Weighing the Prospects of Biosimilars

The addition of biologic agents to the therapeutic armamentarium for psoriasis has opened up a wide range of possibilities for patients with moderate to severe disease. Moreover, each agent has unique properties and characteristics. A biologic can be a complex protein monoclonal antibody, such as adalimumab (Humira, AbbVie) and ustekinumab (Stelara, Janssen), or a genetically engineered recombinant fusion protein, such as etanercept (Enbrel, Amgen). Given their “biologic” nature, the cost of developing these agents is steep. In fact, it's been reported that developing a new biologic agent costs between $800 million and $1.2 billion.¹ Thus, while biologics may represent a significant development in the treatment of psoriasis from a clinical standpoint, access to treatment is unfortunately limited due to their high cost.

However, in recent years much speculation has surrounded the concept of utilizing molecular, analytical, and pharmacodymic knowledge from a reference product (also known as an “originator,” i.e. Humira, Stelara, Enbrel), to form an abbreviated pathway and the subsequent development of “biosimilars.” In theory, biosimilars could decrease the cost of biologic treatment. The cost of developing a biosimilar (depending upon whether the FDA mandates a phase III trial) has been estimated to run between $75 million and $300 million.¹

WHAT ARE BIOSIMILARS?

There is an important distinction between generics as we know them and biosimilars. To simplify the matter, smallmolecule generics are approved by the FDA if they show blood levels of 75 percent or more relative to the parent compound. Blood levels are not the only criteria when it comes to biosimilars.² With small molecule generics, it is much simpler to determine through analytic chemistry that the generic medicine is a molecular equivalent to the originator. Biologic agents vary based upon the cell, the medium, and the technique that is utilized for its production. A slight variation in any of these parameters could result in a slightly different epitope or a different glycosylation, resulting in a different biologic agent with different affinities and a different immunogenic profile.

Fortunately, technologic advances utilizing functional assays and genetic expression have helped in assessing differences in the manufacturing processes for some biologics, i.e. batch to batch.¹ As mentioned, the question of quality attributes, strength, and purity are especially important in the context of manufacturing process changes that occur in the production of biologic agents. The reason for these process changes could be process improvements, scale changes, site transfers, or simply new batches.

Most biologic agents are glycoproteins. Even a wellcontrolled product may consist of proteins with the same amino acid sequences with many different glycosylated compositions. A correspondence in Nature Biotechnology compared the different pre- and post-change batches of etanercept utilizing glycan mapping, cation exchange chromatography (CEX), and antibody-dependent cellular cytotoxicity in vitro bioactivity (ADCC); analysis revealed a highly consistent profile for batches until the end of 2009.³

After 2009, major differences were found in the glycosylation profile. Etanercept continued to remain on the market with unaltered labels, implying that the observed changes did not result in an altered clinical profile and was acceptable by health authorities.³

The burden of proof initially will be determining that the physicochemical and biological characteristics of the biosimilar are equivalent to the originator. If more analytical testing shows efficiency (i.e., chromatography, capillary electrophoresis, antibody affinity, pharmacodynic, genetic markers, etc.), it is more likely that the biosimilar is identical to the originator and therefore would not require a large and costly Phase III trial. However, whether a biosimilar of an antibody to TNF alpha in rheumatoid arthritis can be extrapolated to their use in psoriasis remains to be seen. This question, and hopefully others, will be answered in coming months and years.

IN SEARCH OF ANSWERS

From both a clinical and economic standpoint, biosimilars present a variety of potential benefits in the treatment of psoriastic disease. Nevertheless, we still have much to learn about the exact analytical and pharmacologic processes by which biosimilars are measured and prepared. For instance, the issue of substitution remains a looming concern: Will the prescriber have the right to expect the proprietary drug, or will the pharmacist on his/her own initiative be able to give the patient a biosimilar without contacting the physician? Right now we can only speculate about this.

If they are truly comparable to the originator products, biosimilar agents might offer the possibility of decreasing costs and offering therapeutic benefits to patients. But the million-dollar question is whether the analytical techniques employed can elucidate a comparable efficacy/safety profile to the originator.

Dr. Bagel has served as consultant, researcher, or speaker for Amgen, LEO, Abbott, Janssen, Galderma, and GlaxoSmithKline.

Jerry Bagel, MD, FAAD, is director of the Psoriasis Treatment Center of Central New Jersey.

1. Kozlowski, et al. Woodcock J, Midthun K, Sherman, RB. Developing the nation's biosimilars program. N Eng J Med. 2011; 365(5):385-388.
2. Title VII: Improving Access to Innovative Medical Therapies. Subtitle A: Biologic Price Competition and Innovation (BPCIA) Provsions of the Patient Protection and Affordable Care Act (PPACA) www.fda.gov/downloads/Drugs
3. Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310-312.