Biobetter Development

The biologic drug segment has both expanded rapidly and evolved technologically over the past three decades. Many biopharmaceutical drugs have also reached blockbuster status. Some have already lost patent protection, and many more will during the next decade. All will face competition from biosimilars, which are increasingly accepted by doctors and patients. Biobetters—improved versions of the originator biologic offering advantages such as enhanced efficacy and safety, reduced side effects, and more attractive administration options and dosing frequencies—provide an alternative to biosimilars with greater potential for differentiation in the market. Increased understanding of disease pathologies and more advanced capabilities in the design, engineering, and manufacturing of biologics are leading to growth of the biobetters market, which is predicted to expand at a compound annual growth rate of approximately 8% over the next five years (1,2)

Manufacturing and product performance improvements

Drug developers pursue biobetters to improve the treatment of diseases, overcome the limitations of existing drugs, and better meet the needs of patients, contends Ulrike Herbrand, scientific director, global in vitro bioassays with Charles River Laboratories. “Biobetters are novel drugs that represent an improvement on the original drug and have advantages over the original drug,” she says.

Better treatment options are achieved through improved properties. Examples, according to Herbrand, include a longer half-life, higher stability and selectivity, increased specificity, reduced toxicity and immunogenicity, and/or a different route of administration. “All these factors are related to better efficacy, safety, or patient-friendliness,” she remarks.

Those improved properties can be realized by leveraging innovations in production technology, Herbrand says. “Greater understanding of human biology has enabled identification of opportunities to improve the molecular structure of originator molecules. Advances in cell-line engineering, cell culture processes, and process analytical technologies, meanwhile, enable better control of process parameters and thus more precise control of post-translational modifications and other important quality attributes,” she explains. Similarly, advances in formulation science make it possible to improve upon the formulation of the original therapeutic drug.

There is also an important market driver for the development of biobetters. “Unlike biosimilars,” Herbrand states, “biobetters are considered new drugs and therefore benefit from market exclusivity rights, even if they have similarities to existing therapeutics.”

Chemical modifications

Common chemical modifications include revising the glycosylation profile with the intention of improving the stability, pharmacokinetics, and immunogenicity of the originator biomolecule, according to Herbrand. PEGylation (attachment of polyethylene glycol to proteins) and sialylation (covalent addition of sialic acid to the terminal end of glycoproteins) are also well-known to improve the half-life, reduce immunogenicity, and enhance solubility, she adds.

Another important strategy is to modify the amino acid sequence of the protein. “Such changes can achieve enhanced efficacy and/or reduced side effects as well allow for engineering of the protein structure so it exhibits improved folding properties, which lead to both better stability and function,” Herbrand comments.

If the originator biomolecule is derived from proteins not of human origin, another chemical modification that is often employed is humanization to make the drug substance more like human proteins, according to Herbrand. This change reduces the risk of immune reactions.

Structural modifications

Beyond changing the amino acid sequence, more significant structural modifications are often employed in biobetter development to enhance in-vivo performance. One of the most common structural changes, says Herbrand, is optimization of the binding site to improve its interactions with the target receptor and thus overall function.

As an example, Herbrand points to engineering of the complementarity-determining regions (CDRs) of antibodies. “These are the variable regions of an antibody that directly interact with the target antigen. Rational engineering of CDRs can improve binding affinity and specificity, which can lead to better therapeutic outcomes,” she observes. It is also possible to introduce charged amino acids (so-called charged mutations) near the edges of CDRs to enhance solubility and reduce aggregation. The latter can also be reduced/prevented by introducing other mutations to generate aggregation-resistant domain antibodies, Herbrand adds.

Increasingly, computation approaches are used for structure-based optimization during biobetter development. For instance, predictive computational strategies support the assessment of developability risks early in the lead candidate discovery phase, according to Herbrand. Computational modeling also helps identify key residues involved in binding to optimize binding affinity and predict solubility and stability properties and the potential risk of aggregation.

