The global pharmaceutical industry is approaching a significant patent cliff between 2025 and 2030, with an estimated 190 drugs set to lose exclusivity by 2030. For pharmaceutical companies, over $ 200 billion in revenue is at risk this decade due to LoEs. But for health systems and patients, this transition presents an opportunity for greater access and affordability of high-value therapies.

We examine the major pharmaceutical products expected to go off patent from 2025 to 2030, with a focus on Bulgaria. As an EU member, Bulgaria participates in Europe’s centralized drug approvals; however, its local market dynamics – including pricing regulations, healthcare funding, and international reference pricing (IRP) policies – will influence how and when Bulgarian patients benefit from upcoming generics and biosimilars. We will highlight key drugs by therapeutic area, discuss whether their generic/biosimilar launches will likely use the Centralised Procedure (CP) or Decentralised Procedure (DCP), and consider other factors (pricing, any Most Favored Nation (MFN) actions, reimbursement, etc.) that influence if and when these products reach Bulgaria. This five-year outlook identifies the disease areas that are likely to see the most new competition, as well as the challenges in translating a European LoE into on-the-ground availability in Bulgaria.

Europe’s Patent Cliff and the Bulgarian Context

By 2028, the patent cliff is expected to put nearly half of the top pharmaceutical companies’ sales at risk. However, the impact on smaller markets, such as Bulgaria, depends to a greater extent on local policy. Bulgaria’s pharmaceutical system is highly cost-sensitive, as public funding for medicines is limited, and patient co-payments are among the highest in Europe. Generics and biosimilars are the primary drivers of access, providing lower-priced alternatives. Bulgarian authorities use IRP and other cost-containment measures that can inadvertently delay or discourage product launches. Furthermore, Bulgaria historically pegged reimbursements to the lowest price in a basket of EU countries.

To avoid a double price cut scenario (where mandatory generic price cuts compound an originator’s reference price drop), many European experts advise against applying IRP to generics and biosimilars. Instead, measures like encouraging higher volume uptake of generics and biosimilars are recommended to increase access while sustaining the health budget. Bulgaria is being urged to adopt a more dynamic biosimilar policy, utilizing competitive hospital procurement and provider incentives, as it currently has one of the lowest usage rates of biologic therapies in the EU (Medicinesforeurope). In fact, Bulgaria’s access to important cancer and immunology biologics is the 3rd lowest in the EU.

On the global stage, pricing reforms also influence launch decisions. The US Inflation Reduction Act (IRA) will enable Medicare to negotiate prices for older, high-revenue drugs, and prior MFN pricing proposals signaled a move toward referencing overseas prices. Such trends can make originator companies wary of launching in the lowest-priced countries too soon, as this could undermine prices in larger markets. Generic and biosimilar manufacturers, on the other hand, typically seek a broad market reach, but they still evaluate each country’s profitability and regulatory hurdles. In this context, it can be expected that many post-2025 LoE drugs will see generic/biosimilar entry in Bulgaria – especially via EU-wide approvals. However, the timing and extent of their availability will hinge on factors such as pricing negotiations, reimbursement listing delays, and the number of competitors entering the market.

The upcoming patent expiries span multiple therapeutic areas, including oncology, immunology, cardiometabolic, and rare diseases. Below, we summarize the key drugs slated to lose patent protection during the 2025 – 2030 period and what is currently known about potential generics or biosimilars in Europe (and in Bulgaria). We also note whether a biosimilar (for biologic drugs) or generic (for small molecules) is anticipated, and consider each product’s likely path to Bulgarian pharmacies.

Oncology

Pembrolizumab (Keytruda)

A PD-1 immunotherapy (Merck) with an EU patent expiry scheduled in 2031 (US 2028). This is projected to be the world’s top-selling drug in 2024, putting Merck under pressure as biosimilars arrive. A wave of Keytruda biosimilars is in development, with major players, including Samsung Bioepis (in partnership with Biogen for the EU), Amgen, Sandoz, and Celltrion, currently conducting Phase 3 trials.

• Bulgarian context: The introduction of lower-priced biosimilars after 2031 is expected to broaden patient access and reduce the oncology budget burden. Given that a biosimilar-friendly policy is implemented (hypothesis), these products may see relatively high uptake in Bulgaria.

Nivolumab (Opdivo)

PD-1 immunotherapy (BMS) is facing EU loss of exclusivity by 2026 (U.S. loss of exclusivity is in 2027). Opdivo generated approximately $ 9 billion in sales in 2023. Multiple biosimilars are advancing (e.g., NeuClone/Serum Institute, Xbrane/Intas, Luye Pharma).

