2028 window is not distant. Biosimilar development, even after the FDA streamlined several requirements through its 2025 guidance, still runs five to eight years from target selection to approval. Generic apixaban programs should already be in process. Biosimilar developers targeting Keytruda or Opdivo who are not yet in analytical development will struggle to reach a 2028 filing date.
The 2028 drug list
Four blockbusters are losing US exclusivity in or around 2028. Revenue figures are from the 2024 company annual reports.
| Brand | INN | Originator | 2024 Revenue | Type | US LOE |
|---|---|---|---|---|---|
| Keytruda | Pembrolizumab | Merck | $29.5B | Biosimilar | 2028 (core patent) |
| Eliquis | Apixaban | BMS / Pfizer | $13.3B (BMS-reported) | Small molecule | April 1, 2028 |
| Opdivo | Nivolumab | Bristol Myers Squibb | $9.3B | Biosimilar | 2028 |
| Enbrel | Etanercept | Amgen (US/CA) / Pfizer (EU) | ~$3.3B (Amgen US/CA) | Biosimilar | Late 2028 / 2029 |
Note: Eliquis revenue is reported separately by its two co-marketers, Bristol Myers Squibb (BMS) and Pfizer. In 2024, BMS reported $13.3B in Eliquis sales, while Pfizer reported $7.37B. These numbers overlap because both companies share profits from the same drug. The BMS figure is most commonly used as the main reference because it best represents the overall scale of Eliquis sales.
Drug-by-Drug Analysis
1. Keytruda (Pembrolizumab)
| Company | Global Revenue (2024) | Product Type | US Patent Expiry (LOE) | Biosimilar Status |
|---|---|---|---|---|
| Merck | ~$29.5B | Monoclonal antibody immunotherapy | ~2028 (core US patent) | Multiple programs in development |
Keytruda is the largest patent expiry event in pharmaceutical history, with no other drug reaching this level of revenue at the time of patent cliff entry. Pembrolizumab generated $29.5 billion in global sales in 2024, reflecting 18% year-on-year growth, and is approved across 41+ oncology indications spanning 18 tumour types.
Biosimilar development for Keytruda requires full analytical characterization of a humanized monoclonal antibody, along with comparative PK studies and immunogenicity assessment. However, the FDA’s October 2025 draft guidance has removed the need for comparative clinical efficacy studies in most cases, significantly reducing development costs and timelines. In response, several developers have either cancelled or restructured Phase 3 programs, instead focusing on Phase 1 PK data supported by robust analytical similarity packages.
At least seven companies have already disclosed active pembrolizumab biosimilar programs, including Samsung Bioepis, Amgen, Sandoz, Celltrion, and Bio-Thera. At the same time, Merck’s subcutaneous reformulation (approved in September 2025 as Keytruda Qlex) and a patent estate exceeding 237 filings add significant lifecycle complexity. Despite these changes, the intravenous formulation remains the primary target for biosimilar development.
What does this mean for your development program?
Analytical characterisation alone takes 18 to 24 months for a monoclonal antibody of this complexity. Sponsors who have not yet started are already behind for a 2028 filing position. The indication question, whether to seek all 41 indications or a selected subset, needs to be settled before analytical development begins because it directly affects how you design and scope the clinical program.
2. Eliquis (Apixaban)
| Company | Global Revenue (2024) | Product Type | US LOE (Loss of Exclusivity) | Market Status |
|---|---|---|---|---|
| Bristol Myers Squibb (BMS) / Pfizer | ~$13.3B (BMS‑reported share) | Small‑molecule anticoagulant | April 1, 2028 (per court settlement) | Generic competition anticipated post‑LOE |
Apixaban is considered the most accessible opportunity in the 2028 patent cliff cohort for generic manufacturers. It is a small-molecule Factor Xa inhibitor, meaning development is based on bioequivalence studies rather than a full biosimilar pathway. Although the FDA approved the first generic versions as early as 2019, litigation delayed commercialization, and the US loss of exclusivity is now fixed at April 1, 2028, under a court settlement.
In Europe, key markets already began losing Eliquis patent protection in the second half of 2026, while India has been open to generic competition for a longer period. As a result, companies not yet active in these regions are missing earlier revenue opportunities while waiting for the US entry window. In addition, under the Inflation Reduction Act (IRA), BMS has agreed to a Medicare maximum fair price of $231 per 30-day supply effective from 2026, which will further influence pricing dynamics once generic competition begins.
What does this mean for your development program?
ANDA filings for the US market should already be well advanced. For sponsors not yet active, the EU and India markets offer immediate entry points under different patent landscapes. Completing BE studies in those markets now also builds the data package and regulatory experience that the US filing will require.
