Opportunities and Challenges in Biosimilars Development
Biological drugs constitute one of the largest growing sectors of the pharmaceutical industry, with total global sales in 2010 exceeding $110 billion. With patents for the top-selling biologics either already expired or due to expire within the next decade, there is a growing interest in developing biosimilars. There is a potentially large demand for these driven by the need of health care payers to curb escalating drug costs and the increasing demand for effective but costly biological drugs.
Monoclonal antibodies represent the largest sector of the biologics market and a significant opportunity for biosimilars developers, driven by the rising incidence and prevalence of cancer and the therapeutic success of these targeted therapies. Patents for top-selling monoclonal antibody drugs such as Remicade (infliximab, J&J), Humira (adalimumab, Abbott), Avastin (bevacizumab, Roche), MabThera/Reditux (rituximab, Roche/Biogen Idec), and Herceptin (trastuzumab, Roche) will expire within the next decade, opening the door for biosimilars. Anti-inflammatory fusion proteins such as Enbrel (etanercept, Amgen/Pfizer) and Orencia (abatacept, BMS) represent another prime target for biosimilars development as both products are successful treatments for rheumatoid arthritis and psoriasis. Insulins, epoietins, cytokines such as granulocyte colony stimulation factor (G-CSF), interleukin-2 (IL-2) and interferons, and growth hormone constitute the remainder of the significant opportunities for biosimilars. These various products differ in their complexity and consequently the degree of technical challenge to producing a biosimilar. For example, monoclonal antibody drugs have complex glycan structures which are a function of the expression system used in manufacturing the drug. Even small differences in glycosylation profile can translate into a difference in clinical efficacy. Therefore, while not identical to the reference product, a biosimilar drug product is one that shows highly comparable structure, pharmacokinetics and pharmacological activity to the innovator. The basis of biosimilar drug development is demonstrating the degree of comparability to the innovator drug that is required for regulatory approval in the target jurisdiction.
European regulators were the first to develop a legal pathway for marketing approval of biosimilars once patent protection on the innovator product has expired in the relevant jurisdiction. The EMA has issued a number of guidelines for developing biosimilars, including product specific guidelines, the two most recent being the draft “Guideline on similar biological medicinal products containing monoclonal antibodies” and the draft “Guidline on similar biological medicinal products containing interferon beta”. In the US, as part of the health care reform legislation signed into law in March, 2010, a biosimilar regulatory pathway for approval was defined under the “Biologics Price Competition and Innovation Act”. The FDA issued three draft guidances on biosimilars in February 2012, providing a framework for the development of these products and recommending a stepwise approach to demonstrate biosimilarity. As a result of the delay in regulatory developments in the US versus Europe, the initial focus on biosimilar development for regulated markets has been in the EU rather than in the US although this is now poised to change.
A risk-based approach for non-clinical studies supporting biosimilar development includes in vitro pharmacodynamic studies, and in vivo studies, if warranted, to assess PK, PD and/or safety. Comparison of the PK properties of the biosimilar and the innovator drug forms a key part of the clinical development program. The design of this clinical study depends on the PK characteristics and pharmacological activity for each particular biologic and may range from a single dose study in healthy volunteers to a multidose PK study in patients. If specific PD endpoints are available, PK/PD studies can be conducted to compare dose-concentration-response relationships of the biosimilar and innovator reference product. However, for many biologic drugs lacking specific PD endpoints, clinical efficacy will require conducting a comparative clinical study in a sensitive patient population using an adequately powered, randomized, parallel group design.
All biotechnology products, including biosimilars, have the potential to be immunogenic, something that is generally not associated with chemically-synthesized small molecule drugs. Evaluating the comparative immunogenicity of the reference product and the biosimilar in a clinical study is a critical component of the safety assessment needed for marketing approval in the EU. Such a study requires having validated assays to detect antibodies against the innovator and biosimilar, and it can be logistically challenging to obtain appropriate patient numbers, particularly if the incidence of immunogenicity is low.
Biosimilar developers benefit by having an integrated approach to the research services needed to complete the preclinical and early clinical development activities and regulatory strategy for their proposed product. Celerion has partnered with Ricerca Biosciences to form The Biosimilars Alliance and bring together the specific expertise required to guide clients through the complex development process. The formation of The Biosimilars Alliance was based on client demand for an integrated service solution for the development of biosimilar products and leverages over 20 years of experience in biologic drug development.
The Biosimilars Alliance offers convenient access to all of the specialized services required to perform early assessment of the viability of a potential biosimilar product before beginning costly multi-center comparator studies in the target patient populations. These services include in vitro and in vivo pharmacological assessments of activity and toxicological and immunotoxicological studies to support CTAs and INDs. Importantly, The Biosimilars Alliance also provides access to bioanalytical assay development to enable pharmacokinetic (PK) and pharmacodynamic (PD) assessments in animal and human studies, PK/PD modeling, immunogenicity screening during clinical studies and the regulatory and integrated project management support to ensure timely results for strategic decision-making.
For more information on how The Biosimilars Alliance can assist in your biosimilars drug development needs, please contact us.