The introduction of biological agents to the market has revolutionised therapeutics in dermatology. However, the patents protecting their manufacture are about to lapse, and biosimilars can be expected to improve access to these expensive therapies
Lluís Puig MD PhD
Anna López-Ferrer MD PhD
Department of Dermatology,
Hospital de la Santa Creu i Sant Pau,
Universitat Autònoma de Barcelona, Spain
The introduction of biological therapeutics for treatment of moderate‑to-severe psoriasis has significantly improved therapeutic outcomes, as illustrated by recent head-to-head trials with methotrexate.(1) With some of the reference products approaching patent expiration, a number of manufacturers are developing follow-on versions, or biosimilars, which can be expected to improve access to expensive biological agents by reducing acquisition costs and driving down the price of the originators.
Biosimilars are biological products very similar to the reference product in terms of ‘quality, safety and efficacy’ (European Medicines Agency; EMA) or ‘safety, purity and potency’ (Food and Drug Administration; FDA), with similarity defined by the absence of a relevant difference in the parameter of interest. The demonstration of chemical similarity is not enough, and comparative pharmacokinetic and pharmacodynamic trials in healthy volunteers or patients must be undertaken and at least one clinical trial is required to demonstrate the equivalence of each available formulation.(2)
Biopharmaceuticals are manufactured in living systems, as a result of advances in technological engineering of proteins. These biologic drugs include antibodies, recombinant proteins and vaccines. Biologic drugs exhibit great variability in structure and function is based not only on the primary structure, based on the amino acid sequence, but also the post-translational modifications (for example, glycosylation, methylation, oxidation, deamination) which may influence tertiary and quaternary structure and determine differences in affinity, selectivity, functional activity and immunogenicity of biosimilars.
Because the manufacturers of biosimilars lack access to information about the production process of patented originator agents, it is difficult to replicate the post-translational modifications resulting in differences in biologic activity and immunogenicity. The biosimilar is compared to the reference biologic using validated analytical methods that make it possible to establish the physicochemical properties, biological activity, and purity and impurities of the biosimilar. The directives admit the possibility of differences in processing, but the impact of these changes must be confirmed by the appropriate studies. Biosimilar and biological reference medicines are similar but not identical, but the same can be said about different batches of any reference product; manufacturing processes are updated in the life cycle of any medicine, and changes may range from change in the supplier of cell culture media to new purification methods or new manufacturing sites.(3)
Differences in production process
There are many examples that show that differences in the production process may induce important alterations in the molecule. Erythropoetin (EPO) is a protein that regulates the maturation of blood red cells. The product was originally manufactured by Amgen and approved for the treatment of anaemia under the brand name of Epogen and subsequently licensed to Ortho Biotech under the trade name of Eprex. There was an increase in the number of pure red cell aplasia that was attributed to anti-EPO antibodies but retrospective studies demonstrated that the cases of red cell aplasia were mainly associated to Eprex, and not to Epogen, and related to changes in EPO production that resulted in an increased immunogenicity of the protein.(4)
Glycosylation patterns are extremely sensitive to minor modifications in manufacturing processes, and are likely to provide differences in immunogenicity. Most commonly, immunogenicity contributes to loss of clinical efficacy, and development of antibiological antibodies seems to be more common in patients with autoimmune diseases, when intermittent administration is more frequent and background immunosuppressive medication not utilised. The emergence of biosimilars has contributed to the development of assays able to detect antibodies in the presence of higher circulating levels of biological, which can be used in clinical settings.
As for generic medicines, the basis for regulation on biosimilars is to decrease the price of treatments by reducing the cost of their clinical development, since manufacture and quality control of biologics is equally expensive for originators and biosimilars, and may even be more difficult for the latter, which have to be developed to closely resemble their references.