3. Opdivo (Nivolumab)
| Company | Global Revenue (2024) | Product Type | US LOE (Loss of Exclusivity) | Biosimilar Status |
|---|---|---|---|---|
| Bristol Myers Squibb (BMS) | ~$9.3B | Monoclonal antibody immunotherapy (PD‑1 inhibitor) | ~2028 | Biosimilar development programs in progress |
This matches the style of the previous table for consistency. Would you like me to combine both entries (this one and the earlier BMS/Pfizer anticoagulant) into a single consolidated table for easier comparison?
Nivolumab generated $9.3 billion in global revenue in 2024, reflecting a 3.3% increase compared to 2023, driven by new indication launches and higher international net selling prices. Opdivo is widely used as a combination therapy backbone, especially with Yervoy (ipilimumab), and is approved across multiple cancer types, including lung, kidney, and bladder cancers.
The biosimilar development pathway is broadly similar to Keytruda, as it is a humanized monoclonal antibody targeting PD-1 and involves comparable analytical complexity. A key strategic decision for developers is whether to pursue monotherapy indications, combination regimens, or both, as each approach has different clinical and commercial implications. BMS is also advancing a subcutaneous formulation and expanding indication approvals, which can impact data exclusivity in certain markets. Companies such as NeuClone, Xbrane Biopharma, and Luye Pharma are already actively developing biosimilars.
What does this mean for your development program?
Sponsors entering now face a crowded field. The programs that will generate returns are the ones with a clear view on indication selection, formulation (IV or subcutaneous), and which geographies to prioritise. Markets where combination therapy protocols are less established tend to offer earlier commercial traction for biosimilar entrants.
4. Enbrel (Etanercept)
| Company | Global Revenue (2024) | Product Type | US LOE (Loss of Exclusivity) | Biosimilar Status |
|---|---|---|---|---|
| Amgen (US/Canada) / Pfizer (EU) | ~$3.3B (Amgen US/Canada share) | Fusion protein (TNF inhibitor biologic) | ~Late 2028 / 2029 | Biosimilar development is ongoing, with delayed entry due to the IP landscape |
Enbrel (Etanercept) is a TNF fusion protein marketed by Amgen in the US/Canada and Pfizer in Europe, with approximately $3.3 billion in US/Canada revenue reported by Amgen in 2024. Unlike monoclonal antibodies such as Keytruda or Opdivo, Enbrel is a fusion protein, meaning its biosimilar development pathway involves distinct manufacturing complexity, including CHO cell expression systems and molecule-specific glycosylation requirements.
The US patent landscape is also more complex than a single loss of exclusivity date. Two key Roche licensed patents covering the fusion protein (expiring November 2028) and a manufacturing process (expiring 2029) have been upheld in multiple court rulings, preventing US entry until expiration. As a result, FDA-approved biosimilars from companies such as Samsung Bioepis and Sandoz cannot launch in the US until at least late 2028, with practical market entry expected closer to 2029.
Amgen’s 2024 US/Canada Enbrel revenue has declined to about $3.3 billion due to price erosion and competition from newer immunology therapies. In Europe, where biosimilars have been available since 2016, Pfizer’s experience provides a strong reference point for post-LOE dynamics, including rapid payer-driven switching, sustained price erosion over 24 to 36 months, and relatively predictable market share redistribution.
What this means for your development program
For any sponsor with an Enbrel biosimilar interest, studying the European market in detail is the most productive near-term activity. Pricing patterns, payer switching behaviour, and market share trajectories in France, Germany, the UK, and Scandinavia give a live view of what will unfold in the US. For financial modelling, use a 2029 US entry point, not 2028.
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Regulatory shifts worth knowing
The biosimilar regulatory landscape changed significantly between 2024 and 2025. Sponsors building programs today operate under different rules than those who filed five years ago.
FDA removed comparative efficacy study requirements (October 2025)
FDA’s October 2025 draft guidance stated that comparative clinical efficacy studies are no longer generally required for therapeutic protein biosimilars where robust analytical similarity and a well-designed PK study are in place. For Keytruda and Opdivo programs, this removes the largest single cost and time item from the development path. Several developers have already restructured or cancelled Phase 3 trials in response.
Interchangeability without switching studies (June 2024)
FDA’s June 2024 guidance removed the requirement for dedicated switching studies to achieve an interchangeability designation. This clears a meaningful hurdle for sponsors seeking automatic pharmacy-level substitution status, which is particularly important for apixaban generic programs where substitution at dispensing drives volume.
