The Science Behind Biosimilars

Although six biosimilar agents have now been approved by the U.S. Food & Drug Administration for use in rheumatology, scientific, clinical, economic and prescribing questions about the use of biosimilars abound. In fact, at the 2017 ACR/ARHP Annual Meeting in San Diego, Joseph Huffstutter, MD, a rheumatologist in private practice in Chattanooga, Tenn., said that no one has yet used biosimilars in a rheumatology practice in the U.S. To assist rheumatologists and rheumatology health professionals gain an understanding of biosimilar agents, the ACR has produced a white paper on biosimilars for rheumatic diseases.

Below we summarize some of the paper’s key points. Read the whole paper at https://www.rheumatology.org/Portals/0/Files/ACR-White-Paper-Science-Behind-Biosimilars.pdf.

The FDA defines a biosimilar as a biologic product that is “highly similar to” an approved biologic product (i.e., the reference, originator or bio-originator product) and that has “no clinically meaningful differences” in safety or effectiveness compared with the reference product.

Biosimilars should not be confused with generic medications, despite the fact that for both, pathways for regulatory approval are abbreviated when compared with the approval pathways for new drugs. Because biologics are proteins produced in living cells, biosimilars usually are not identical to their reference products.

The biosimilar manufacturer reverse engineers the biosimilar’s DNA sequence based on the primary protein sequence of the reference drug (available in the public domain) and transfects the synthesized gene into host cells, in which transcription and translation by the host cell generates the core protein of the biosimilar. Several factors integral to the manufacturing process influence the degree to which the molecular structure of the biosimilar matches that of its reference product. These include choice of host cell, which influences post-translational modifications of the protein (e.g., glycosylation), and methods used to purify and stabilize the final product. Importantly, to achieve FDA approval, a biosimilar must be highly similar in structure and function, equivalent in efficacy, and comparable in safety and immunogenicity to its reference product, despite potential slight molecular differences between the two agents.

Nomenclature for biosimilars in the U.S. uses the common nonproprietary name followed by a 4-letter suffix, so that each drug, both reference product and biosimilar, will have a unique nonproprietary name. Proprietary names, in contrast, are generated by the manufacturer and may vary from country to country for the same drug.

As of Dec. 31, 2017, the FDA had approved the following biosimilars, listed with their reference product, for use for rheumatologic conditions:

Many additional biosimilars of reference products with indications for both rheumatologic and nonrheumatologic diseases are under development.

The white paper discusses in detail the:

• Regulatory pathways for approval;
• Immunogenicity and scientific aspects of manufacturing;
• Extrapolation of indications, switching and substitution, and interchangeability; and
• Economics of biosimilars and patient access.

For all biosimilars, regulatory agencies expect that clinical trials will include a single crossover from the reference product to the proposed biosimilar, to assess whether this transition induces antidrug antibody formation with a resultant loss of efficacy. If a biosimilar is intended for long-term administration, as is the case for rheumatologic indications, the white paper authors recommend that immunogenicity data be acquired over at least one year.

An important implication of the comparative immunogenicity studies carried out to date is that a patient who develops antibodies to a reference drug with resultant loss of clinical response should not be switched to its biosimilar.

Although none of the biosimilars approved to treat rheumatologic and other inflammatory diseases has been studied in children, several have been approved for pediatric indications by extrapolation.

The authors state that postmarketing surveillance of biosimilars should be conducted in children and adolescents, as well as in adults.

Insurance companies and PBMs will continue to play key roles in determining the economic impact of biosimilars, according to the authors. Even under ideal circumstances, it will likely take several years for overall savings to the U.S. health system from the use of biosimilars to be realized.

The white paper concludes: “it is reassuring to recognize the scientific rigor with which the FDA and other regulatory agencies around the world have evaluated biosimilars. Healthcare providers should now incorporate biosimilars, where appropriate, into regimens to treat patients with rheumatologic diseases. It is important to maintain a working knowledge of approved biosimilars and to monitor evolving policies and guidelines regarding the development and use of new biosimilars. …

“Communication between providers, pharmacists and patients will be critical to alleviate anxiety and reduce skepticism regarding the use of these newly available agents. We remain optimistic that the use of biosimilars will improve patient access to biologic agents, allowing continued delivery of high-quality healthcare to be realized at a lower cost to the individual patient.”

Excerpted and adapted from:

Bridges SL Jr., White DW, Worthing AB, et al. The science behind biosimilars: Entering a new era of biologic therapy. Arthritis Rheumatol. 2018 Mar;70(3):334–344.