Clinical data requirements differ in the EU and US, but they share the requirement for at least one, adequately powered equivalence trial to determine the efficacy and safety comparability of the biosimilar, which must be both ‘non-inferior’ and ‘non superior’ to the reference product; as regards immunogenicity, it must be assessed during the safety trial according to EMA regulations, whereas at least two comparative trials, one pre- and one post-marketing, are required according to the FDA,(5) and a pharmacovigilance programme must be ready for implementation after the approval of the product.
Extrapolation of clinical data permits the approval of a biosimilar for a therapeutic indication in which it has not been clinically evaluated, but this will be considered on a case-by-case basis. Where mechanisms of action differ or are not fully understood, separate clinical trials are likely to be necessary. Extrapolation should be clearly indicated in the product label.
The latest versions of the EMA regulations are silent regarding the allowance of biosimilar products to be interchanged for the originator drugs and this decision is for each EU country to be made, whereas in the case of generics, these can be freely interchanged for an original drug by the pharmacist, without prior consent of the prescribing physician. By contrast, US legislation allows the FDA to designate which biosimilars that can be switched on pharmacist’s decision without consulting the prescriber, similarly to what occurs with generics, but the exact criteria allowing ‘interchangeability’ are still under consideration by the FDA. Substitution may complicate effective pharmacovigilance, and it will be important to be able to distinguish biosimilars with automatic substitution from the reference product; pharmacists should be aware of their own national guidelines and understand that retention of international non-propietary (generic) names (INN) is not a signal for automatic substitution.(5)
The first biosimilars that came onto the European market were EPO, somatotropin and several colony stimulating factors with 20–30% discount on the original molecule. Even though there is no biosimilar of a monoclonal antibody on the European market yet, approval of the first biosimilar (Inflectra, Remsima) of a monoclonal antibody (infliximab) has been recently recommended by the European Medicines Agency’s Committee for Medicinal Products for Human Use.
Rituximab is the oldest monoclonal antibody and several companies have different products in advanced stages of clinical development. Sandoz started a Phase II clinical trial for the two most important indications of rituximab, rheumatoid arthritis and non-Hodgkin’s lymphoma, in January 2011. Sandoz’s biosimilar will be a potential competitor to Roche’s originator brand-name drugs Rituxan and MabThera. Rituximab ranks among the top biological (biopharmaceutical) drugs worldwide, with projected 2012 sales of about US$7 billion; the podium is reserved to Humira (9.3 billion), Remicade (9.1 billion), and Enbrel (8.1 billion).(6)
The patents of Remicade, Enbrel and Humira will expire in most EU countries in 2014, 2015 and 2018 respectively, but in the case of the US, the situation is different because of extensions of the patents for Humira and Remicade. In the case of Enbrel, the history of the patent has been tortuous, giving to Amgen 16 more years of protection for Enbrel in the US. Eventual producers of biosimilars can also become targets in fierce legal battles over patents in that country, and in consequence, even biosimilar manufacturers will probably ignore the abbreviated procedures and instead follow the traditional pathway for biologics –section 351(a) of the Biologic License Application – in order to avoid having to publish manufacturing procedures and specifications and to reduce their vulnerability to litigation.(7)
Several products labelled as ‘biosimilars’ are approved in a number of countries that did not have stringent regulatory processes to ensure comparability as defined by EMA and FDA, and they should not be considered biosimilars but ‘intended copies’. The fusion protein etanercept has different equivalent products: Yisaipu and Etanar, produced by Shangai CP Goujian Pharmaceutical Co, and are sold in China and Colombia, respectively. The etanercept biosimilar Qiangke, produced by Shangai Celgen in partnership with Simcere Pharmaceuticals, was recently approved in China.
