Biosimilars Expand Patient Access to Novel Treatments

Adam M. Brufsky, MD, PhD

Biologic products represent the cutting-edge of biomedical research and are the fastest-growing class of therapeutic products in the United States.¹ By 2024, the global cancer biologics market is expected to reach $87.6 billion, partially driven by the expiration of more than 20 biologic patents by 2023, which is anticipated to lead to a hugely expanded arsenal of biosimilars over the next few years.^2,3

Although these more cost-effective biologic medicines enable a greater proportion of patients to gain access to novel life-prolonging or life-saving treatments, incorporating them into US clinical practice has been slow. Studies show that many US clinicians still have a poor understanding of biosimilars and may be wary of them, despite there being more than 10 years of data from Europe showing that these agents have comparable safety and efficacy to their reference biologics.³

During an OncLive Peer Exchange®, a panel of hematology-oncology experts discussed the emergence of biosimilar use in oncology. They focused on how biosimilars compare with their biologic originators, how they are assessed and approved, and strategies for incorporating them into clinical practice, including hurdles to their use and efforts to expand their use. The panel also briefly discussed some of the currently approved biosimilars that are being used to treat patients with metastatic non–small cell lung cancer (NSCLC) or metastatic HER2-positive breast cancer.

“There is great value in educating physicians about the use of biosimilars in clinical practice,” moderator Adam M. Brufsky, MD, PhD, said. “When providers understand their scientific rationale and justification, they can appropriately convey clinical messages to their patients and potentially help to streamline the process for increased biosimilar adoption.”

Biosimilar vs Biologic: Comparisons and Approval Process

A 2018 survey-based US study of 77 oncology clinicians, including 52 physicians, 16 pharmacists, and 9 advanced practice providers, showed that 74% (n = 57) of respondents could not satisfactorily define biosimilars.⁴ Additionally, 40.3% (n = 31) of respondents considered biosimilars to be the same as generic drugs, showing a lack of understanding of these agents.

“A biosimilar is a new entity that is highly similar to [but not the same as] the original or approved referenced biologic,” panelist Lee S. Schwartzberg, MD, said. “The basic structure is the same, but there are additions created in cells through complex processes, so there may be slight variations from batch to batch. That is different from a generic, where every single molecule will look the same as every other single molecule.” Although there are slight differences between biosimilars and their reference products, these agents need to show equivalent safety, efficacy, purity, and potency in drug studies to be approved.

A lack of understanding of biosimilars among US clinicians may be partially attributable to these medicines being a recent addition to the treatment armamentarium in this country. Schwartzberg explained that the United States has lagged behind Europe in approving these medications. Whereas the European Medicines Agency (EMA) approved its first biosimilar in 2006, a recombinant human growth hormone medicine called Omnitrope (biosimilar of somatropin), the FDA did not approve its first biosimilar until almost a decade later in 2015, the oncology drug Zarxio (filagrastim-sndz).^5,6 In comparison, the EMA had approved its first filagrastim biosimilar in 2008.3

“The FDA process for approving a biologic is different than that for approving an originator or reference product,” Schwartzberg said. He explained that the process resembles an inverted pyramid, whereas the process for approving a biosimilar resembles a true pyramid (Figure). “For a biosimilar, most of the work is done showing the analytic purity and [structural and functional] similarity to the originator, with less work on the clinical process. If you show that the biosimilar is highly similar to the originator product in terms of the way it looks, the product itself, its functional attributes, its pharmacology and its pharmacokinetics, then you can do fewer clinical trials,” he said. This also keeps the costs of biosimilars down because it eliminates the need to conduct expensive large-scale clinical trials. “You’re conducting only 1 large trial, and that suffices for the FDA to approve the biosimilar for the same indication as the originator,” he said. Schwartzberg explained that the rigorous part of the process with biosimilars is quality assurance, when manufacturing standards comparable with those of the reference biologic are established and maintained.

