The majority of the 10 top-selling drugs in 2016 were biologicals, each exceeding sales of $5 billion. With increasing pressure to reduce healthcare costs, there is a need for cheaper biologicals and thus greater demand for biosimilars, biological drugs similar to the already approved biological. The first biosimilar was approved in the EU in April 2006 but hesitation that biosimilars of the very complex reference product would be as efficient and safe led to slow initial uptake. The Biosimilars Global Congress 2017 Europe, held in September 2017 in London, brought together experts from the pharmaceutical industry and from regulatory and medical affairs to discuss the latest developments and challenges facing biosimilars.
The biosimilar market and its challenges
The delegates heard that a general trend in recent years has seen an increasing comfortability with biosimilars. So far, lots of topline data have shown that biosimilars are safe and effective, and the acceptance of biosimilars has been growing among stakeholders. The pace in the development and uptake of biosimilars in the U.S. and EU has been accelerating, particularly since the approval of the first biosimilar monoclonal antibodies (infliximab biosimilars Remsima/Inflectra in September 2013 in the EU), but the U.S. continues to be behind the EU. Following the first biosimilar approved by the FDA in 2015, there are only seven approved biosimilars to date in the U.S., while 11 years after the first EMA-approved biosimilar, the number is approaching 40 in Europe. There is a move to more rapid adoption due to better education and understanding, with the quality of the products and clinical data increasing the confidence that biosimilars are as good as the original product. Following recent launches of biosimilar etanercept and rituximab in Europe, monoclonal antibodies continue to dominate the biosimilar pipeline, and exciting launches expected in the next two years were highlighted at the congress. Particularly anticipated are adalimumab biosimilars, which are expected in Europe in October 2018. Other likely EU market entries in the next two years include biosimilars for trastuzumab, bevacizumab, insulin aspart and eculizumab.
Despite progress, there remain several challenges, including stringent regulatory requirements, continued education of patients and physicians, the issue of switching between originator reference product and biosimilar, knowing what the competition is doing and the mix of the portfolio, for which the focus should be long term. Hot topics in the biosimilar field that are evolving quickly are extrapolation, interchangeability, immunogenicity, traceability and risk management. Pricing is a contested issue and while in some, mainly smaller, resource-constrained countries, aggressive price reductions are key, no such dramatic price cuts are expected in the U.S. and the big 5 (France, Germany, Spain, Italy and the UK). Experts highlighted, however, that crucial for the success of biosimilars is not just the price, but the value proposition, with a greater emphasis on patient-centric care. Different pricing models were discussed, including risk-share agreements, where the biosimilar developer will give considerable discounts to hospitals, for instance, if there is a full switch to the biosimilar product.
The role of pharmacy and the implications of Amazon’s planned move into the prescription drugs retail industry were also touched upon. Biosimilars have intensified the dialogue between clinicians and pharmacists and Amazon is expected to be just one of the distribution channels in the fragmented U.S. system. Pharmacists are expected to continue to play an important educational and training role, which is essential for biosimilar acceptance.
Hot topic of interchangeability and switching
In January 2017, the FDA issued draft guidance for the industry on interchangeability between a follow-on and the reference product, a topic that was discussed in several sessions across the event. A product is likely to see increased market uptake in the U.S. if it can be automatically switched at the pharmacy, which is of importance for long-term treatments such as TNFalpha inhibitors but less so for short-term treatments such as filgrastim. The FDA guidance provides an overview of the scientific considerations in demonstrating interchangeability with a reference product, including considerations for the sample size, pharmacokinetic, pharmacodynamic and immunogenicity sampling and study design. In terms of the study design, the FDA proposes either a dedicated switching study, where only the effect of switching between the reference and already approved biosimilar product is examined, or an integrated study, where a single study assesses both biosimilarity and interchangeability. Several challenges were highlighted such as large sample size, complex pharmacokinetic sampling not relevant to each molecule, and the use and cost due to the requirement to use a U.S. reference product in the switching studies. If adhering to the guidance, approximately 500 patients would need to take part in a 45-week study. However, the example of Boehringer Ingelheim’s interchangeability VOLTAIRE-X study, comparing Boehringer’s adalimumab biosimilar BI-695501 with Humira, was cited. VOLTAIRE-X is the first study in the U.S. to investigate an interchangeability designation for an adalimumab biosimilar candidate and will enroll 240 patients, significantly fewer than expected based on the FDA guidance. The conclusion to a talk on the FDA guidance was that interchangeablity studies are here to stay and that the guidance should not be taken word-for-word but should be challenged and discussed with the agency.