ICH M13 global harmonisation
ICH M13A, effective January 2025, established the first globally harmonised bioequivalence standard for immediate-release oral products. For apixaban generic developers, this potentially allows a single BE study design to satisfy FDA, EMA, and PMDA requirements simultaneously, removing the need for duplicate studies across markets.
| ON DEVELOPMENT COMPETENCIES: The shift toward a totality-of-evidence model changes what matters most in biosimilar development. Strong analytical characterisation, PK study design for complex biologics, and immunogenicity assessment are now the core of a well-built program. Large-scale Phase 3 execution is no longer where programs succeed or fail. Sponsors and their CRO partners who have depth in the analytical and PK layers are better positioned than those whose strength sits mainly in Phase 3 operations. |
Biosimilar vs generic development
Three of the four 2028 drugs are biologics. The two development pathways differ enough that running them as a single planning exercise leads to bad assumptions on cost, timeline, and risk.
| Factor | FacBiosimilar (Keytruda, Opdivo, Enbrel)tor | Generic (Eliquis / Apixaban) |
|---|---|---|
| Development cost | $100M to $300M per program | $2M to $5M per ANDA program |
| Timeline to approval | 5 to 9 years from start | Bioequivalence studies in healthy volunteers. Typically, 2 to 3 studies across dose strengths. |
| Clinical requirements | 2 to 4 years, including BE studies | Bioequivalence studies in healthy volunteers. Typically 2 to 3 studies across dose strengths. |
| Price erosion post-launch | 20 to 40% in years 1 to 2. Payer-driven formulary switching takes time. | 70 to 90% within 12 months when multiple generics enter simultaneously. |
| Primary development risk | Analytical similarity failure; immunogenicity differences; indication-specific exclusivity blocks. | Day-one competition from multiple filers; aggressive price compression from launch. |
Five priorities for sponsors planning 2028 programs
To navigate the complexity of upcoming biologics expiries, sponsors should align on the following five strategic priorities:
1. Run the IP audit by market, not globally
Patent expiry dates, litigation settlements, and data exclusivity periods differ by jurisdiction. Apixaban is already generic in India and the EU. Keytruda’s expiry dates vary across patent families and markets. Enbrel’s US biosimilar window is 2029, not 2028. A country-by-country IP audit across your target markets should happen before resource commitments are made, not after.
2. Start analytical work earlier than feels necessary
Pembrolizumab and nivolumab are large, complex glycoproteins. Analytical comparability work with the reference product takes 18 to 24 months at a minimum. Reference product procurement for these studies is competitive. Multiple developers are sourcing from the same limited markets. Supply agreements for the quantity you need should be in place before you need them.
3. Build payer engagement into the development schedule
Formulary decisions in oncology biosimilars are made 18 to 24 months before a product reaches the market. Sponsors who begin payer engagement after regulatory approval are already behind. Institutional and formulary contracting in oncology is relationship-driven. The payer narrative and market access team need to be built in parallel with the clinical program, not handed off afterward.
4. Treat Keytruda and Opdivo as a shared platform where possible
Both are PD-1 inhibitors. Both are humanised monoclonal antibodies with similar analytical profiles. Sponsors who share analytical infrastructure, manufacturing platforms, and clinical expertise across both programs will run them more efficiently than those treating each as a fully separate investment. The incremental cost of a second PD-1 biosimilar program, once the first is operational, is substantially lower.
5. Track Merck’s regulatory filings each quarter
Merck’s subcutaneous Keytruda formulation, new combination indication submissions, and potential authorised generic strategies all affect how much of the market is available to biosimilar competitors. The formulation you develop, the indications you target, and your pricing model should all be revisited whenever Merck makes a material regulatory move.
Planning timeline by phase
Below is a working timeline for sponsors across the four 2028 drugs. Biosimilar timing assumes programs starting now. ANDA programs should already be underway.
| When | What sponsors must do |
|---|---|
| Now through Q1 2026 | Generic apixaban launches in the US (court-settlement date). Biosimilar approvals for Keytruda and Opdivo are possible. Enbrel US biosimilar market opens no earlier than late 2028 and practically 2029. Activate commercial contracts. |
| Q2 to Q3 2026 | Cell line development and early manufacturing scale-up for biosimilars. Run bioequivalence studies for apixaban in priority markets. Begin comparative PK study design for Keytruda, Opdivo, and Enbrel programs. |
| Q4 2026 to Q3 2027 | Complete PK and immunogenicity studies. File BLA or biosimilar application. Begin payer engagement. Formulary discussions in oncology run 18 to 24 months ahead of launch. Scale commercial manufacturing. |
| Q4 2027 to Q1 2028 | Target regulatory approval. Finalise pricing and formulary strategy. Build launch inventory. Monitor Merck regulatory filings on Keytruda formulation updates and new indication submissions. |
| April 2028 onward | Generic apixaban launches in the US (court-settlement date). Biosimilar approvals for Keytruda and Opdivo possible. Enbrel US biosimilar market opens no earlier than late 2028 and practically 2029. Activate commercial contracts. |
Market opportunity by geography
Patent expiry dates differ significantly by country. The table below shows where sponsors can expect to compete earliest, with the considerations that affect which markets to prioritise.