• Bulgarian context: BMS’s Opdivo is used in Bulgarian oncology clinics; biosimilars, expected to be available in 2026–2028, could significantly lower therapy costs.

Daratumumab (Darzalex)

Anti-CD38 mAb for multiple myeloma (J&J) with EU composition patent expiry in March 2026. It was a $ 11B+ blockbuster in 2024. Several biosimilars are in clinical trials, including those developed by Henlius/Dr. Reddy’s (HLX15) and Celltrion (CT-P44 in global Phase 3), among others.

• Bulgarian context: Darzalex’s biosimilars (expected in 2026 – 2027) are expected to improve affordability for Bulgaria’s National Cancer Fund, given the high current prices.

Lenalidomide (Revlimid)

Oral immunomodulator (BMS/Celgene) that lost EU exclusivity earlier (data exclusivity ended in 2017). Generic entry began in parts of Europe by 2022, with full generic licensing from 2026 in the U.S. Multiple companies (Natco via partners, Alvogen, Teva, etc.) have launched lenalidomide generics.

• Bulgarian context: Revlimid generics are already available in the EU, driving significant price erosion; Bulgaria benefits from the IRP (the original Revlimid’s price cannot exceed the lowest among reference countries).

Ibrutinib (Imbruvica)

BTK inhibitor (AbbVie/J&J) for CLL/MCL. EU patent expected to expire by the end of 2026 (with pediatric extension into 2027). Generic companies have attempted early entry; Pfizer (partnered) obtained a 4-year extension to 2027 in the U.S. Some ibrutinib generics are already approved but tied up in legal hurdles.

• Bulgarian context: Imbruvica is a high-cost hematology drug; the imminent arrival of generics is expected to improve affordability for Bulgarian patients with CLL.

Palbociclib (Ibrance)

CDK4/6 inhibitor (Pfizer) for breast cancer, losing exclusivity in 2027. Pfizer fended off patent challenges, extending protection to 2027. Generic manufacturers are poised to enter the market once patents lapse.

• In the Bulgarian context, lower-cost palbociclib generics, expected to be available from 2027, will help contain oncology treatment costs in Bulgaria, where Ibrance is a key therapy for HR+ breast cancer.

Enzalutamide (Xtandi)

Androgen receptor inhibitor (Astellas/Pfizer) for prostate cancer. EU patent protection is set to end by 2026 (US in 2027). Generic developers like Zydus have advanced generic enzalutamide (US FDA filing underway).

• Bulgarian context: Prostate cancer patients in Bulgaria may have expanded access to enzalutamide as a generic option becomes available. However, physician prescribing (brand vs INN) will determine uptake (automatic substitution is not allowed in Bulgaria).

Oncology Insights

In Oncology, these LoEs herald aggressive competition from biosimilars and generics. For Bulgaria, a member of the EU, market authorization via CP means biosimilars will be available locally soon after EMA approval. However, since pharmacists in Bulgaria cannot substitute generics for brand-name cancer drugs without prescriber consent, actual uptake will depend on physician practices and hospital procurement. The introduction of competition is expected to put downward pressure on oncology drug prices and improve budget sustainability in Bulgaria’s oncology sector.

Autoimmune & Inflammatory Diseases

Ustekinumab (Stelara)

IL-12/23 inhibitor (J&J) for psoriasis, IBD, etc. EU data exclusivity ended in 2018; key patents expired in September 2023. A wave of biosimilars is expected to enter the market in 2024 and 2025. The first EMA-approved ustekinumab biosimilar (e.g., Stelarix by STADA) is scheduled to launch in January 2025, and multiple others from Teva, Sandoz, Celltrion, and other companies are expected to be approved in the same year.

• Bulgarian impact: Stelara is widely used for Crohn’s disease and psoriasis; biosimilars, expected in 2025, will sharply reduce prices, aiding reimbursement. Bulgaria’s reference pricing (lowest EU price) ensures that as cheaper biosimilars launch in the EU, Stelara’s price in Bulgaria will drop accordingly.

Secukinumab (Cosentyx)

IL-17A inhibitor (Novartis) for psoriasis, psoriatic arthritis, etc. Despite being a top seller (€6.1B in 2024), its core patents last until 2030 in the EU. No biosimilars can launch before then, though several are in development (Celltrion’s CT-P55, Bio-Thera’s BAT2306 in Phase 3). Thus, no EU biosimilar competition is expected until late 2029 or 2030.

Bulgarian context: Cosentyx will remain monopoly-priced through 2030 in Bulgaria, barring any early patent challenges; the National Health Insurance Fund must budget accordingly until biosimilars arrive at the end of the decade.

