Opportunity Abounds as the Biosimilars Market Prepares for the Next Biologics Patent Cliff

The biopharmaceutical industry’s first patent cliff occurred beginning in 2010, and twelve years later, many of the best-selling biological drugs worldwide are again poised to lose patent protection. However, the biosimilars market is positioned much differently than it was twelve years ago. Advancing analytical and characterization technologies, legislative and regulatory support within the world’s leading markets, and the biosimilar development experience gained put the market in a much more advantageous position to leverage this next pending patent cliff.

In fact, the global biosimilars market is expected to reach USD 44.7 billion by 2026 from USD 15.6 billion in 2021, at a CAGR of 23.5% during this period.

Analytical Excellence Is Imperative for Biosimilars Developers to Capitalize on This Next Biologics Patent Cliff

Regulatory approval of biosimilars is based on the totality of evidence supporting the comparability of the proposed biosimilar to the reference product. The basis for establishing this compatibility is a detailed characterization of the reference product’s quality attributes, including structural, functional, and other analytical properties.

Extensive characterization, analytical expertise, and experience are required to deeply understand how a variation of any attribute directly impacts the efficacy or safety of the reference product. Ultimately, a quality target product profile of the reference product is established, defining the targets the biosimilar must achieve.

Currently, both the FDA and EMA recommend a step-wise approach to assess and demonstrate evidence of biosimilarity. These steps include structural and functional studies, animal studies, and human clinical studies.

Structural studies must evaluate multiple lots or batches of the proposed product. Characteristics such as amino acid sequence and composition, higher-order structure including secondary and tertiary structure, post-translational modifications of the protein, chemical modifications, and intentional modifications such as changes to glycosylation patterns must be determined to establish biosimilarity.

Physicochemical properties like molecular weight and/or size, isoform pattern, extinction coefficient, electrophoretic pattern, liquid chromatographic patterns, and spectroscopic profiles must also be well understood.

Functional studies such as binding assays and enzyme kinetics must be performed on multiple batches of product to understand how the molecule behaves thoroughly. In addition to structural/functional studies, animal studies are often utilized to compare toxicity, pharmacokinetic and pharmacodynamic (PK/PD) properties, and immunogenicity. Finally, human trials, commonly structured as double-blind studies with the reference product, are currently required to demonstrate no meaningful difference between the biosimilar and reference product.

20 Years of Experience Supports Today’s Market Opportunities

ProtaGene has supported more than 80 biosimilar programs within the last two decades. First-generation programs included filgrastim, EPO, and insulin, later flanked by the first mABs like adalimumab, arastuzumab, and finally turning to immune checkpoint mABs or biospecifics. Some ProtaGene team members still remember how partly unreal yet overly satisfying it felt to hold the first biosimilar drug pack in their hands.

However, twenty years ago, we knew very little about biosimilars in terms of how to analyze and characterize molecules. Regulatory guidances and approval structures were also nonexistent. On the small molecule generics side, one can reverse engineer the chemical structure, fully matching the molecule’s structure, and then emulate the solid form and formulation properties. When structural properties are the same, there is a reasonable expectation that the product will perform similarly. However, biologics do not work this way.

When working with biologics, one must determine which characteristics of the molecule deliver the needed therapeutic performance and safety profiles. When biosimilar development started 20 years ago, the analytics programs were massive. We were trying to fully characterize every aspect of the molecule because the industry and regulators were not nearly as confident in the specific characteristics driving the desired mechanisms of action. Analytical programs were unwieldy in these early days of the biosimilars market—extensive, time-consuming, and costly.

Today, we are much more confident in our understanding of these molecules. As a result, biosimilar analytics and characterization programs are much more targeted, faster, and more cost-effective. This progress, coupled with process development and manufacturing process understanding, is truly helping to advance the field.

Pending Elimination of Phase III Studies Further Support Opportunities in the Biosimilars Market

Leading global regulators and industry are currently collaborating to conclude whether current characterization, analytical capabilities, and biologics understanding are now strong enough to support the elimination of phase III, comparative efficacy, studies.

While the FDA and EMA remain undecided on the issue, the UK’s MHRA has concluded that clinical comparability should always include pharmacodynamic markers if available but has determined that a comparative efficacy trial may not be necessary if sound scientific rationale supports the elimination of the study.

We agree with the MHRA’s position. At least, speaking for the ProtaGene organization, our characterization capabilities and expertise are robust enough to support the elimination of phase III in many cases.

These studies cost a great deal, and if the product’s critical quality attributes are well-characterized and well-understood, and the phase I trial confirms the product’s safety, we have found that little additional knowledge is gained from phase III trials.

Phase III studies add costs and lengthen the time to market, delaying patients’ access to these therapeutics. The elimination of comparability trials will remove a significant barrier to entry, further driving investment in biosimilars investment.

ProtaGene Is Supporting the Next Wave of Biosimilars Development

Achieving biosimilarity is not a check-box exercise; extensive experience and scientific rationale are required. ProtaGene is extremely current with the evolving expectations of global regulatory bodies, and acceptance of our data in our customers’ MAA and BLA dossiers demonstrates that our high-quality, strategic partnership approach leads to success.

Having invested 20 years of time and resources amassing biosimilar development expertise, we are confident that we are well-prepared to help our clients capitalize on this next wave of opportunity.

ProtaGene now has a significant presence in Europe and North America to prepare for this and other opportunities. We currently operate four laboratories, including a brand-new, state-of-the-art laboratory in the Burlington Bio Center, located in suburban Boston’s rapidly growing biotechnology hub.

We are excited about the biosimilars market’s growth and look forward to supporting the many new programs that are manifesting. Contact us if we can help support your biosimilars development program.

About the Author

Roland Moussa, PhD

Roland Moussa, PhD, is the President of ProtaGene. Previously, Dr. Moussa was the Chief Operating Officer and Senior Vice President of Biologics at Protagen Protein Services. In this role, he provided leadership and oversight of corporate development strategy and cross-functional operations at a company-wide executive level. When first joining PPS in 2015, he served as Director of Operations for the Dortmund site.

His academic background is rooted in two major pillars, namely Biotechnology and Bioinformatics, as he holds a PhD in Molecular Biotechnology from the University Düsseldorf and a Master of Science in Molecular Biotechnology from the RWTH Aachen. Earlier, he earned his Bachelor of Science in Bioinformatics and Genome Research from the University of Bielefeld and a certified computer