Five Biggest Drug Face-Offs in Pharma History

Obesity is the most competitive space in biopharma right now. The two frontrunners, Novo Nordisk and Eli Lilly, are locked in a very tight fight for leadership in a market that by some estimates could reach a jaw-dropping $150 billion in the next few years.

Novo moved first. Its GLP-1 analog semaglutide was first cleared by the FDA in 2017 as Ozempic for type 2 diabetes. Some four years later, in July 2021, semaglutide won another approval as Wegovy, this time specifically indicated for chronic weight management.

Lilly’s weight-loss blockbuster tirzepatide, in comparison, is a relative late-comer, first reaching the U.S. market in 2022 as Mounjaro for type 2 diabetes Then in November 2023, the FDA approved the drug as Zepbound for obesity, setting up the head-to-head battle with Wegovy in the massive and swiftly growing weight loss market.

Despite being years behind, Lilly is chipping away at Novo’s lead. Costanza Alciati, pharma analyst at GlobalData, told BioSpace in an email that tirzepatide’s efficacy edge has helped Lilly catch up.

Broadly speaking, according to Alciati, the safety profiles of Zepbound and Wegovy are similar, with both drugs sharing common side effects like nausea and vomiting. Both products are also matched in terms of the route and frequency of administration. However, Zepbound’s “weight loss efficacy seems to be higher than Wegovy’s,” Alciati said, adding that “according to trials, there seems to be less muscle mass loss associated with Zepbound’s treatment than Wegovy’s.”

Currently, Novo’s first-mover advantage and sprawling global footprint has allowed it to maintain a slight lead over Lilly. Last year, the Danish pharma logged roughly $26 billion in sales for Ozempic and Wegovy worldwide, while Lilly’s tirzepatide franchise brought in nearly $16.5 billion globally.

But with an aggressive commercial strategy, Lilly is quickly gaining ground. “Eli Lilly’s drug has now been launched in all major markets,” Alciati said. Last month, the Indianapolis pharma launched Mounjaro in India, beating Novo to tap the market of the world’s most populous country.

Aside from Wegovy and Zepbound, pharma has witnessed many other dramatic drug rivalries play out over the years, from Keytruda’s comeback and subsequent dominance over Opdivo and the burgeoning competition between Leqembi and Kisunla. In this article, BioSpace looks at some of the biggest pharma face-offs.

In the oncology arena, few drugs can hope to stand up against Merck’s blockbuster PD-1 inhibitor Keytruda, which has become a cornerstone of cancer care since its first approval in September 2014.

As of writing, Keytruda has more than 41 approvals under its belt. These include several forms of melanoma, hepatocellular carcinoma, breast cancer and, crucially, lung cancer. For the last two years, it has also been the pharma’s top-selling product, bringing in $29.5 billion in 2024.

But it wasn’t always that way. Keytruda once played second fiddle to Bristol Myers Squibb’s PD-1 blocker Opdivo. Approved in December 2014, just months behind Keytruda, Opdivo initially took a sizeable lead in the market, bringing in $942 million in 2015 versus Keytruda’s $566 million.

“Initially, Bristol Myers Squibb was dominating that race,” William Blair partner Matt Phipps told BioSpace in an interview last month. “They had broader approvals and bigger indications.” Merck, according to Phipps, “completely overtook” BMS due to better trials and crucial approvals in lung cancer.

Opdivo never recovered. Last year, the drug brought in $9.3 billion—less than a third of Keytruda’s sales.

Still, BMS continues to carve out a cancer niche for Opdivo. In January, BMS won the race to bring a subcutaneous PD-1 treatment to the market, with the FDA signing off on a new formulation of Opdivo that can be delivered with an injection under the skin. Merck’s application for subcutaneous Keytruda is still under review. Meanwhile, an NSCLC approval in October 2024 made Opdivo the first PD-1 blocker that can be used both before and after surgery.

Two blood thinners brought by four of the biggest pharmas are battling it out in cardiovascular disease.

Bristol Myers Squibb and Pfizer’s oral anticoagulant Eliquis is the stronger competitor. Despite being approved more than a decade ago, Eliquis’ market presence continues to grow, surging 9% year-on-year to bring in $13.3 billion in 2024.

Meanwhile, its closest competitor is a distant second. Though it won the FDA’s blessing a year ahead of Eliquis in 2011, Bayer and Johnson & Johnson’s Xarelto has fallen behind its competitor in terms of market share. The drug peaked in 2021 when it earned J&J $2.44 billion in the U.S. and Bayer just over $5 billion in international markets, for a total of around $7.5 billion. Last year Bayer reported roughly $3.85 billion in international sales for Xarelto, while J&J recorded $2.37 billion in the U.S.—a total of over $6.2 billion.

There are likely several reasons for why Eliquis has cleanly outperformed Xarelto, and one of them might be a question of clinical value. A 2021 study published in JAMA showed that in a Medicare population of more than 580,000 patients with atrial fibrillation, Xarelto was associated with significantly elevated risks of major ischemic or hemorrhagic events, such as fatal bleeding, as compared with Eliquis. Total mortality was also worse with Xarelto. Similarly, a 2023 study in Circulation found that Xarelto significantly heightened the risk of ischemic stroke and major bleeding versus Eliquis in patients in the Optum Clinformatics Data Mart database.

