Biosimilars in Hematology: A Work in Progress

Recently, I was reviewing editorial content for ASH Clinical News, when I came across an article covering the U.S. Food and Drug Administration’s (FDA’s) approval of emicizumab-kxwh, which was indicated for prevention or reduction of the frequency of bleeding episodes in patients with hemophilia A. Naturally, because of the “-kxwh” drug extension, I assumed that emicizumab-kxwh was a biosimilar version of emicizumab. Since Europe is far ahead of the U.S. in terms of the approval of and experience with biosimilar agents, I was excited to learn that another biosimilar agent finally was approved for use in the U.S.¹

My joy quickly turned to confusion when I learned that this drug was not a biosimilar agent, but a biologic product. Two questions popped into my head: “When did the naming of biologics change?” and “How could I not know about this?”

If I had questions about biosimilars, it made me wonder what questions other providers might have about biosimilars. What is the state of biosimilars and biologic agents in the U.S.? Has the global impact of biosimilars changed? Does the medical community feel confident enough to use these drugs in their clinical practice?

In this column, I hope I can answer these questions – and help you answer questions from patients – about the similarities and differences between biosimilar and biologic drugs in hematology.

The Same, but Different

In December 2017, ASH Clinical News ran a series of articles reviewing important and relevant concepts about biosimilars, including immunogenicity, extrapolation, manufacturing, and economic impacts. In the past year, the science of biologics and biosimilars has continued to move ahead rapidly, and now, in December 2018, U.S. practitioners have 14 biosimilar agents available for use (see TABLE).

ASH Clinical News readers likely are familiar with the key concepts of biosimilar drugs and their reference products, but to quickly review: A biosimilar is a biologic product that is similar (but not identical) to a biologic product already approved by the FDA (also known as the “originator” or “reference product”).²

Biologic agents are developed from living organisms, which can include bacteria, yeast, or even human cell lines, and unlike traditional medications, they cannot be made through synthetic chemical processes.

Biologics and biosimilars share features – such as a particular mechanism of action and a common amino acid sequence – but biosimilars are not identical copies of originator products. Each product is marked by differences in its host cell line, protein structures, and manufacturing processes. Despite the structural and functional differences that can emerge in the manufacturing of a biosimilar product, the FDA mandates that there are “no clinically meaningful differences in terms of safety and effectiveness from the reference product” and only minor differences in the clinically inactive components.²

An interchangeable product is a biosimilar product that meets additional requirements showing that the drug is expected to produce the same clinical result as the reference product in any given patient and the agent can be substituted for the originator without any involvement from the prescriber. As of yet, no biosimilars have been approved with this designation.

Patients and providers may inaccurately refer to biosimilars as generic drugs because these drug classes share a common goal – providing patients with equally effective but less expensive versions of branded or biologic agents. However, generic drugs follow a specific blueprint, and manufacturers can replicate a branded agent’s chemical structure.

In the case of biologics and biosimilars, it is impossible for biosimilars to follow a standard manufacturing scheme, given their complex protein structures and differences in host cell lines. Thus, biosimilars are not generic drugs, nor are they intended to replace a reference product.³

Biosimilars on the World Stage

The global impact of biosimilar drugs is difficult to quantify, and the economic benefit is even more difficult to measure. This is due, in part, to the glaring fact that only a handful of biosimilars are approved for use in the U.S. The approvals cover a wide swath of indications, and, unfortunately, there are only five approved biosimilars in the hematology space.

Further, complex pharmacoeconomic analyses are required to measure the potential effect of biosimilars, both locally and globally. The literature on this topic is scarce, with few papers relevant to the hematology market. Economists and drug manufacturers seem eager to cash in on the promises of marked price savings and reduction in health-care costs if more biosimilar drugs are prescribed for use in the clinic.

A RAND Corporation analysis estimated that the potential cost savings could reach $54 billion over 10 years based on recent available data, but the actual savings “will hinge on industry and regulatory decisions, as well as potential policy changes to strengthen the biosimilar market.”⁴

Before those savings are realized, health-care plans and insurance payers need to “buy into” biosimilars, recommending them for their hospital formulary. Yet most of what has been reported in terms of cost savings are estimated projections of the potential effect of the drugs on various U.S. markets. Many factors, such as physician or practitioner uptake of biosimilar drugs, availability of biosimilar drugs, and skepticism around competitive pricing, will ultimately decide how biosimilars will be used in clinical practice.