| Drug | United States | European Union | India | Key consideration |
|---|---|---|---|---|
| Keytruda | 2028 (core patent) | 2028 (EU core patents) | 2027 onward | India’s biosimilar guidelines require locally generated clinical data in most cases. |
| Opdivo | 2028 | 2028 | 2027 onward | EU and India are accessible now. The US entry date is fixed by litigation outcome. |
| Eliquis | April 1, 2028(settlement date) | Second half of 2026(key EU markets) | Already open | EU and India are accessible now. US entry date is fixed by litigation outcome. |
| Enbrel | Late 2028 / 2029 | Open since 2016 | Available | Pricing dynamics and payer switching patterns in Europe are the best available preview of US post-2029 dynamics. |
Key takeaways
Keytruda is the largest biosimilar development opportunity in pharma history.
$29.5 billion in 2024 revenue. The IV formulation’s 2028 core patent expiry is the target. Analytical development must begin now; it takes 18 to 24 months before clinical work begins. FDA’s October 2025 guidance removed the Phase 3 requirement for most programs, but it did not shorten analytical or PK study timelines.
The Enbrel US biosimilar window is 2029, not 2028
Court rulings through 2021 confirmed that two key patents, expiring in November 2028 and 2029, respectively, block US biosimilar entry until then. Multiple FDA-approved biosimilars (Erelzi, Eticovo) are cleared but cannot launch. Factor 2029 into US financial projections. The European market, open since 2016, is your best available data on what happens next.
Apixaban is the clearest path to near-term revenue in this class
Small molecule, BE study pathway, fixed US entry date of April 1, 2028. EU and India are already accessible. Sponsors without ANDAs well advanced should move on to that now. Day-one launchers capture the majority of volume before price compression fully sets in.
Revenue figures in much industry commentary are wrong
2024 actuals from audited reports: Keytruda $29.5B, Eliquis $13.3B (BMS-reported), Opdivo $9.3B, Enbrel approximately $3.3B in Amgen’s US/Canada territory. Financial models built on third-party estimates will misrepresent the opportunity.
FDA removed Phase 3 comparative efficacy requirements for biosimilars in October 2025
The development model has shifted. A robust analytical similarity package plus a well-designed comparative PK study is now the expected path to approval. The competencies that determine program quality have shifted to analytics, PK study design, and immunogenicity assessment.
Patent expiry is not global. Run a market-by-market audit
What is open in India, pending in the EU, and locked in the US can all apply to the same drug at the same time. A global IP audit across your top ten markets is the first investment any sponsor should make, not a downstream one.
Payer strategy is part of development, not a post-approval activity
In oncology biosimilars, formulary decisions happen 18 to 24 months before commercial availability. Sponsors who begin payer engagement after approval are already behind. Build the market access narrative and the payer team in parallel with the clinical program.
Price erosion timelines differ significantly between the two pathways
Generic apixaban: 70 to 90% price erosion within 12 months of multi-generic launch. Keytruda and Opdivo biosimilars: 20 to 40% erosion over the first two years, driven by formulary decisions. Revenue projections that use the same curve for both pathways will get the economics wrong.
Conclusion
- The development decisions that determine who captures the 2028 patent cliff are being made now, not in 2027. Four drugs, over $56 billion in 2024 revenue, three distinct development pathways, and one fixed calendar date for apixaban. Each drug has a different IP complexity, a different clinical development path, and a different commercial trajectory once competition arrives.
- Keytruda’s patent expiry will reshape the oncology biosimilar market for the next decade. FDA’s 2025 guidance lowered the barrier to approval but did not shorten the analytical or PK work. Sponsors with that work underway now are the ones who will file in 2026 or 2027 and be positioned for 2028 approval.
- Eliquis offers the most predictable path for generic manufacturers. The US date is fixed. The development requirement is bioequivalence studies. The EU and India markets are already accessible for sponsors who want to act before April 2028.
- Enbrel’s US biosimilar market opens no earlier than late 2028 and practically in 2029. The European market, since 2016, has provided the most relevant data on what the US entry will look like.
- Opdivo adds a second major oncology biosimilar opportunity in the same year as Keytruda. Sponsors who can run both programs on shared analytical and manufacturing infrastructure will do so more efficiently and at lower cost than those treating each as a standalone.
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