Figure. Process for Approving Biologics Versus Biosimilars

Biosimilars in Treating NSCLC and Breast Cancer

In patients with metastatic NSCLC, 2 bevacizumab biosimilars are currently approved in the United States: Mvasi (bevacizumab-awwb), approved in 2017, and Zirabev (bevacizumab-bvzr), approved in 2019.^7,8 Both are indicated for use in combination with carboplatin and paclitaxel in chemotherapy-naïve patients. These agents are also approved for several other indications, including metastatic colorectal cancer, recurrent glioblastoma, metastatic renal cell carcinoma, and persistent, recurrent, or metastatic cervical cancer. On March 9, 2020, the FDA also accepted a biologics license application (BLA) by Mylan and Biocon Biologics for MYL-1402O, another bevacizumab biosimilar, for review under the 351(k) pathway.9 The companies are seeking approval for the same indications as both of the approved bevacizumab biosimilars have. The FDA decision goal date, as set under the Biosimilar User Fee Act, is December 27, 2020.

For patients with HER2-positive breast cancer, the FDA has approved 5 trastuzumab biosimilars: Ogivri (trastuzumab-dkst), approved 2017; Herzuma (trastuzumab-pkrb), approved 2018; and Kanjinti (trastuzumab-anns), Ontruzant (trastuzumab-dttb), and Trazimera (trastuzumab-qyyp), approved in 2019.^10-14 All 5 agents are also indicated for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

Despite their being approved, some for several years, not all the agents may be available, Schwartzberg said. “[This has] to do with operational issues at the manufacturers’ level and lawsuits and other things among the originators,” he explained, noting that when trastuzumab biosimilars first became available, his clinic started by offering Kanjinti because it was the first one that came to market.

Regardless, Schwartzberg said that he would feel comfortable using any of the trastuzumab biosimilars. “I believe in the process of approval. I believe that all of the boxes have been checked, and I can feel comfortable that if I use a biosimilar trastuzumab it will work the same way as the originator trastuzumab did,” he said. However, once he has decided upon a biosimilar, that is the agent he sticks with for any given patient. Each biosimilar has a 4-letter suffix as part of its generic name, which does not have any meaning other than to help pharmacists and clinicians distinguish between individual agents. “We don’t just say ‘biosimilar trastuzumab’; it’s the actual name that we use,” he noted.

Incorporating Biosimilars Into Clinical Practice

When patents expire, multiple biosimilars for the reference biologic are typically developed. For example, approximately 9 filgrastim biosimilars are available in Europe and 2 in the United States.³ As biosimilars are not exactly the same as their reference counterparts, the panelists explored how clinicians decide which one to choose. Kashyap Patel, MD, said the decision is based on multiplefactors, one of the most important of which is the reputation of the manufacturer.

“Once you start treating patients with drug A, drug B, or drug C, [you] want to make sure that company has a history of maintaining supply chains,” he said. Two other important factors concern cost, including patient assistance programs, which may be especially important for patients who do not have adequate insurance coverage, and payer coverage, which can vary greatly between managed care organizations, including Medicare Advantage Plans.

Although biosimilars are less expensive than their reference biologics, they do not provide the same cost savings as generic drugs, which has resulted in some skepticism regarding their use. Patel explained why the 2 are vastly different. “A generic drug is a small molecule, which probably has about 180 to 300 dalton atomic weight. When we look at the biosimilar, it’s about 180,000 dalton atomic weight. It’s much more complicated. And the manufacturer must spend hundreds of millions of dollars [on rigorous evaluation]. It’s not like buying a 1-kg molecule for $1 million and then cutting pills and filling bottles,” Patel said.

Nevertheless, he said these agents are still enabling significant cost savings. At his clinic in the South Carolina tobacco belt, where he sees many patients with metastatic NSCLC, use of a bevacizumab (Avastin) biosimilar is projected to result in significant cost reductions. “By December 2021, my total drug spending will go down by about 15% to 17%. And it’s based on the fact that the history of biosimilars has shown in the last 2 years, that within 2 years, the ASP [average sales price] drops by about 30% to 35%. Fifty percent of my total drug budget is in biologics. So, when I extrapolate 35% savings in biologics, my total drug budget would go down by 15%, which is almost $1 million-plus savings to us,” he said.

But the cost savings does not just extend to clinics, he noted. Patel said that this also translates to cost reductions for patients. “Even a 30% reduction in out-of-pocket cost could save them $100 a month,” he said. Although this may not seem to be a big savings, it can be significant, especially for those who depend on Medicare or Medicaid.

