Pharmaceutical giants with revenue streams worth tens of billions typically rely on at least one blockbuster product generating over USD 5 billion annually. However, creating a USD 10 billion "mega-blockbuster" requires precise targeting of clinical needs and substantial R&D investment. Tracking the evolution of these top-selling drugs reveals market shifts driven by scientific breakthroughs, unmet medical needs and product lifecycles.

By late 2024, COVID-19 products had completely exited the "billion-dollar club", with four new contenders claiming the crown: AbbVie’s Skyrizi (risankizumab), Johnson & Johnson’s (J&J) Darzalex (daratumumab), Eli Lilly and Company’s Mounjaro (tirzepatide) and Vertex Pharmaceuticals’s Trikafta/Kaftrio (elexacaftor + tezacaftor + ivacaftor). This brings the total number of drugs exceeding USD 10 billion in annual sales to 12, surpassing 2023’s record of 10.

This potential is mainly concentrated in the areas of oncology, immunology and endocrine/metabolic disorders — areas characterised by large patient populations, high disease burdens and chronic treatment needs, creating fertile ground for high-revenue therapies.

These drugs establish market dominance in different ways. Some achieve broad applicability, as in the case of MSD’s Keytruda (pembrolizumab), which is currently approved for dozens cancer indications. Others dominate niche markets, as in the case of Trikafta/Kaftrio (irreplaceable in cystic fibrosis).

As the number of billion-dollar molecules grows, the bar for "top drug" status keeps rising. Excluding pandemic outliers, the revenue ceiling has jumped from USD 10 billion for AbbVie’s Humira (adalimumab) to USD 20 billion in the Keytruda era, and is now nearing USD 30 billion.

The race for dominance is intensifying, with shorter reigns at the top. Keytruda, the current leader, faces fierce competition from two GLP-1 stars: Novo Nordisk’s Ozempic/Wegovy/Rybelsus (semaglutide) reached USD 29.3 billion in 2024, closing in on Keytruda, while Lilly’s Mounjaro/Zepbound surged to USD 16.5 billion, demonstrating explosive growth.

The era of single-therapy dominance is fading, replaced by a dynamic battlefield where metabolism, immunology and cancer drugs vie for supremacy.

Both PD-1 and GLP-1 therapies target vast patient populations — one dominating oncology, the other revolutionising metabolic disease management. Their respective collisions with competitors are likely to result in protracted battles.

What’s particularly intriguing is the recurrence of single targets spawning multiple blockbusters. PD-1, GLP-1, and IL-23 have each produced therapy pairs with comparable commercial success. This isn’t coincidence but proof that certain targets deliver transformative clinical value and expansive market potential.

Beyond the headline shifts in revenue rankings and "top drug" narratives, the evolving billion-dollar drug roster tells deeper stories.

Shifting Generals, Building Fortresses

In an industry where "products reign supreme", flagship therapies are critical to sustaining revenue. Patent expiries loom like deaths foretold — when a market leader falters, the resulting drop in revenue can devastate a company.

Facing this challenge, firms adopt one of two divergent strategies: replacing generals or fortifying defences.

Product succession is an eternal theme in pharma innovation as the most direct answer to patent cliffs. A prime example is Humira. With rapid indication expansion, it dominated immunology for a decade as the world’s top-selling drug. Its longevity stemmed not just from broad applicability but from AbbVie's "patent thicket", delaying biosimilars by six years and buying time to groom successors Skyrizi (risankizumab) and Rinvoq (upadacitinib).

Though Skyrizi launched two years after J&J’s Tremfya (guselkumab), it leveraged Humira’s brand legacy to overtake its IL-23 rival, becoming a 10-billion therapy in 2024 and securing AbbVie’s revenue stability. Meanwhile, Rinvoq shines as a potential first-in-class JAK inhibitor to crack USD 10 billion, proving that strategic transitions can turn patent cliffs into stepping stones.

Novo Nordisk and Eli Lilly and Company have written similar succession stories in the GLP-1 arena: from liraglutide to semaglutide, and from dulaglutide to tirzepatide. Each new generation outperforms its predecessor, extending the diabetes giants' legacies.

