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It has been a long time coming, but stakeholders in the US are now seriously debating a route to market for cheaper copies of biopharmaceutical drugs. The European Agency for the Evaluation of Medicinal Products (EMEA) has led the way on this issue by publishing clear guidelines on what companies must do to get their versions of drugs such as erythropoietin (EPO), an advanced treatment for anÃ¦mia, and similar products approved.
It has been a long time coming, but stakeholders in the US are now seriously debating a route to market for cheaper copies of biopharmaceutical drugs. The European Agency for the Evaluation of Medicinal Products (EMEA) has led the way on this issue by publishing clear guidelines on what companies must do to get their versions of drugs such as erythropoietin (EPO), an advanced treatment for anaemia, and similar products approved.
Biotech drugs such as Herceptin and Avastin — monoclonal antibodies approved for treating breast and colorectal cancer — are valued because they have an innovative mode of action. But this value is reflected in the price tag: a biopharmaceutical medicine can cost up to 30 times more than a conventional small molecule drug. Put simply, if everyone who could benefit from a recombinant protein or monoclonal actually received them, it would sink healthcare budgets everywhere. So, of course, there is pressure to produce cheaper copies as patents begin to expire on drugs such as EPO, the interferons (used to treat multiple sclerosis and hepatitis B and C), growth hormone and the clot buster tissue plasminogen activator.
The debate regarding how cheaper versions of biotech products should be regulated began — on both sides of the Atlantic — around 3 years ago. At the time, there was much confusion over what these drugs should be called — biogenerics, generic biologics, follow-on biologics or biosimilars. In Europe most people now refer to 'biosimilars' — a term introduced by EMEA in early drafts of its regulatory framework. "The word biosimilar reflects the fact that these drugs are not generic in the same way as small molecules," explains Andrew Fox, a regulatory expert for Amgen — a company that produced some of the first biotech blockbusters such as EPO and G-CSF (granulocyte colony stimulating factor, which is used to protect the bone marrow in cancer chemotherapy). Manufacturers can be assured that a generic version of a small molecule drug really is identical to the original because chemical synthesis is, generally, reproducible, and well-established analytical techniques such as mass spectrometry (MS) can provide a full characterization of the molecule. Biologic drugs are made in living cells and their manufacture is, by its very nature, less predictable and reproducible.
A pharmaceutical manufacturer hoping to enter the biosimilars market would actually face a double challenge. First, it is harder to make biotech drugs than small molecules because of their increased complexity. "There is a quantum leap between making chemicals and making proteins," warns Fox. Additionally, making a biosimilar involves making a copy of someone else's protein without their experience and know-how (which the innovator can keep secret indefinitely).
A major issue in biosimilar manufacture is that big molecules, such as antibodies and proteins towards the higher end of the molecular weight spectrum, are difficult to characterize fully with the current range of analytical technologies. "When it comes to characterizing proteins there is not one test and one answer. It is more a case of doing 20 different tests and getting an answer that does not necessarily describe all the characteristics of the protein," says Fox. "We know that minor differences in biophysical properties can have clinical consequences, but we do not have the ability to predict these as yet."
Professor Daan Crommelin of the University of Utrecht (The Netherlands) and cofounder of Octoplus, a Leiden-based drug delivery and drug development company, agrees that there is "never a concrete answer" when it comes to characterizing either an original or a copy of a biological molecule. "For the smaller molecules such as insulin or growth hormone, the characterization, and the ability to demonstrate similarities and differences between different versions are easier. The larger the molecule, the harder it is to show real equivalence."
One problem chemical manufacturers never have to worry about is glycosylation — the tendency of proteins to link some of the amino acids in their sequence with oligosaccharide chains. The glycosylation pattern of a protein can affect its biological activity and can elicit immune responses in patients.
"Some molecules such as EPO are highly glycosylated and this presents a real challenge," comments Crommelin. The biotech manufacturer is usually dealing with a mixture of molecules with differing glycosylation patterns. "If the process is controlled, at least this mixture is well-defined, but its composition depends upon process conditions, the host cell, downstream processing factors and formulation of the final product," he says. Hence, the biosimilar manufacturer will have to come up with plenty of data to show the regulatory authorities that their product does not have a glycosylation profile that is going to compromise efficacy or, more seriously, patient safety. Companies such as Teva (which markets biosimilars in developing countries), Sandoz and BioPartners are meeting these challenges. Sandoz' Omnitrop, a growth hormone, was the first biosimilar to be approved in Europe (after extended legal wrangles in the European court). But the drug was not without teething troubles — the presence of host cell protein (often an issue in biotech manufacturing) led to antibody generation among some clinical trial participants. Sandoz fixed the problem, but it illustrates the inherent unpredictability of biosimilar production. Valtropin, another growth hormone, from BioPartners, was the second product to be approved by EMEA and biosimilar versions of EPO and G-CSF may soon follow. The costs of biosimilars may turn out to be higher, compared with the original drug, than conventional generics because of manufacturing and regulatory issues. And, of course, biosimilars are versions of relatively old drugs. Biotech companies have hardly been standing still while the drugs now up for copying progressed through their patent lives. Their latest products, and those in the pipeline, are likely to be safer and more effective than the earlier versions — such as Amgen's darbepoetin alfa (Aranesp, an advanced treatment for anaemia, which could be used instead of EPO). Will the patient offered a biosimilar be getting an inferior medicine? That's a debate still to come.