Changes in formulation

Biobetters can offer advantages other than those related to their quality, stability, safety, and therapeutic efficacy. A key goal of drug developers today is to provide medicines that take into consideration the specific needs of the target patient population so they are easy and convenient to use. As a result, a key aspect of biobetter development includes modification of the formulations of originator drugs to allow for greater patient-centricity.

“Changes in a formulation to support another route of administration, such as allowing the switch from intravenous to subcutaneous delivery, can make the patient experience more convenient and lead to healthcare savings,” notes Herbrand. “Higher concentration formulations, for instance, lead to a reduced application volume and thereby allow for administration via auto-injection devices, which is crucial for patients with chronic diseases (e.g., asthma, diabetes, colitis, or arthritis) who are dependent on regular drug administration,” she adds.

Formulation changes also involve using excipients that enhance drug stability, solubility, and bioavailability, Herbrand comments.

Leveraging technological developments

Protein engineering, including site-directed mutagenesis, molecular dynamics, PEGylation, sialylation, and bioconjugation, remains a foundational technology for biobetter development, with advances occurring in many of these areas, according to Herbrand. “Application of nanotechnology to drug design and development is a newer addition to the portfolio of engineering capabilities, with examples including formation of drug products as encapsulated or immobilized nanoparticles to improve pharmacokinetics,” she says.

One development area of particular interest to Herbrand is antibody-drug conjugate (ADC) biobetters. ADCs combine the tumor-targeting properties of antibodies and the cytotoxic potency of chemotherapeutics with the goal of delivering destructive compounds specifically to cancer cells while minimizing damage to healthy tissue. On the innovator side, Herbrand notes that manufacturers are currently working to identify new targets and/or payload mechanisms of action (MoAs).

ADC biobetter development, meanwhile, is focused on ADCs that leverage established target/payload MoA combinations but incorporate novel delivery components to achieve a best-in-class profile. “Non-specific and insufficient payload delivery remains a challenge with approved ADCs. Issues include premature payload release, poor tumor penetration, variable drug-to-antibody ratios, and aggregation,” Herbrand explains. Next-generation ADC technology aims to improve these aspects (3).

Always a balance between costs and benefits

Biobetters are designed to be an upgrade from existing therapeutics with structural or chemical changes that lead to improved efficacy and safety, lower side effects, and other advantages. “These improvements must lead to measurable benefits for patient and healthcare systems to justify the necessary developmental efforts and costs and to support regulatory approval,” states Herbrand.

As a result, the choice to pursue biobetter development depends on both safety and cost-benefit considerations, according to Herbrand. “Intensive research is needed to optimize therapeutic products, but it is not always the case that attempts to change and optimize an originator biomolecule will lead to better results. The efficacy or safety may not be sufficiently improved, and without superior performance there is no point in advancing such projects. It is also possible the cost-benefit ratio will not be clearly in favor of the biobetter, leading healthcare systems and patients to prefer the originator product or a biosimilar,” she explains.

The benefits, therefore, must be carefully weighed against the resources invested in biobetter development, Herbrand concludes.

References

1. Grand View Research. Biobetters Market Size, Share & Trends Analysis Report By Drug Class, by Application, by Route of Administration, by Distribution Channel, by Region, and Segment Forecasts, 2023–2030. Grandviewresearch.com (accessed June 3, 2024). https://www.grandviewresearch.com/industry-analysis/biobetters-market-report
2. Mordor Intelligence. Biobetters Market Size & Share Analysis–Growth Trends & Forecasts (2024–2029). Mordorintelligenc.com (accessed June 3, 2024). https://www.mordorintelligence.com/industry-reports/biobetters-market
3. Sasso, J. M.; Tenchov, R.; Bird, R.; Iyer, K.A.;, Ralhan, K.;, Rodriguez, Y.;, and Zhou, Q.A. The Evolving Landscape of Antibody-Drug Conjugates: In Depth Analysis of Recent Research Progress. Bioconjug Chem 2023 34 (11), 1951–2000. DOI: 10.1021/acs.bioconjchem.3c00374

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 7
July 2024
Pages: 14–15, 19

Citation

When referring to this article, please cite it as Challener, C. Biobetter Development. Pharmaceutical Technology 2024 48 (7).