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 ARA and TGA about what rheumatologists 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, rheumatologists 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.

What the ARA has to say

Speaking for the Australian Rheumatology Association, Dr Paul Kubler, a rheumatologist and clinical pharmacologist, sees a bright future for biosimilars, but is aware of the pitfalls.

“Although we already have some biosimilars in Australia, you’ve got to remember, not all biosimilars are the same. The ones we already have are fairly straightforward (many are simple replacement hormones) but the biologics used in inflammatory arthritis have complex 3-dimensional molecular structures.

“That’s where you start wondering – knowing that the biosimilars will not be identical and that the differences could have an effect on safety and efficacy – or they could have no effect at all. From a regulatory point of view, a biosimilar medicine has to demonstrate similarity in terms of physicochemistry, mechanism of action and clinical outcomes. And if any differences are identified then they have to be justified with regard to their potential impact on safety and efficacy.

Even though the procedure for approval has to be more thorough than that for generic conventional pharmaceuticals, he says that it is far less arduous for Big Pharma than licensing an innovative biological.

“You usually don’t have to do a full clinical programme for a biosimilar to show efficacy. Instead at least one study in a sensitive clinical model may be sufficient,” says Dr Kubler.

Dr Kubler is enthusiastic about the potential for biosimilars to reduce health costs. “There’s a biosimilar infliximab (CT-P13) made by Korean company, Celltrion, which is approved overseas and there are suggestions that a price reduction of up to 30% in infliximab costs may be achievable. That’s the promise of these drugs from a public perspective.”

He says rheumatologists “have got to get used to the fact that biosimilars are coming. We are still at the start of this journey in Australia and I think people are still trying to understand the pros and cons of using biosimilars. There are a few clinical issues that are going to arise down the track,” he adds.

“One of the most contentious issues is being able to claim all of the original drug’s treatment indications with only a couple of clinical studies, says Dr Kubler. He cites the example of the biosimilar infliximab CT-P13 that has been approved in Europe and Canada. “Infliximab has six approved treatment indications, including inflammatory bowel disease and inflammatory arthritis in adults and children. CT-P13 has published data in rheumatoid arthritis and ankylosing spondulitis – two adult populations with inflammatory arthritis.

In Europe they have said that data is sufficient to permit all six treatment indications; whereas in Canada, only the inflammatory arthritis and skin psoriasis indications have been approved.”

There are also questions about switching patients from the original biological to cheaper biosimilars, if they are put on the PBS, he says. “Will we perhaps be mandated to switch to the cheapest drug, or will the patient maybe have to pay a premium to stay on the original biological?” he muses.

Despite the unanswered questions, biosimilars are coming, he says, and coming soon. Specialists will need to be comfortable with them.

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

Source: IP Australia

Appendix: 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.

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