For readers who are wondering about the approval of a biosimilar version of rituximab, this issue is still on hold. Novartis and Sandoz’s GP2013 candidate appeared the closest to approval, until the FDA rejected the agent’s biologics license application. In November 2018, the pharmaceutical manufacturers announced they had decided “not to pursue” a U.S. biosimilar for rituximab.⁵ The previous month, however, the FDA’s Oncologic Drugs Advisory Committee unanimously voted to recommend approval of CT-P10, another rituximab biosimilar candidate.⁶

The Name Game

Now back to the question that prompted my reflection: When did the naming of biologics and biosimilars become indistinguishable from biologic agents? Apparently, in January 2017. In a guidance document for industry (“Nonproprietary Naming of Biological Products”), the FDA laid out strict suggestions about the naming of biosimilars: The proposed suffix should be unique, devoid of meaning, and include exactly four lowercase letters of which at least three are distinct and attached to the core name with a hyphen (FIGURE).⁷

Also, the suffix cannot be false or misleading, contain or suggest any drug substance name or core name, look similar to or otherwise connote the name of the license holder, or be too similar to any other FDA-designated nonproprietary name suffix.

This was a departure from the original naming convention, when the four-letter suffix attached to the nonproprietary name signaled the biosimilar’s manufacturer (as with Sandoz’s filgrastim-sndz) and distinguished the biosimilar agent from its reference product.

Whether the new process clarifies or confuses remains to be seen, but more than 70 groups, led by the Alliance for Safe Biologics, already submitted a letter to the FDA requesting the agency reinstate “meaningful” suffixes.⁸

Implications for Practice

Large hospitals and commercial payers generally are responsible for making the decision to switch a patient from a biologic to its biosimilar drug, but advanced practice providers (APPs) typically are the ones “on the frontlines” with patients. APPs often are responsible for prescribing biosimilar drugs and monitoring the patients who receive them and, as a consequence, field questions about safety and costs.

Practitioners have the largest experience with biosimilars to the granulocyte-stimulating factor filgrastim in the setting of hematopoietic cell transplantation. A recent analysis of published studies by the World Marrow Donor Association (WMDA) showed no evidence of a higher risk of filgrastim antibody formation using filgrastim biosimilars.⁹ Based on these findings, the WMDA recommended that stem cell donor registries use filgrastim biosimilars for the mobilization of peripheral blood progenitor cells in healthy donors, provided that they are approved by national and/or regional agencies.

Because the currently available hematopoietic growth factor biosimilars are supportive care agents, rather than agents intended to treat a cancer, these drugs are less likely to raise concerns for patients. If biosimilar versions of targeted chemotherapies are approved by the FDA in the future, this might change.

As APPs, our goal should be to educate patients and peers about the similarities and differences between biosimilars and their reference products, including if there are any differences in handling, administration, and storage of the agents.

In my experience, I have not encountered a single patient who has been fearful of the transition to a biosimilar. Rather, most patients seek the provider’s opinion about what is the best drug for them. Navigating a cancer diagnosis is difficult enough for most patients and their caregivers; determining which supportive care agent to use remains less of a concern.

Thanks to the rising costs of health care in today’s climate, hospitals and consumers are interested in cost savings. No biosimilar products are approved as interchangeable for their reference products, but analyses suggest that the biosimilars are often so similar to the originator that these drugs should be a standard part of our practice. Time will tell if the projected dramatic cost savings are realized. If nothing else, these drugs provide more options for patients and providers.

References

1. Kos IA, Azevedo VF, Neto DE, Kowalski SC. The biosimilars journey: current status and ongoing challenges. Drugs Context. 2018;7:212543.
2. Biosimilar and interchangeable products. Accessed November 8, 2018.
3. Cai XY, Wake A, Gouty D. Analytical and bioanalytical assay challenges to support comparability studies for biosimilar drug development. 2013;5:517-20.
4. Mulcahy AW, Hlavka JP, Case SR. Biosimilar cost savings in the United States: initial experience and future potential. Rand Health Q. 2018;7:3.
5. Sandoz press release. Sandoz decides not to pursue US biosimilar rituximab; will focus on robust biosimilar portfolio for unmet access and sustainability needs. November 2, 2018. Accessed November 8, 2018.
6. FDA Briefing Document: BLA 761088. October 10, 2018. Accessed November 8, 2018.
7. Nonproprietary Naming of Biological Products: Guidance for Industry. Accessed November 8, 2018.
8. 70 groups call on FDA to revert back to meaningful suffixes for biosimilar names. May 12, 2016. Accessed November 8, 2018.
9. Pahnke S, Egeland T, Halter J, et al. Current use of biosimilar G-CSF for haematopoietic stem cell mobilization. Bone Marrow Transplant. 2018 October 3. [Epub ahead of print]