Assessing Development Needs for Biobetters and Biosimilars

Development requirements and regulatory guidance for biosimilars and biobetters.
Feb 01, 2013
By BioPharm International Editors
Volume 26, Issue 2

Christina Satterwhite, PhD
During the past 30 years, biotherapeutics have emerged as targeted drugs for indications such as cancer, autoimmune diseases, and hormone/enzyme disorders. Because of their specificity and generally reduced toxicity profiles, biotherapeutics have gained market share from classic small-molecule therapeutics. The invention of recombinant DNA technologies in the early 1980s as well as enhanced biomanufacturing procedures over the past several decades have driven growth, giving rise to complex drug products including cytokines, growth factors, fusion proteins, enzymes, hormones, and monoclonal antibodies (mAbs). Despite continued progress, biotherapeutic development is costly and can take up to 15 years from discovery to market with the total cost estimated to be $100 million to $1 billion per molecule (1). With many approved biotherapeutics coming off patent in the next several years, a new market for biologic products such as biosimilars and biobetters/biosuperiors is gaining ground.

Follow-on biologics, which include biosimilars and biobetters, are approved subsequent versions of innovator biopharmaceutical products, typically made by a different sponsor following or nearing expiration of patent protection of the innovator product. Biosimilars are follow-on biologics that have the same molecular profile as the reference product. Biobetters include modifications to the originator molecular profile with the specific aim to enhance the efficacy, thereby marketing a superior product. Biobetter companies accomplish this through chemical (e.g., polyethylene glycol [PEG]) or molecular (e.g., recombinant gene technology site-directed mutagenesis or amino acid additions) modifications with functional changes that include, but are not limited to, increased half-life, reduced toxicity, reduced immunogenicity, and enhanced pharmacodynamic effects (2).

There are an increasing number of examples of companies using biobetter strategies for improvement of innovator products. For instance, Pegasys (peginterferon alfa-2a) marketed as a biobetter by Genentech, a member of the Roche group, was re-engineered to increase the half-life relative to the innovator interferon drug product, Roferon, which was originally marketed by Hoffmann-La Roche (3). Xencor is an example of a company marketing proprietary protein engineering using its XmAb technology to enhance Fc effector function (i.e., antibody-dependent cell-mediated cytotoxicity, ADCC), and EpiVax uses in silico technologies to reduce T-cell epitopes in an effort to reduce immunogenicity.


Several innovator biotechnology companies have made strategic decisions to produce biobetters in an effort to maintain the market share of their innovator products. For example, in 2010, MedImmune, the biologics arm of AstraZeneca, announced its strategy to develop biobetters as opposed to concentrating on biosimilars (2). Other examples of this strategy include Amgen with Neupogen (filgrastim) and Genentech, a member of the Roche Group, with Herceptin (traztuzumab). Amgen developed Neulasta (pegfilgrastim), a biobetter of Neupogen in which the originator molecule, a form of granulocyte stimulating factor, was PEGylated. Neupogen and Neulasta both have the same mechanism of action, which is increased neutrophil production. Similarly, the intended patient population of both is cancer patients treated with chemotherapeutic drugs that experience decreased white blood cells. Neulasta has a longer half-life and, therefore, can be administered once every chemotherapy cycle as opposed to daily injections required for Neupogen. Genentech licensed technology from ImmunoGen to use a proprietary technology to develop an antibody-drug conjugate form of Herceptin. Genentech's traztuzumab emtansine, or T-DM1, is a mAb that targets HER-2 positive breast cancers, linked to the chemotherapy, DM1. The antibody-drug conjugate technology enhances the killing of HER2-positive cancer cells and reduces untoward side effects of the chemotherapy DM1 drug by delivering the DM1 directly to the cell. A recent press release indicated that trastuzumab ematansine reduced the risk of worsening or death by 35% in a phase III clinical trial (4).

One of the attractions in developing a biobetter rather than a biosimilar is the regulatory perspective that a biobetter is an innovator drug (i.e., new biologic entity). The categorization of the biobetter as an innovator drug gives companies the advantage of reduced R&D costs because the efficacy is already established, reduced risk of failure from both business and clinical perspectives because of the available data and clinical history known from the originator product, and the benefit of patent protection and data exclusivity. New biologic entities are given data exclusivity of 12 years in the US and eight years in the European Union (5). The main disadvantage is the time associated with following the regulatory pathway for submission of a new biologic license application (BLA), which could take five to 10 years (1). In addition, if the biologic has not come off patent, the originator data available to sponsors are often sparse and difficult to obtain.

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