Other notable biologics

Adalimumab (Humira) lost EU exclusivity in 2018, with many biosimilars launched – a precedent that resulted in ~80% price cuts across Europe. Dupilumab (Dupixent), an IL-4/IL-13 blocker (Sanofi/Regeneron), is another top immunology drug; its primary patents extend to ~2031, so it falls outside the 2025–2030 horizon (one biosimilar by Bio-Thera is in early development). Etanercept (Enbrel) biosimilars have been on the EU market since 2016, and Infliximab (Remicade) since 2015 – thus not covered here but already contributing to savings in Bulgaria.

Autoimmune & Inflammatory Insights

Autoimmune therapy LoEs in 2025–2030 are dominated by high-value biologics shifting to biosimilars. Bulgaria will participate in these EU-wide transitions; for example, the arrival of ustekinumab biosimilars in 2025 will offer lower-cost alternatives for Bulgarian patients with Crohn’s disease or psoriasis. However, policy barriers remain; Bulgaria does not permit pharmacy-level biosimilar substitution, so physician education and tenders will be key to realizing savings. As biosimilars penetrate the market, budget impact in Bulgaria is expected to be positive, thereby improving access to costly autoimmune therapies.

Cardiovascular & Metabolic Diseases

Apixaban (Eliquis)

Oral anticoagulant (BMS/Pfizer) is widely used for AF and thrombosis. Key EU patents expire in H2 2026, after which generic apixaban will enter. Thanks to litigation and settlements, no generics are expected in the EU before late 2026 – 2027. (In the U.S., pediatric extension pushes generic entry to 2027–28.) Many generic companies (e.g., Teva, Mylan/Viatris) have products ready to launch.

• Bulgarian context: As one of the top-selling drugs in Bulgaria for stroke prevention, Eliquis going generic in 2027 will substantially cut costs. Bulgarian law mandates that medicine prices cannot exceed the lowest price in a basket of EU countries. Therefore, once any EU country sees a cheap generic apixaban, the Bulgarian price for Eliquis will likely plummet.

Rivaroxaban (Xarelto)

Oral anticoagulant (Bayer/J&J) with EU patent expiry in 2026. Bayer’s blockbuster (€4.5B in 2022) has faced numerous patent challenges; it is expected to lose exclusivity in 2026 across major EU markets. The first EU generic rivaroxaban approvals have already been granted in 2021 (the FDA approved generic 2.5 mg tablets in March 2025). Commercial launch timing varies by litigation/SPCs. A key German dosage patent (EP 1 845 961) was revoked in 2025, thereby accelerating local competition.

• Bulgarian context: Xarelto’s generic will likely arrive in Bulgaria soon after Western EU; however, since Bulgaria has no generic substitution at pharmacies, cardiologists must actively prescribe the generic to realize savings. The price of brand Xarelto will also be reduced via reference pricing once generics are launched in any reference country.

Sacubitril/valsartan (Entresto)

Heart failure ARNI combo (Novartis). A key combination patent expired in July 2025. Multiple manufacturers have already obtained approvals for generic Entresto (e.g., Alembic, Torrent) in anticipation of its launch. Novartis unsuccessfully attempted to extend U.S. protection to 2026, so generics are set for mid-2025 launch in both the U.S. and the EU. Route: DCP/national filings (the original procedure was centralized in 2015).

• Bulgarian context: Entresto is on Bulgaria’s reimbursement list for heart failure; a generic entry in 2025 will dramatically reduce costs. Novartis has signaled a mid-2025 launch of the LoE and is bracing for revenue loss; correspondingly, Bulgaria’s NHIF can expect significant savings on heart failure treatment from late 2025 onward.

Ticagrelor (Brilique/Brilinta)

Antiplatelet agent (AstraZeneca) with patent expiry in 2025. Although not as large as Eliquis, Brilinta reached a peak of $ 1.6 billion in global sales. Generic ticagrelor is expected in 2025 (already, some EU countries have seen early generics following patent litigation). Its generic entry will likely prompt formulary switches to cheaper alternatives.

• Bulgarian context: Ticagrelor is used for post-acute coronary syndrome; with generics, Bulgarian hospitals can procure it at significantly lower prices, although clopidogrel is already a cost-effective alternative.

Dulaglutide (Trulicity)

GLP-1 agonist injection (Eli Lilly) for Type 2 diabetes. Protected by a compound patent until late 2027. Trulicity was the world’s 17th top-selling drug in 2023, and its LoE will open the floodgates to generics/biosimilars. Because dulaglutide is a biologic peptide (a fusion protein), follow-on products will be biosimilars via CP. Several firms are known to be developing dulaglutide biosimilars (e.g., Gan & Lee). Biosimilar Trulicity is expected to be available in the EU by 2028. Lilly has already pivoted to next-gen diabetes drugs (e.g., tirzepatide).