While seamless product transitions are ideal, many pharma giants also focus on maximising existing therapies' clinical value and reinforcing defences against patent cliffs. MSD’s strategic handling of Keytruda is a masterclass. A decade after launch, the drug remains the gold standard in immuno-oncology — an unavoidable benchmark for competitors. Facing Keytruda’s 2028 patent cliff, the company has deployed a multi-pronged defence:

• Expanding indications: Keytruda now covers nearly all major solid tumours, far outpacing rivals. Its broad use as first-line therapy in many cancers — backed by years of data and physician trust — creates steep competition barriers.
• Novel formulations: Exploring new delivery methods to extend its lifecycle.
• Combo networks: Building a web of combination therapies with ADCs, targeted drugs, and cancer vaccines (dozens of ADC pairings alone are in testing). Even post-patent, these regimens could sustain Keytruda’s clinical role.

MSD isn’t betting solely on Keytruda, though. The company is diversifying its future revenue streams with pipeline assets like third-generation BTK inhibitor MK-1026, KRAS G12C blocker MK-1084 and cancer vaccine mRNA-4157, all of which are nearing approval.

Johnson & Johnson’s narrative is equally compelling. While steadily advancing its pipeline, its oncology and immunology divisions are locked in a revenue race. 2024 marked a historic milestone: Johnson & Johnson became the first company to simultaneously own two 10-billion therapies, namely Stelara (ustekinumab) in immunology and Darzalex in oncology.

For years, immunology has been Johnson & Johnson's pharmaceutical growth engine, with Stelara as its crown jewel. While Stelara became Johnson & Johnson's first 10 billion+ blockbuster in 2023, it also faced biosimilar competition that same year. Unfortunately for the company, its follow-up therapies like Tremfya failed to fill the gap, leaving immunology growth sluggish.

Meanwhile, Johnson & Johnson's oncology division has steadily gained ground, surpassing immunology in revenue contribution in 2024, a tipping point driven by Darzalex's meteoric rise. With a robust oncology pipeline, including CAR-T therapy Carvykti (ciltacabtagene autoleucel) and bispecific antibody Rybrevant (amivantamab), Johnson & Johnson is well-positioned for sustained growth. The ongoing tug-of-war between its oncology and immunology businesses will remain a key narrative in future earnings reports.

Reshuffling the Global Pharma Top 10

Drug development is a marathon, not a sprint, and thus requires endurance and vision. In this endless race, a single USD 10 billion blockbuster can redefine a company's global standing or even reshape the industry.

The 2024 pharma rankings revealed a seismic shift: Eli Lilly and Company broke into the global top-10 for the first time. This leap was powered by tirzepatide-based twin stars Mounjaro and Zepbound. Unlike single-target GLP-1 drugs, tirzepatide's dual agonism of GLP-1R/GIPR delivers superior glycemic control and weight loss, making it a preferred choice for diabetes and obesity patients. Notably, Zepbound hit nearly USD 5 billion in its debut year.

Before tirzepatide, Lilly was an insulin leader but languished in pharma's second tier. By capitalising on the GLP-1 revolution, Lilly didn’t just elevate its market position — it transformed investor perceptions. Its market value doubled in two years, propelling it to the industry’s upper echelon.

While 10-billion+ blockbusters undeniably shape a pharma giant's revenue scale, the industry's competitive landscape isn't solely dictated by single products. Notably, four 2024 top-10 pharma companies — Roche , AstraZeneca (AZ), Bayer and Novartis — achieved their rankings without relying on any mega blockbusters.

Diversified and balanced business structures can equally fuel long-term competitiveness — a hallmark of these four multinationals. Roche thrives with dual engines in diagnostics and pharmaceuticals, boasting 17 drugs exceeding USD 1 billion annually — the industry’s largest portfolio of blockbusters.

AstraZeneca posted a 21% revenue surge in 2024, driven by balanced growth across oncology, metabolism and immunology. Its near-billion-dollar therapies Farxiga (dapagliflozin) and Tagrisso (osimertinib) are poised to join the elite USD 10 billion club.

Bayer maintains steady USD 50 billion+ revenue through its trinity of crop science, pharma and consumer health.

Finally, Novartis leverages four balanced pillars (oncology, immunology, cardio-renal-metabolism and neuroscience) to drive growth across therapeutic frontiers.

Epilogue

Mega blockbusters emerge from the alchemy of commercial strategy and scientific breakthroughs, transforming patient lives while generating immense value. Yet these crown jewels are both a blessing and a curse: they provide reliable cash flow to fund R&D, but over-reliance risks concentration vulnerability.

The strategic dilemma — replacing flagships versus fortifying moats, diversifying versus doubling down — tests leadership foresight.

As science evolves, new contenders will join the 10-billion club. Which disease areas will spawn the next commercial legends as the pharma titans continue their battle for dominance?