ProtaGene Weighs in on the Future of the Biosimilars Market

The biosimilars market is about 20 years old, and ProtaGene has been involved since its beginning. What has ProtaGene learned, and what has changed over these 20 years?

André: We have 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, trastuzumab, and finally turning to immune checkpoint mAbs or biospecifics. Some of our colleagues still remember how partly unreal yet overly satisfying it felt to hold the first biosimilar drug pack in their hands.

Twenty years ago, we knew very little about biosimilars in terms of how to analyze and characterize molecules. Regulatory guidance and approval structures were also non-existent. On the generics side, you merely have to reverse engineer the chemical structure, fully matching the molecule’s structure. When the structure is the same, you can be confident that you have a product that will perform the same. However, biologics do not work this way.

When working with biologics, you have to determine which characteristics deliver the needed therapeutic performance and safety profiles. When biosimilar development started 20 years ago, analytics programs were massive. We were trying to fully characterize every aspect of the molecule because the industry and regulators were not confident in their understanding of the specific characteristics driving the desired mechanisms of action. Analytical programs were extensive, time-consuming, and costly.

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

What is the most meaningful change within today’s biosimilars market?

Roland: Perhaps the most significant advancement for the biosimilars market is the potential end to phase III trials. Over the past two decades, there has been much progress in assay technology advancements and a growing understanding of the impact of molecule variations on efficacy and safety.

Monitoring and testing processes can cover more data and go a long way to demonstrating that a biosimilar is similar to its reference product. Against this backdrop, many in the industry question the need for phase III testing in biosimilar development.

Considering scientific and regulatory experience gained since the first biosimilar product was licensed in the EU in 2006, the UK’s MHRA states that clinical comparability should always include pharmacodynamic markers if available. In contrast to EMA and FDA, the UK guidance also considers that a comparative efficacy trial may not be necessary in most cases if sound scientific rationale supports this approach.

André:  From our experience, encompassing phase I studies leave little uncertainty about the equivalence of a biosimilar and its originator. However, this means that even in the earliest studies, more assays must be performed and more samples analyzed to explain any differences directly.

Our experience and access to different originators allow us to understand structure-activity relationships from the earliest stages of development through process development and the manufacturing floor. Above all, our extensive know-how and experience ensure that our comprehensive CMC packages provide sufficient information to demonstrate biosimilarity.

Ultimately, we believe that the EMA and FDA will align with the MHRA’s position, which concluded that robust CMC understanding from the earliest phases of development eliminates the need for a comparative efficacy trial.

Why is analytical expertise foundational for leveraging opportunities in the biosimilars market?

André: 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 expertise and capabilities 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 (QTPP) of the reference product is established, defining the targets the biosimilar must achieve.

Extensive characterization of the reference product, analytical expertise, and perspective that comes from experience are required to create a QTPP and assure that the biosimilar is moving toward these targets throughout its development.

Roland: 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 intention modifications such as changes to glycosylation patterns must be evaluated 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.

Additionally, functional studies such as binding assays and enzyme kinetics must be performed on multiple batches of product to thoroughly understand how the molecule behaves.

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.

Are current characterization and analytical capabilities strong enough to support the elimination of phase III studies?

Roland: Yes. At least speaking for the ProtaGene organization, we believe our characterization capabilities and expertise are robust enough to support the elimination of phase III, or the comparative efficacy trial, in many cases.

These studies cost a great deal, and if the product’s critical quality attributes (CQAs) are well characterized and well understood and the phase I trial confirms the safety of the product, we believe phase III trials can often be eliminated. We believe that there is an argument for phase III elimination to at least be on the table when a biosimilar development organization sits down with regulators early in their development process to discuss their holistic development plan.

When a product is well characterized and well understood, the learnings from a phase III study are minimal, yet the costs and time required are very significant. This added cost and time to market slows the availability, delaying patients’ access to these therapeutics.

How does manufacturing process understanding tie into biosimilar product development?

André: In essence, manufacturing processes for biosimilars must be “reverse engineered” as the details of a reference product’s manufacturing processes and manufacturing inputs are not publicly available.

The cell line selection and expression approach are critical decisions that can affect biosimilar translational and post-translational modifications and significantly contribute to the number and nature of product impurities and contaminants.

However, in our experience, it is critical to avoid locking oneself into one cell line. Instead, different lines are examined because focusing on incremental adjustments to one cell line can result in a dead-end and wasted time.

Analytical and characterization exercises are also fundamental to assuring upstream process development, downstream process development, and the product’s formulation, which result in the defined CQAs.

What are the biggest challenges within biosimilar development programs?

André: What is similar enough has been the pressing question since initial biosimilar development efforts began 20 years ago. Which differences can you justify because the differences are negligible, and which are critical and need attention?

Sometimes a 1-2% difference in the molecule can profoundly affect the mode of action. Other times, there can be a 10-15% difference in an attribute, for example, the glycan profile of the molecule. However, if the glycan profile is not important to the mode of action for that specific molecule or PK profile, even this seemingly large difference is unimportant.

Successful biosimilar programs and regulatory approvals rely on these understandings. Ultimately, biosimilar programs require much knowledge, experience, and expertise. We are in an excellent position in these regards due to our extensive engagement and wealth of experience in the development of biosimilars here at ProtaGene.

Interestingly, biosimilar developers arguably understand originator molecules better than the originator developers themselves. The highly detailed analytics and characterization needed for biosimilar efforts are more in-depth than the understanding required for initial approval. This extensive knowledge of the biosimilar developer is the basis for the current discussion that a deep characterization of the biosimilar candidate and the originator might be sufficient to skip the phase III studies.

When you look across the market, how does ProtaGene’s approach to biosimilar development differ from other players in the space?

Roland: Achieving biosimilarity is not a check-box exercise; extensive experience and scientific rationale are required.

We are extremely current with the evolving expectations of global regulatory bodies. Acceptance of our data in our customers’ MAA and BLA dossiers demonstrates that our high-quality, strategic partnership approach with our customers for more than 20 years has led to successful developments for our customers worldwide.

André: We do a very detailed characterization of the originator product very early on to support thoroughly defining CQAs and understanding degradation kinetics. Ultimately these insights support robust process development programs and smooth journeys to the manufacturing floor.

Detailed characterization early in the development process positions the process development work, and ultimately manufacturing processes, to go in the right direction.