Biosimilars are coming…are you ready?

With patents for many biologics due to expire in the next decade, the world of biological medicine is about to enter a new era. In our first in-depth feature we explore the pros and cons of  biosimilars and talk to the TGA about what doctors need to know about these latest drugs to emerge in their speciality. 

The world of biological medicines is entering a new era. Patents for many of these successful biopharmaceuticals will expire over the next ten years (see table), and competing drug companies are racing to produce the biological medicine equivalent of ‘generics’, hoping to grab a share of a lucrative market. Some of the currently patented ‘biologicals’ are very lucrative: adalumimab (Humira) was the world’s top-selling drug in 2013, bringing in USD 874.6 billion, with etanercept (Enbrel) not far behind.

Governments such as Australia’s are likely to welcome copy-cat versions of such high-flying biologicals with open arms, enticed by the gleam of significant cost savings with cheaper generic biopharmaceuticals. At about $887 a dose, drugs like adalumimab, cost the taxpayer dearly.

The drugs that aim to copy these innovative biologicals (or ‘biologics’) after patent expiry are known as ‘biosimilars’. Australian renal specialists and oncologists have been prescribing biosimilars for some years. The recent TGA approval of a biosimilar insulin glargine (Abasria) means that endocrinologists now too have a biosimilar on their treatment list.

Similar but not the same

Inevitably, gastroenterologists will need to be knowledgeable about the biosimilars that are starting to emerge for their specialty. So, can biosimilars be regarded simply as ‘generic biologicals’ or is the situation more complex?

Although doctors are comfortable with generic versions of conventional pharmaceuticals, it is incorrect to think of biosimilars as ‘generic biologicals’, says Conjoint Professor Simon Roger, a renal physician at Gosford Hospital, who has reviewed the subject.

“Most chemical drugs are low molecular weight compounds made from standard chemicals and reagents, using organic chemistry”, says Professor Roger. As a result, they are easy to copy, and a generic is molecularly identical to the original product, he explains.

“In contrast, biopharmaceuticals are complex high molecular weight compounds with a production process involving living cells.” He says it is almost impossible for another manufacturer to duplicate the production process of the innovator company. This is the reason biosimilars are so-called, he adds.

The problem is that biologics are usually proteins, and often highly complicated proteins at that. Although the chain sequence of amino acids in a biosimilar will be identical to that in the original biologic, the folding of the protein may be slightly different, and as every biochemistry student knows, such an alteration in structure may affect function.

Another factor is that many proteins are decorated with a dusting of sugar molecules. Biologicals are made by living cells, and slight differences in cell lines, or the conditions in which the cells live, may mean the sugar molecules on a biosimilar differ perhaps in type and placement from those in the original biological.

Biosimilars could be better than their parent drug

“A biosimilar erythropoietin (EPO), Novocrit, came out in Australia about 5 years ago”, says Professor Roger.

Although he was involved in clinical trials of Novocrit, Professor Roger hasn’t used it in his own patients since. “That’s simply because it is a first generation EPO and as such should be given three times a week.” He prefers to use the latest biological EPOs (still under patent) because they only have to be given once a month.

Professor Roger says that renal specialists tend to be cautious about biopharmaceuticals. “There’s the well-known case of epoetin alfa (EPREX) in Europe, Asia and Australia, where the combination of a new stabiliser with a change in the materials used in the syringe resulted in a rise in pure red cell aplasia cases. That’s made the nephrology community a little bit nervous – we’ve had our fingers burned once.”

It is thought that the pure red cell aplasia problem was caused by an increase in the immunogenicity of EPREX. Immunogenicity is a potential concern for all biologicals, and hence the EMA (and TGA) require human immunogenicity data before licensing a biosimilar.

Professor Roger’s concerns about immunogenicity apply to biopharmaceuticals in general, though, rather than to biosimilars in particular. In fact he thinks that in some ways biosimilars may be better than the original biologicals they seek to replace.

“There are huge companies making these biosimilars with production techniques that are much more advanced than what the innovator company production techniques were. The consistency and quality of the drug may well in fact be a lot better than the innovator ones.”

The TGA has licensed five biosimilars so far. Besides epoetin lambda (Novocrit), there are three filgrastims for use in oncology, and insulin glargine. The TGA’s approach to biosimilars (see appendix) follows guidelines produced by the European Medical Agency, which has led the way on licensing biologics for over a decade. The American FDA lags behind, with their first biosimilar, a filgrastim, about to hit the market. The delay in the US has been legislative, as biological medicines come under a different Act to traditional drugs, and that had to be amended to allow for generic-type medicines.

The TGA’s approach to biosimilars

A TGA spokesperson told the limbic: “The guiding principle…is to establish similarity between the biosimilar and the reference product by the best possible means, ensuring that the previously proven safety and efficacy of the reference medicinal product also applies to the biosimilar.”

Three types of study are required by the TGA, starting with “quality studies: a comprehensive characterisation of the biosimilar product’s properties using state of the art analytical techniques.”

Then animal studies are performed, comparing the biosimilar with the reference biological. These are designed to detect any differences in response between the two products.

Next clinical trials are carried out to demonstrate comparable efficacy and safety of the biosimilar to the reference biological. Immunogenicity must be investigated at this stage.

Finally, as for all drugs, pharmacovigilance is essential for biosimilars post marketing.

Table: Expiry dates for some Australian patents for biologicals used in rheumatology

Source: IP Australia

Registered Drug Name Patent Number AUSPAT Final Expiry date of Patent
Adalimumab HUMIRA 722077 10/12/18
2012261708 10/02/17
2013257402 10/02/17
2013203420 10/02/17
2009202707 10/12/18
Etanercept ENBREL 630497 17/07/15
Certolizumab CIMZIA 783756 20/01/25
Golimumab SIMPONI 2001279227 13/11/24
Infliximab REMICADE 668864 2/08/15
Rituximab MABTHERA 688743 12/11/13
606320 27/10/06
606653 7/01/08
627443 9/01/09
632462 25/07/08
Tocilizumab ACTEMRA 668349 24/04/17
744715 21/05/24
615715 23/01/09
732764 7/06/15
700819 7/06/15
Abatacept ORENCIA 661854 16/06/17
682325 21/01/14
696664 19/07/16
701310 13/04/15



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