Zydus Cadila, an Indian biopharmaceutical company, has launched the world’s first biosimilar antibody-drug conjugate of trastuzumab emtansine. The biosimilar, which uses Genentech/Roche’s trastuzumab emtansine (Kadcyla®) as the reference product, will be marketed under the name Ujvira®.

The development of biosimilar drugs is a complex endeavor and industry leaders focusing on this development of antibody-drug conjugates say that this development is a milestone proving that the ADCs have come to age.

“The launch of Ujvira reinforces the innovation capabilities that India has to be able to create complex therapies like ADCs and Zydus’ ongoing commitment to offer breakthroughs backed by science and innovation,” said Sharvil Patel, MD, Managing Director of Cadila Healthcare.

“This research breakthrough enables access to a critical drug for patients who are undergoing therapy for breast cancer. We hope that with this innovation, patients will be able to adhere to the treatment and stand to benefit from the advanced technology without worrying about the cost of the treatment.”

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Breakthrough
Developing a biosimilar form of trastuzumab emtansine is a developmental breakthrough due to its complexity in manufacturing and similarity assays.

The concept of biosimilar drugs and the framework to develop these agents, was official established by European regulators in the early 2000s. The the years following, regulatory frameworks for the develoipment of biosimilar was also been established in the United Startes, Japan, and other countries. As a results, since 2018, biosimilars versions of like infliximab, adalimumab, rituximab, trastuzumab, and bevacizumab have been approved. [1][2]

In general terms, to be called a biosimilar, regulators must conclude that a drug is highly similar to the original biologic – or reference drug – and that it has no clinically meaningful differences from the original. Only minor differences in clinically inactive components are allowable in the development of biosimilar products.

This means that patients can expect the same safety and effectiveness from the biosimilar over the course of treatment as they would from the original reference product. Hence, before approving a drug as a biosimilar, a thorough evaluation is required that helps to ensure that a biosimilar product is as safe and effective and meets the regulator’s high standards for approval.

Rigorous analytics
The process for biosimilar development of drugs like ADCs, involves rigorous analytical studies to establish a comprehensive understanding of the similarity and quality of the biosimilar to the reference product. For therapeutic antibodies including trastuzamab, quality attributes include FcRn binding and related structures which are known to affect the pharmacokinetic profile of the product. Antigen binding, glycan structure, and isoelectric point are also considered to have a potential impact on the pharmacokinetic profile of the product. By using multiple state-of-the-art analytical methods, scientistsare able to extensively characterize protein structures so that the reference product and biosimilar can be directly compared.  In turn, this ensure comparability of both functional integrity and performance of the biosimilar in vivo. The results of the analytrical comparisons, with respect to the structure and function of the molecule, provides the foundation for the ongoing development, which, in part, builds on the clinical experience with the reference biologic.[1][2]

In addition, regulators also have stringent requirements for the manufacturing of biosimilars. In general, they want to see that the same quality manufacturing standards that apply to the original biologic also apply to the biosimilar. Further, biosimilars must be manufactured in accordance with Current Good Manufacturing Practice requirements, which cover methods, facilities, and controls for the manufacturing, processing, packaging, or holding of a drug product. Overall, these requirements help to prevent manufacturing mistakes or unacceptable impurities and to ensure product quality.

Antibody-drug conjugates combine the targeting capabilities of monoclonal antibodies with the cancer-killing ability of anti-cancer cytotoxic drugs. Drug developers at Zydus had to make sure thst they met the these requirements in developing an ADC biosimilar, which combines trastuzumab (the antibody) and the cytotoxic anti-cancer compound emtansine (or DM1) linked via a stable linker.

Lower costs
One of the promises made by Zydus is that the new therapy will be priced at nearly 80% less than the currently available option in the market.

Developed in-house, the antibody-drug conjugate is considered to be one of the most complex technologies in drug development. Ujvira is not yet approved by the FDA for distribution in the United States.

Highlights of prescribing information
Trastuzumab emtansine (Kadcyla®; Genentech/Roche) [Prescription information]

Reference
[1] Ishii-Watabe A, Kuwabara T. Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies. Drug Metab Pharmacokinet. 2019 Feb;34(1):64-70. doi: 10.1016/j.dmpk.2018.11.004. Epub 2018 Dec 7. PMID: 30600193.
[2] Vulto AG, Jaquez OA. The process defines the product: what really matters in biosimilar design and production? Rheumatology (Oxford). 2017 Aug 1;56(suppl_4):iv14-iv29. doi: 10.1093/rheumatology/kex278. PMID: 28903544; PMCID: PMC5850795.

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