- Since November 2019, biosimilar versions of pegfilgrastim, rituximab, bevacizumab, and trastuzumab have launched in the United States.
- FDA approved fifth Humira® (adalimumab) biosimilar, but it will not launch until 2023.
- FDA approved third Neulasta® (pegfilgrastim) biosimilar and all three have launched.
- FDA approved fourth Remicade® (infliximab) biosimilar.
As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years. Global sales for the top ten branded biologic drugs totaled approximately $81 billion in 2018. In the FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, the FDA highlighted the ten biosimilar approvals in 2019 under the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which was “designed to create competition, increase patient access, and potentially reduce cost of important therapies.” The FDA’s Biosimilars Action Plan, unveiled in 2018, has been designed to aid the development of a market for biosimilars in order to increase competition for biologic drugs, which make up 40% of U.S. pharmaceutical spending. Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems. To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options. The RAND Corporation estimates that biosimilar products can save the U.S. health system approximately $54 billion over the next decade, as discussed here.
Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA). The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA. Since Sandoz’s somatotropin biosimilar, Omnitrope®, was first authorized on April 12, 2006, an additional 59 applications have been approved in Europe. Seven of the authorizations have been withdrawn post-approval (Table 1).
The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009. Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States. Sandoz’s filgrastim biosimilar, Zarxio®, received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008. Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991. Subsequent to Zarxio®’s approval, 25 other biosimilar drugs have gained U.S. approval to date (Table 2).
As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States, although the U.S. FDA reversed that trend in 2019 with ten approvals.
Currently, nine biosimilar applications are under review by the EMA for marketing authorization (Table 3). As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing. Biosimilars for at least 24 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).
On November 5, 2019, Sandoz announced the approval of its pegfilgrastim biosimilar ZiextenzoTM. “When a cancer patient with febrile neutropenia gets an infection, it can have serious consequences such as delays or dose reductions of chemotherapy,” said Carol Lynch, President of Sandoz Inc. “The approval of Ziextenzo expands our oncology portfolio, providing physicians with a long-acting supportive oncology biosimilar option. It builds on the foundation of trust and experience we developed with our short-acting filgrastim Zarxio® – the leading filgrastim by market share in the US – including consistent product supply and reliable patient services.”
On November 18, 2019, Pfizer announced the approval of its adalimumab biosimilar AbriladaTM. “Biosimilars like ABRILADA represent an opportunity to help improve access to important treatment options for patients living with chronic, and often debilitating, inflammatory conditions,” said Richard Blackburn, Global President, Pfizer Inflammation and Immunology. “Our current portfolio of approved biosimilar products is one of the broadest in the industry and we are proud to offer additional treatment options for patients.”
On December 6, 2019, Amgen announced the approval of its infliximab biosimilar AvsolaTM. “The approval of AVSOLA represents an important milestone across our biosimilar and inflammation portfolios,” said Murdo Gordon, executive vice president of Global Commercial Operations at Amgen. “Following July’s exciting launches of our two biosimilars in oncology, AVSOLA highlights Amgen’s long-term commitment to providing more affordable biological treatment options to patients across critical disease states, including chronic inflammatory conditions.”
In addition to these biosimilar approvals, on December 23, 2019, AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) announced the approval of EnhertuTM, which is a HER2 directed antibody drug conjugate (ADC) designed to delivery cytotoxic chemotherapy to cancer cells via a human epidermal receptor 2 (HER2) antibody (trastuzumab) attached to a novel topoisomerase I inhibitor payload and a tetrapeptide-based linker. José Baselga, Executive Vice President, Oncology R&D, said: “Enhertu has shown impressive results in women with HER2-positive metastatic breast cancer, with the majority of women benefiting from treatment and the median duration of the response exceeding 14 months. With this first approval, we are proud to bring Enhertu to patients with high unmet need and we look forward to further exploring its potential in additional settings.” Antoine Yver, Executive Vice President and Global Head, Oncology R&D, Daiichi Sankyo said: “The approval of Enhertu underscores that this specifically engineered HER2-directed antibody-drug conjugate is delivering on its intent to establish an important new treatment for patients with HER2-positive metastatic breast cancer. Since the beginning of our clinical trial programme four years ago, we have focused on the opportunity to transform the treatment landscape for patients with HER2-positive metastatic breast cancer, and we are extremely proud of how quickly we delivered Enhertu to patients in the US, as Enhertu represents one of the fastest-developed biologics in oncology.”
Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated January 24, 2020).
Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs.
Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines compiled on January 6 2020 and published on January 7, 2020).
Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.
 Based on sales reported by respective manufacturers (1. Humira—Abbvie ($19.94B), 2. Opdivo—Bristol-Myers-Squibb ($7.57B), 3. Keytruda—Merck ($7.17B), 4. Enbrel—Pfizer/Amgen ($7.126B), 5. Herceptin—Roche ($6.981B), 6. Avastin—Roche ($6.847B), 7. Rituxan—Roche ($6.75B), 8. Eylea—Aflibercept ($6.551B), 9. Remicade—Johnson & Johnson/Merck ($5.908B), 10. Stelara—Johnson & Johnson ($5.156B)).