While the FDA provides for a path to obtain an interchangeability designation, the EMA considers an EU authorized biosimilar as an alternative therapeutic option to the reference product and supports that biosimilars licensed in the EU are interchangeable. The first European study designed to generate safety and efficacy data to reassure physicians that the first approved biosimilar monoclonal antibody infliximab is just as good as the originator product (Remicade) was the NOR-SWITCH study. Results showed that switching from originator infliximab to biosimilar infliximab was not inferior to continuing treatment with originator infliximab, and confirmed that extrapolation of data across indications is sound and safe. Other switching studies have been conducted, including with originator adalimumab (Humira) and biosimilar adalimumab (Amjevita) and originator etanercept (Enbrel) and biosimilar etanercept (Erelzi).
Nevertheless, there remains the clinician perception that interchangeability is a sign of better quality, a point with which many delegates did not agree. They argued that interchangeability was no big deal and focus should be on real-life data.
Early studies confirming similar activity between biosimilar and originator infliximab
The comparability concept resulting in approval of infliximab biosimilar Remsima/Inflectra was also a topic discussed at the conference. The mechanism of action of soluble TNFalpha in mediating inflammatory bowel diseases is through pro-inflammatory cytokines, and the biosimilar was similar to originator in neutralizing soluble TNFalpha, suppressing pro-inflammatory cytokines and inducing apoptosis in Caco-2 cells. Studies also showed that both induced apoptosis via transmembrane TNFalpha-mediated reverse signaling in peripheral blood monocytes, enhanced induction of regulatory macrophages and inhibited T-cell proliferation, while neither exerted any significant antibody-dependent cell-mediated cytotoxicity. These studies showing the highly similar biological activities of biosimilar and originator supported approval and inflammatory bowel disease extrapolation.
Considerations for biosimilars for orphan drugs
In the orphan drug disease setting, showing non-clinical analytical comparability of the biosimilar to the originator was stated as being straight forward, but there are other challenges, such as the requirement that the same group of patients as tested by the originator needs to be compared with patients with less severe disease, and due to the rarity of the disease, more studies in healthy volunteers for extrapolation are required. Another challenge is that no guidelines for orphan biosimilars are in place yet and while the FDA seems to require some kind of phase III studies, the EMA has stated that robust non-clinical and pharmacokinetic studies but no phase III trials were needed. The financial implications of orphan biosimilars were discussed and cost reductions of approximately 20-fold relative to the originator can be expected. Implementing a unique patient assistance plan was also deemed vital for success in the orphan drugs field.
A lot of topics were debated at the Biosimilars Global Congress 2017 Europe. Interchangeability was a recurring theme due to the perception among physicians that if a product is interchangeable it is better, a view disputed by many delegates. Education across stakeholders continues to be highly important despite increasing recognition that biosimilars deliver safe and effective treatment for patients, and offer greater access because of a lower price and pricing pressure on the innovator. However, factors such as stringent regulatory requirements remain challenging. Directly talking to and working with the regulators is deemed vital for successful biosimilar development, and focusing on patient care, and not just price, is crucial for differentiation from competitors.
For a complete, in-depth look at the global biosimilars landscape, download the new BioWorld biosimilars report from Clarivate Analytics.