Biosimilars to treat inflammatory arthritis: the challenge of proving identity.

The introduction of targeted biological therapies has revolutionised the treatment of patients with inflammatory joint diseases. These medications are highly effective in reducing disease activity, improving physical function, and retarding or arresting the progression of structural damage. Their relative benefits and risks have been ascertained and contraindications to their use are well known. However, the high price of these drugs has limited their widespread application. The potential availability of biosimilar versions of these targeted therapeutics promises accessibility to biopharmaceuticals with similar efficacy and safety but at a lower cost. 2 In a forthcoming issue of Annals of the Rheumatic Diseases and published online first, the results of the first randomised, prospective clinical trials comparing a biosimilar to an original (or ‘innovator’) biopharmaceutical for a rheumatic disease indication, are published. 4 A biosimilar is defined as a ‘biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product’, in which similarity is defined as the ‘absence of a relevant difference in the parameter of interest’. In this context, it is important to note that there are complexities inherent in producing large proteins. A biosimilar must ensure similarity to the reference product with respect to many attributes, such as amino acid sequence, conformation, post-translational modifications, immunogenicity, affinity for its ligand or receptor, and function. However, it must be recognised that subtle process changes in the production of an innovator product inevitably occur over time and have resulted in variations between commercial lots, such as changes in the glycosylation profile of rituximab that resulted in more potent antibodydependent cellular cytotoxicity in vitro. Many of the commercially available innovator biopharmaceuticals that are used now to treat patients could thus be considered to be biosimilars of the originally produced lots of those products, all of which had undergone rigorous testing and are subject to ongoing quality assurance by their manufacturers. To establish the biosimilarity of a biopharmaceutical to an innovator reference biopharmaceutical, in-vitro analytical studies and in-vivo animal studies are required to demonstrate that the two proteins are ‘highly similar,... notwithstanding minor differences in clinically inactive components.’ The US Food and Drug Administration (FDA) requires that clinical studies must then show ‘that there are no clinically meaningful differences’ between the biosimilar and the reference biopharmaceutical in ‘the safety, purity, and potency of the product’. The European Medicines Agency (EMA) requires ‘an appropriate comparability exercise... to demonstrate that the similar biological and reference medicinal products have similar profiles in terms of quality, safety and efficacy’. These studies must demonstrate that the pharmacokinetics and pharmacodynamics, efficacy, and safety of the biosimilar are essentially equivalent to those of the innovator biopharmaceutical at the same dose, and that the biosimilar is not more immunogenic than the reference product. Because the therapeutic doses of the innovator biopharmaceutical have already been established and the biosimilar must be administered at the same doses as the innovator biopharmaceutical, the development programme for a biosimilar need not include dose-ranging studies in patients. Instead, at least one ‘non-inferiority’ clinical trial comparing the biosimilar and the innovator reference biopharmaceutical is required to show that there are no significant differences in efficacy between the two drugs. CT-P13 is a biosimilar infliximab that was compared to innovator infliximab in in-vitro analytical studies, which demonstrated similar transmission on Fourier transform infrared spectrometry, relative tumour necrosis factor α (TNFα) neutralising potency, and comparative complementdependent cytotoxicity. Subsequently, CT-P13 was studied in two randomised, double-blind, parallel-group, prospective clinical trials to assess its potential noninferiority to the reference product with respect to efficacy and safety over 30 weeks. The PLANETAS trial was a phase 1 study that compared the pharmacokinetics, efficacy, and safety of CT-P13 to those of innovator infliximab, each as monotherapy in patients with ankylosing spondylitis. The PLANETRA trial was a phase 3 study that evaluated the efficacy and safety of CT-P13 compared to innovator infliximab, each in combination with methotrexate in patients with active rheumatoid arthritis. The PLANETAS trial achieved its primary endpoint, demonstrating that the steady state pharmacokinetic profiles of CT-P13 and innovator infliximab were equivalent between weeks 22 and 30. In addition, the secondary pharmacokinetic parameters were ‘highly similar’ between treatment groups for each of the six intravenous doses of CT-P13 and innovator infliximab that were infused over the 30-week study. In the PLANETRA trial, pharmacokinetic parameters were also ‘highly similar’ between treatment groups for each of the six doses of study drug. Some differences were observed in the change from baseline in levels of IgG rheumatoid factor at week 14 and anticyclic citrullinated peptide antibodies at week 30, which were measured as pharmacodynamic parameters. However, the relevance of changes in autoantibody levels to the pharmacological effects of a therapeutic anti-TNF monoclonal antibody in patients with rheumatoid arthritis is unclear. It is necessary that a biosimilar be noninferior to the originally licensed biopharmaceutical. The goal of a comparative effectiveness trial that assesses a biosimilar in relation to the reference biopharmaceutical is to demonstrate that any difference in efficacy between the two drugs is less than a prespecified ‘non-inferiority margin’ or ‘clinical equivalence margin’. This margin becomes the upper bound for the 95% two-sided CI of the difference between the treatment effect of the biosimilar and that of the innovator reference biopharmaceutical. Ideally, the magnitude of this ‘non-inferiority margin’ is based on historical information obtained from placebo-controlled clinical trials about the treatment effect of the innovator Division of Rheumatology, Department of Medicine, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, Massachusetts, USA; Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria; 2nd Department of Medicine, Hietzing Hospital, Vienna, Austria