There have been no well-designed and well-controlled head-to-head trials to compare the drugs.

Decades of dispiriting clinical failures have finally produced two winners in Alzheimer’s disease. A tough market showdown has followed. In one corner is Biogen and Eisai’s embattled Leqembi and on the other is Eli Lilly’s newer challenger Kisunla.

The anti-amyloid antibody Leqembi first won regulatory clearance in January 2023 under the FDA’s accelerated pathway before becoming the industry’s first fully approved Alzheimer’s therapy in July 2023. The buzz around Leqembi was strong, despite questions about the strength of the efficacy results and whether the benefits outweighed the risks. Phase III data presented in September 2022 helped revitalize the anti-amyloid theory, experts said at the time. In June 2023, an FDA advisory committee unanimously endorsed Leqembi’s full approval.

Meanwhile, Kisunla’s path to approval was more fraught. In January 2023, the FDA turned down Lilly’s bid for accelerated approval, citing the need for more data from patients who had been treated for at least 12 months. The drug eventually won the regulator’s blessing in July 2024, almost a year to the day behind Leqembi.

Now, however, Leqembi’s edge doesn’t seem so large. Biogen and Eisai have struggled to get the drug off the ground and have been forced at least twice to lower their sales projection for the asset. In March, for instance, Eisai revealed that it expects Leqembi to bring in from ¥250 billion to ¥280 billion (approximately $1.7 billion to $1.9 billion) in its fiscal year 2027—a roughly 50% decline from a prior projection. For fiscal year 2024, which ends this month, the Japanese firm expects full-year sales of around $280 million for Leqembi.

Lilly has already launched Kisunla in the U.S. but has yet to report sales figures.

But both drugs have faced concerns about side effects called ARIA, which can signal bleeding or swelling in the brain. They have also faced slow uptake as physicians and health systems struggle to adapt to the new treatment paradigm.

Two pharma giants are duking it out in the immunology space with blockbuster drugs that are past their prime.

AbbVie’s Humira was for six straight years the world’s best-selling drug. The biologic peaked in 2022, bringing in $21.2 billion. But since losing key patent protections in 2023, its sales have declined steeply: last year, Humira made just under $9 billion.

On the other hand, J&J’s Stelara never reached the same sales heights as Humira. At its peak in 2023, Stelara raked in $10.86 billion before dipping 4.6% to $10.34 billion last year. Like AbbVie’s biologic, Stelara is contending with copycat competitors. After it lost market exclusivity in 2023, several biosimilars have entered the U.S. market, including Amgen’s Wezlana and Sandoz’s Pyzchiva.

Both Humira and Stelara work by tamping down the inflammatory response and share a substantial overlap in their indications, including psoriatic arthritis, plaque psoriasis, Crohn’s disease and ulcerative colitis.

The specific mechanisms by which the drugs exert their therapeutic effects differ, however. Humira targets TNF-alpha, while Stelara acts on IL-12 and IL-23. All three molecules are crucial parts of the inflammatory cascade and often act synergistically, with slight differences in functionality. IL-12 and IL-23 explicitly encourage inflammation, for instance, while TNF-alpha can have both pro- and anti-inflammatory effects.

In May 2021, a head-to-head study showed that despite these mechanistic nuances, Stelara and Humira are largely clinically similar. In patients with Crohn’s disease, Stelara induced a 64.9% clinical remission rate at 52 weeks, while Humira achieved a 61% remission rate at the same time point—a difference that failed to reach statistical significance.

The blood cancer field is witness to a BTK inhibitor battle between AbbVie and J&J’s Imbruvica, the first-comer, and AstraZeneca’s Calquence, which entered the ring four years later.

The bad blood between the two goes way back to the biotech days, when Pharmacyclics developed what would become Imbruvica and rival Acerta Pharma championed Calquence. The rivalry was chronicled in Nathan Vardi’s book For Blood and Money: Billionaires, Biotech, and the Quest for a Blockbuster Drug.

Both drugs work by blocking the Bruton’s tyrosine kinase, an enzyme that plays a crucial signaling role in the proliferation and activity of B cells. Because they share a mechanism of action, the two products also have wide overlap in their indications. Imbruvica and Calquence are both approved for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

Currently, Imbruvica has a slight edge. Last year, AbbVie reported nearly $3.35 billion in worldwide sales for the drug, as opposed to Calquence’s $3.13 billion. Imbruvica also has broader coverage: Aside from the indications that it shares with Calquence, it is also approved for chronic graft versus host disease and the rare blood cancer Waldenström’s macroglobulinemia.

But Calquence is quickly gaining ground. In 2024, AstraZeneca’s asset grew 24% year-on-year, while Imbruvica slid 6.9%. Calquence is also catching up clinically. A May 2024 readout showed that AstraZeneca’s drug, when combined with standard chemoimmunotherapy, can boost progression-free survival in untreated patients with mantle cell lymphoma (MCL).

AbbVie and J&J had pulled Imbruvica’s accelerated approval in this indication nearly a year before. Calquence remains approved for MCL under the FDA’s accelerated pathway.

Meanwhile, real-world data presented at the 2024 Congress of the European Hematology Association showed that patients with CLL or SLL who were treated with Calquence had longer time to discontinuation or death than comparators on Imbruvica. Time to next treatment was also longer in the Calquence group, as reported by OncLive at the time.