The biosimilar HD203 developed by the Korean laboratory, Hanwha, has been registered by the Korean regulators and it is supposed to be distributed outside the US in collaboration with Merck. In Japan, etanercept and rituximab biosimilars have been manufactured by Coherus BioSciences, a US company, to be distributed by the Japanese company Daiichi Sankyo in Japan, South Korea and Taiwan. India-based generics manufacturer Cipla announced on 17 April 2013 the launch of its ‘similar biologic’ product Etacept, a result of Cipla’s collaboration with China-based Shanghai CP Guojian Pharmaceutical, which marks Cipla’s entry into the ‘similar biologic’ market.(8)
In the case of adalimumab, Boehringer Ingelheim’s adalimumab biosimilar (BI695501) is in the clinical development phase. In Brazil, PharmaPraxis is planning to develop an adalimumab biosimilar, and so does Fujifilm Kyowa Kirin Biologics in Japan.(3)
Currently, there are no biosimilar monoclonal antibodies or fusion proteins approved by the EMA or FDA for rheumatologic or dermatologic diseases, but in 2012 the South Korean company, Celltrion, filed for EMA approval of a biosimilar infliximab product, Remsima (CT-P13), which was approved by the South Korea FDA in July 2012. Clinical trials with CT-P13 have included a phase III trial in 606 patients with rheumatoid arthritis,(9) and a Phase I trial in 250 patients with ankylosing spondylitis,(10) using innovator infliximab as comparator.
The role of biosimilars in dermatological diseases will be determined in part by the confidence placed on them by dermatologists and, perhaps to a greater extent, by economic pressures aimed at cost saving by payers. Stringent regulatory approval processes are designed to provide the basis for physicians’ acceptance, but economic factors are more complex. Up to now, the uptake of biosimilars in European and US markets has been relatively limited, which may be explained by the relatively modest cost savings of 15–30% compared with those afforded by generic drugs. Nevertheless, under tightening economic conditions even minor percentage savings will be embraced by health authorities, taking into account that biosimilars’ reduced cost of acquisition can be expected to drag the prices of the originals down. On the other hand, manufacturers of original compounds may be flocking to produce biosimilars of other drugs in an attempt to diversify their biopharmaceutical business and minimise price reductions, with the consequent expectable impact on stock value.
In Korea, several high-tech industries have emerged through joint ventures with giant industrial companies, such as Samsung Electronics, that are redefining the strategic importance of the pharmaceutical sector. Similar associations are being established in Japan.(8)
It remains to be seen if both established manufacturers and newcomers will truly compete and make these significant drugs more accessible to patients in different health systems.
- Biosimilar and biological reference medicines are similar but not identical, but the same can be said about different batches of any reference product.
- Glycosylation patterns are extremely sensitive to minor modifications in manufacturing processes, and are likely to provide differences in immunogenicity. Most commonly, immunogenicity contributes to loss of clinical efficacy
- Extrapolation of clinical data permits the approval of a biosimilar for a therapeutic indication in which it has not been clinically evaluated, but this will be considered on a case-by-case basis.
- Pharmacists should be aware of their own national guidelines and understand that retention of international non-propietary (generic) names (INN) is not a signal for automatic substitution.
- Even minor percentage savings will be embraced by health authorities, taking into account that biosimilars’ reduced cost of acquisition can be expected to drag the prices of the originals down.
- Barker J et al. Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1). Br J Dermatol 2011;165:1109–17.
- Tsiftsoglou AS, Ruiz S, Schneider CK. Development and regulation of biosimilars: current status and future challenges. BioDrugs 2013;27:203–11.
- Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis 2013;72:315–8.
- Roger SD. Biosimilars: current status and future directions. Expert Opin Biol Ther 2010;10:1011–8.
- Dörner T et al. The role of biosimilars in the treatment of rheumatic diseases. Ann Rheum Dis 2013;72:322–8.
- Biologic drugs set to top 2012 sales. Nat Med 2012;18:636.
- Wiatr C. US biosimilar pathway unlikely to be used: developers will opt for a traditional BLA filing. BioDrugs 2011;25:63–7.
- Puig L. Biosimilars in dermatology: starting with infliximab. Actas Dermosifiliogr 2013;104:175–80.
- Yoo DH et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013; May 21. [Epub ahead of print]
- Park W et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013; May 16 [Epub ahead of print].