14-15 - Biosimilars

Biosimilars require the reverse-engineering of staggeringly complex molecules such as monoclonal antibodies. Antibodies are 1,000 times larger than conventional synthetic drugs, such as aspirin. Being made in living cells, they show natural variation – such that a biologic drug is never identical to itself over time. Instead, manufacturers control biologic drug production to ensure each batch is ‘similar’ enough in structure so that there are no meaningful differences in clinical effect over the lifetime of the drug.

It can take the launch of biosimilars to remind us that biotechnology and chemical analytics innovates faster than computer science. Mass spectrometry, the key analytic tool for mapping chemical structure, has had a 10 million-fold increase in sensitivity between 1990 and 2011, such that a difference in one molecule in 1,011 can now be detected. This analytic approach to determining the critical attributes of drug structure and function determines the target that a biosimilar maker must copy. This creates around 60 to 100 tests of equivalence used by regulators to check that a biosimilar is, as regulators frame it, ‘essentially the same’.

When biosimilars were first launched in Europe in 2006, many doubted that such technology would work. However, a decade later, with more than 50 biosimilars approved and more than 2 billion patient days’ use, Europe’s medicines regulator wrote that ‘the evidence acquired over 10 years of clinical experience shows that biosimilars approved through EMA can be used as safely and effectively in all their approved indications as other biological medicines’. Biosimilars have proven similar enough to be switched mid-treatment, and to be approved for most or all the indications granted to the original reference medicine, a process called extrapolation of indications.

One of the many challenges health systems face is that biologic drugs are expensive. Although only 1% of patients may need them, they are taking an increasing share of the total drug spend. In Europe, over 30% of all drug spend is on now biological medicines, a figure that has increased by 3.4% over the last five years.

Biosimilar development has created a new economically competitive market expanding access. For example, filgrastim, which reduces the risk of infections during cancer chemotherapy, showed five-fold increased uptake in the UK and Sweden while budgets remained static.

Faced with patent loss, manufacturers are driven to offer new and improved medicines and services to customers. Biosimilars not only power this new drug innovation, they also create the budget to afford it; they return savings to spend on next-generation innovative medicines. For the UK National Health Service, biosimilar savings in 2018 were £294 million (323 million euros) and are on track to meet its ambitious target of a further £400 million (444 million euros) annual savings by 2021.

A 2019 IQVIA study showed how such savings funded innovation. Tracking uptake of novel oncology biologics worldwide showed only patients in three nations, the US, Germany and the UK had access to more than 70% of them. Those same countries are all amongst the world’s greatest users of patent-expired medicines. All three have generic prescription rates at 80% or higher and their recent biosimilar launches have reached 80% uptake by two years in the UK and Germany, and will likely reach 60% in the USA in the same time period.

Biosimilars develop another level of innovation. Many illnesses, such as cancer, are driven by multiple different disease processes. Optimal disease control logically requires treatment targeted to all the different mechanisms of disease. In metastatic high-risk breast cancer, combining trastuzumab and pertuzumab prolongs life by more than a year, but at a cost that few health systems can afford. For the UK National Health Service, reimbursement of combination biologic therapy was explicitly linked to the launch of biosimilar trastuzumab and the expectation that rapid uptake of biosimilars would be successful in cutting prices. There is a degree of irony in all this – that novel drug developers need biosimilars to enable the sales of their next-generation innovative therapies.

Biosimilars manufacturers’ return on investment will be largely determined by the ability to win large value competitive drug tenders. Tenders are typically won on a combination of drug price and guarantees of regular deliveries without stock shortages. This competition rewards manufacturers who can deliver more efficient drug development, production and distribution. This is the catalyst for more innovation – improvements in the technology to develop next generation biologics.

Examples of such innovation include more efficient gene cloning and selection, higher yielding host cells, more efficient bioreactor technology, tighter manufacturing control to reduce structural variation in biologics, higher purity products with longer shelf lives for more cost-effective storage, stock control and distribution. Such gains are real; researchers have already demonstrated that biosimilar products may have even better quality compared with the original reference medicines.

Since they require reverse engineering, biosimilars create an incentive to develop better and better analytic tools. The result is that the biosimilar may be characterised with a higher number of analytical methods and assays than were used to describe the original reference biologic at its time of launch. There is a further incentive, in that the greatest research and development costs for biosimilars may now be the mandatory clinical trial component. A 2020 study of comparative efficacy trials conducted to obtain US regulatory approval for a biosimilar tended to be larger, longer and more costly than clinical trials required for the originator product the biosimilar had copied. Regulators in Europe and the US have pointed out clinical studies are already often the least critical component in deciding biosimilarity and may not always be needed if better analytics and pharmacological studies can justify their use instead. In contrast to the primarily clinical approach to approving novel medicines, the extensive analytical characterisation of large biotherapeutics, such as monoclonal antibodies, is the most critical part of drug development and regulatory approval of biosimilars.

Competition between manufacturers to improve those analytic steps such as sample preparation, more efficient sequencing strategies, minimised artefact formation, faster and more accurate quantitative peptide mapping, better cell-based functional assays and the development of multi-attribute data methodology will not only deliver better biosimilars with lower development times and costs, but will feed back to improve novel drug development as well.

So, while payers for healthcare may see biosimilars as purely an economic innovation, we should not ignore their wider innovation benefits. They enable innovative drugs to reach low access health systems, they make the dream of combination precision targeted therapy a reality, through competition after patent expiry they encourage original drug developers to bring forward new and better products, and they drive advances in science and biotechnology that will benefit us all.

The innovation opportunity