Orlando, FL—Expect biosimilars to be adopted into clinical rheumatology practice in the United States before long. Biosimilars are not simply generic biologic products but instead must demonstrate similar biological activity in a patient without being “biosuperior,” said Grace C. Wright, MD, PhD, at the 2015 Annual Conference of the Rheumatology Nurses Society.1
Issues surrounding the process of creating a biosimilar, from manufacturing to regulatory approval, were reviewed by Wright, Clinical Associate Professor of Medicine and Attending Rheumatologist, New York University Langone Medical Center, New York City.
The Recipe for Biologics
Biologics are large proteins made in living cell systems and are more complex than chemically synthesized small molecules. To understand the biosimilar process, one must understand how biologics are made, she said.
The recipe for a biologic starts with isolating the gene encoding the protein of interest, then inserting the gene into a plasmid or viral vector, transfecting a host cell (hamster, rabbit, bacterial), and growing the host cell in culture to produce the desired protein. The human protein is then isolated from the cells, and the cells are either separated from the soluble components or lysed to release the protein product. Once the protein is purified, its purity is verified through confirmed testing protocols.
After the attributes of the protein product are characterized and the protein is formulated according to specifications, it is distributed for testing in clinical trials or for use after regulatory approval.
“The properties of biologics are dependent on the manufacturing processes, which may be similar but not identical between manufacturers,” Wright said. It is important to realize that lot-to-lot variability can occur with reference biologics. Analytical and biological studies are conducted to evaluate and confirm that there are no significant changes to the potency, safety, or immunogenicity of the final product.
A biosimilar is not the same as a generic product. The active ingredient in a generic is required to be identical to the active ingredient in the brand product. A biosimilar product is engineered in an upside down manner, first by characterizing the reference product and then establishing a product quality profile for the reference product, including protein sequence, functional attributes, and ranges of variability. The manufacturing process cannot be duplicated exactly.
“Each biologic or biosimilar is manufactured using a unique cell line,” said Wright. “The final product is expected to be highly similar but not identical.”
Monoclonal antibodies are among the most structurally complex proteins, with multiple mechanisms of action, Wright explained. They are heterogeneous, and scans show significant changes in biological effects from small structural changes. She noted that what looks like a minuscule thing can have a substantial effect on the function, “so we need to have strict manufacturing codes in place to guard against this.”
An abbreviated licensure pathway for biosimilars is intended to reduce the length of time for getting biosimilars to market. In addition to demonstrating biosimilarity (producing the same clinical result), the manufacturer must include information to show that the biosimilar is interchangeable with the reference biologic. In this way, a biosimilar can’t be “biosuperior” to the reference product, she said. Efficacy and potency cannot be greater than the reference product.
Clinical Trials of Biosimilar Candidates
Biosimilar candidates in progress include adalimumab, infliximab, and etanercept. Three studies that Wright reviewed were presented at the 2015 annual meeting of the European League Against Rheumatism.
A 3-arm, single-blind, phase 1 study in healthy participants compared an adalimumab biosimilar candidate called SB5 with a European Union (EU)-sourced adalimumab product and US-sourced adalimumab.2 The study demonstrated pharmacokinetic bioequivalence between SB5 and EU adalimumab, SB5 and US adalimumab, and the 2 reference products, with no significant differences in immunogenicity between the 3 groups.
A phase 1 study of an infliximab biosimilar (SB2) in healthy individuals demonstrated pharmacokinetic bioequivalence between SB2 and the EU-sourced infliximab, between SB2 and US-sourced infliximab, and between the 2 reference products, with similar immunogenicity.3
A phase 3 study of SB4, an etanercept biosimilar candidate, was conducted in patients with moderate to severe rheumatoid arthritis despite previous treatment with methotrexate.4 The study results showed that SB4 was equivalent to etanercept in terms of the American College of Rheumatology 20% response rate with a comparable safety profile, but with a significantly lower immunogenicity profile (antidrug antibody formation: SB4 0.7% vs etanercept reference 13.1%; P <.001). Postmarketing studies will need to be conducted to understand the implications of the difference in immunogenicity, said Wright.
Manufacturers will not be required to demonstrate clinical comparability for every disease state for which a biosimilar will be used, she said.
- Wright GC. Biosimilars: a clinical perspective. Presented at: 2015 Annual Meeting of the Rheumatology Nurses Society; August 6-8, 2015; Orlando, FL.
- Shin D, Kim Y, Kim HS, et al. A phase I pharmacokinetic study comparing SB5, an adalimumab biosimilar, and adalimumab reference product (Humira®) in healthy subjects. Ann Rheum Dis. 2015;74(suppl 2):459. www.abstracts2view.com/eular/view.php?nu=EULAR15L_FRI0110.
- Shin D, Kim Y, Kim YS, et al. A phase I pharmacokinetic study comparing SB2, an infliximab biosimilar, and infliximab reference product (Remicade®) in healthy subjects. Ann Rheum Dis. 2015;74(suppl 2):703. www.abstracts2view.com/eular/view.php?nu=EULAR15L_SAT0144.
- Emery P, Vencovský J, Sylwestrzak A, et al. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy [published online July 6, 2015]. Ann Rheum Dis. doi:10.1136/annrheumdis-2015-207588.