• Bulgarian context: Diabetes is a high-prevalence area. In the late 2020s, Trulicity biosimilars are expected to enhance access to GLP-1 therapy in Bulgaria, particularly for cardiovascular risk reduction in individuals with diabetes, as prices are anticipated to decrease.

Semaglutide (Ozempic, Rybelsus, Wegovy)

GLP-1 analogs (Novo Nordisk) for diabetes and obesity. Despite some sources listing a 2026 date, the primary patents extend much further. Novo’s key semaglutide patents are set to expire in 2031–2032 in the US and in a similar timeframe in Europe. No true generics or biosimilars can launch in the EU before 2030 (the March 2026 date cited by some refers to secondary patents/data exclusivity, not the composition-of-matter patent). Indeed, Novo Nordisk’s own disclosures confirm no EU biosimilar competition is likely until the next decade. Thus, semaglutide will remain exclusive through 2025–2030.

• Bulgarian context: Demand for Ozempic and Wegovy is surging in Bulgaria; absent generics, Novo’s monopoly and high prices will persist. Bulgarian payers must wait until post-2030 for relief on semaglutide spending.

Cardiovascular & Metabolic Insights

In Cardiovascular and metabolic therapeutics, 2025–2030 is expected to bring a prominent patent cliff for small molecules (such as anticoagulants and heart failure drugs) and some biologics (including GLP-1s). For Bulgaria, the anticoagulant LoEs in 2026 (Eliquis, Xarelto) are especially impactful – these drugs consume substantial public funds. Generic competition is likely to result in price cuts of 50% or more, yielding significant savings for the healthcare system. However, the GLP-1 obesity/diabetes revolution remains protected; critical drugs like semaglutide won’t see generic competition this decade, meaning Bulgaria’s recent cost pressures in diabetes care will continue. Policymakers may leverage tendering and prescribing guidelines to manage costs until patents expire. Importantly, Bulgaria’s IRP and lack of generic substitution mean that the mere availability of an EU generic reduces the branded price nationally; however, active measures (e.g., prescriber incentives) are needed to encourage patients to switch to the lower-cost alternatives.

Neurology & Other Notable LoEs

Ocrelizumab (Ocrevus)

Anti-CD20 monoclonal antibody (Roche) for multiple sclerosis (relapsing MS and PPMS). Approved in 2017, it is Roche’s top-selling drug (circa CHF 6.7B in 2023). Core EU patents are set to expire by 2028 (US patents by 2029). Biosimilar development is underway: Celltrion received regulatory approval to start a Phase 3 trial of an ocrelizumab biosimilar in 2023. Several other firms are likely to follow, given the drug’s success. Route: CP for biosimilars.

• Bulgarian context: Ocrevus is expensive; its patent expiry in 2028 should usher in biosimilars by ~2029. Bulgaria, as part of the centralized EU approval, will automatically recognize any EMA-approved ocrelizumab biosimilars. This will increase competition in the MS market – a welcome relief for the Bulgarian NHIF, which currently pays a premium for MS therapies.

Dolutegravir (Tivicay, in Triumeq, Dovato)

HIV integrase inhibitor (ViiV Healthcare/GSK). Patent expiry is expected in 2029. Dolutegravir-based regimens are the backbone of modern HIV therapy. So far, no generic challengers have reached approval (likely due to ongoing patent protections and the ViiV–Gilead settlement on bictegravir). We anticipate the availability of generic dolutegravir and combination pills in Europe around 2029–2030.

• Bulgarian context: Bulgaria provides HIV treatment via national programs; generic dolutegravir will lower costs for HIV once available, though this is at the end of the decade. Until then, GSK’s new long-acting injectables (e.g., cabotegravir) and other innovations will dominate, potentially delaying generic uptake.

Aflibercept (Eylea)

Anti-VEGF biologic (Regeneron/Bayer) for retinal diseases (nAMD, DME, RVO-ME, myopic CNV). The first EU aflibercept biosimilar was approved on 15 Sep 2023 (Yesafili, Biocon). Additional EU approvals followed in Nov 2024 (Afqlir, Sandoz; Opuviz, Samsung Bioepis/Biogen), Jan – Apr 2025 (Ahzantive/Baiama, Formycon/Klinge; Eydenzelt, Celltrion; Pavblu, Amgen), and Aug 21, 2025 (Mynzepli, Advanz/Alvotech). All were granted via the centralised procedure and cover the standard 2 mg presentation.