However, there have been challenges getting payers onboard with biosimilars, despite the cost savings. Patel said he had to write a letter to his state’s Medicaid making a case for their use. To his surprise, his appeal worked, and the agency started approving them. He also met several times with the chief medical officers of his state’s commercial insurances, explaining that they may ultimately be able to save billions of dollars by providing coverage for biosimilars, which was nevertheless met with reluctance.

“There are so many middlemen between them,” Patel said, noting that these middlemen often advise commercial insurers that the use of biologics will provide greater discounts at the back end, such as through rebates. He emphasized the importance of educating all players, including payers and physicians, regarding the benefits of biosimilars. “I think in my experience, it [comes down to] the education of the payers, when you look at the payer battle, as well as the education of physicians concerning the approval of biosimilars. Europe has been using biosimilars since 2006. They have used over 700 million unique doses and still have not seen any adverse outcomes,” he said.

Improving Biosimilar Access: ION and COA Efforts

Patel has worked with both the International Oncology Network (ION), a business group, and the Community Oncology Alliance (COA), a not-for-profit advocacy group, to expand access to biosimilars. He has been involved in multiple educational events at ION’s national meetings to educate physicians about biosimilars. He has also contacted payers to advocate for coverage and is currently chairing a biosimilars committee. The organization advocates for the use of biosimilars across the board, rather than for individual products, he explained.

“ION tends to be agnostic regarding the manufacturer. They want to work with all the manufacturers who are willing. And there’s going to be regional variation based on the payer coverage,” he said. According to Patel, the organization helps to steer the contracting and then lets individual practices decide how they want to work with the suppliers. Subsequently, if 5 different biosimilars are available for a product, ION will try to contract with all 5 of them, and it will then leave it up to individual practices to determine which one(s) to use.

In contrast to ION, COA has been working to educate clinicians on the relevance of biosimilars in addressing Part B drug pricing and keeping pricing as low as possible. “We want to do everything possible to reduce the drug price in conjunction with the government, Senate, Congress, and payers,” Patel concluded.

References

1. What are “biologics” questions and answers. FDA. Updated February 6, 2018. Accessed June 30, 2020. bit.ly/37Fg8PO

2. The global cancer biologics market is expected to reach USD 87.6 billion by 2024. News release. PR Newswire; October 8, 2018. Accessed June 30, 2020. prn.to/2BHQTk2

3. Konstantinidou S, Papaspiliou A, Kokkotou E, Switchenko JM, Harvey RD, Pentz RD. Current and future roles of biosimilars in oncology practice. Oncol Lett. 2020;19(1):45-51. doi:10.3892/ol.2019.11105

4. Cook JW, McGrath MK, Dixon MD, et al. Academic oncology clinicians’ understanding of biosimilars and information needed before prescribing. Ther Adv Med Oncol. 2019;11:1758835918818335. doi:10.1177/1758835918818335

5. Schiestl M, Zabransky M, Sörgel F. Ten years of biosimilars in Europe: development and evolution of the regulatory pathways. Drug Des Devel Ther. 2017;11:1509-1515. doi:10.2147/DDDT.S130318

6. Raedler LA. Zarxio (filgrastim-sndz): first biosimilar approved in the United States. J Hematol Oncol Pharm. 2016;6:100-104. Accessed June 27, 2020. bit.ly/2ZdvB5O

7. Mvasi. Prescribing information. Amgen; 2019. Accessed June 26, 2020. bit.ly/384FV49

8. Zirabev. Prescribing information. Pfizer; 2020. Accessed June 26, 2020. bit.ly/2Zg1f2P

9. U.S. FDA accepts biologics license application (BLA) for Mylan and Biocon’s proposed biosimilar bevacizumab for review. News release. Biocon Ltd. March 9, 2020. Accessed June 22, 2020. bit.ly/38AHuWb

10. Ogivri. Prescribing information. Mylan; 2019. Accessed June 26, 2020. bit.ly/3dvA1KE

11. Herzuma. Prescribing information. Celltrion Inc; 2019. Accessed June 26, 2020. bit.ly/3eCRz93

12. Kanjinti. Prescribing information. Amgen, Inc; 2019. Accessed June 26, 2020. bit.ly/3dCyVNl

13. Ontruzant. Prescribing information. Merck; 2019. Accessed June 26, 2020. bit.ly/2NA9YaF

14. Trazimera. Prescribing information. Pfizer; 2019. Accessed June 26, 2020. bit.ly/2A5BLwn