• Bulgarian context: Eylea is typically procured in hospitals at a high cost; the 2023–2025 wave of EU-approved biosimilars is expected to intensify tender competition and expand access as prices fall. Note that Eylea 8 mg (originator high-dose) was approved in the EU in Jan 2024 and received a June 27, 2025, label extension allowing dosing up to every 6 months in nAMD and DME; standard-dose biosimilars still exert substantial price pressure in tenders even alongside the 8 mg line extension.

Denosumab (Prolia/Xgeva)

RANKL inhibitor (Amgen) for osteoporosis (Prolia) and bone metastases (Xgeva). Amgen’s patents have started to expire in Europe (some markets lost protection in 2022); major EU countries and the US will lose coverage by 2025–2026. Competition is imminent: four denosumab biosimilars were approved by the FDA in 2023–2024 (Sandoz’s “denosumab-bbdz” and “-bbgn”, Samsung’s “-bexm” and “-bkzt”) and are set to launch by July 2025. In Europe, multiple marketing authorization applications are under review by the EMA (e.g., Sandoz, Pfizer, Celltrion biosimilars). All will use the CP route.

• Bulgarian context: Prolia is commonly used for osteoporosis in Bulgaria’s aging population. Biosimilars from 2025 will substantially reduce prices – indeed, two years after biosimilar entry, the prices of biologics typically drop by 30–50%. Bulgaria does not allow automatic substitution, even for biosimilars; however, given Prolia’s administration (clinic injection every 6 months), payer-driven switches are feasible. The result will be improved access to osteoporosis treatment and savings in oncology supportive care (Xgeva for cancer patients).

Neurology Insight

Beyond the primary categories, neurology and other specialty areas are expected to see a few key LoEs by 2030. Ocrevus’s and Soliris’s patent cliffs (2025–2028) illustrate that biosimilars are expanding beyond oncology and immunology into neurology and rare diseases. For Bulgaria, participation in EU-wide procurement and regulatory frameworks means these shifts will be felt domestically with little lag. However, Bulgaria’s healthcare system must be prepared, as there is no automatic generic substitution; authorities may need to update reimbursement lists and educate prescribers to capitalize on LoEs. Overall, the 2025–2030 period in Bulgaria will be marked by significant cost savings and market shake-ups as blockbuster drugs in oncology, cardiology, and immunology face their long-anticipated loss of exclusivity.

Expanded EU Loss-of-Exclusivity (LoE) Table, 2025–2030

Pharmaceutical products by sales, with therapeutic area and expected EU competition timelines

Table Notes: LoE = loss of exclusivity. EU LoE dates include granted Supplementary Protection Certificates (SPCs) and any applicable extensions. “Phased” indicates staged generic entry via volume-limited settlements. Therapeutic areas abbreviated: CA = Cancer, IBD = inflammatory bowel disease, AMD = age-related macular degeneration, PNH = paroxysmal nocturnal hemoglobinuria, aHUS = atypical hemolytic uremic syndrome. Dates beyond 2030 are noted for context but fall outside the 2025–2030 focus.

Regulatory Pathways

All biosimilars above will be authorized via the EMA centralized procedure (one EU-wide approval). Small-molecule generics can utilize national or decentralized routes; notably, generics of centrally approved drugs also have automatic access to centralized EU approval. In practice, many generics (e.g., apixaban, sacubitril/valsartan) will file via DCP to expedite national market entry. Hybrid applications may be used for complex generics that require additional data. Bulgaria, as an EU member, will recognize centralized approvals and also participate in decentralized procedures as a Concerned Member State.

Market Access in Bulgaria

Upon LoE, originator drug prices in Bulgaria are re-evaluated against the reference basket and typically drop to match the lowest EU price. The uptake of generics and biosimilars in Bulgaria will depend on physician prescribing, as pharmacy-level generic substitution is not permitted. The Bulgarian Drug Agency ensures that once a patent or data exclusivity expires, approvals of generics/biosimilars can be fast-tracked (often within months of EMA approval for centrally authorized products). The 2025–2030 patent cliff is expected to significantly improve competition. The challenge will be to update treatment guidelines and incentivize the use of these new products (competitors) to capture the full benefits of patent expiries.

Sources

Key data were compiled from EMA filings, industry reports, and patent databases. Notable references include GaBI/EMA for patent timelines – Gabionline.net and Gabi-journal.net, industry analyses for sales and competitor activity – Proclinical.com and Biospectrumasia.com, and regional policy insights for Bulgarian market specifics – Pharmaceutical-technology.com and Ncbi.nlm.nih.gov.