Review Article Submitted: 3.6.2013 Accepted: 12.12.2013 Conflict of interest Dr. Marc Alexander Radtke and Prof. Dr. Matthias Augustin have performed clinical or healthcare studies and re­ gistry projects, medical consultations, served on advisory boards and been invited to lectures in cooperation with, or for, Abbott, Abbvie, Almirall, Amgen, Biogen, Celgene, Janssen, Leo, Lilly, Medac, MSD, Novartis, Pfizer, and UCB.

Marc Alexander Radtke1, 2, ­Matthias Augustin1 (1) CVderm – Center of Excellence for Health Services Research in ­Dermatology, IVDP – Institute for ­Health Services Research in ­Dermatology and Nursing, University Medical ­Center Hamburg-Eppendorf, Hamburg, ­Germany (2) Hamburg Dermatologie, ­Dermatology Practice, Hamburg, ­Germany­

DOI: 10.1111/ddg.12294

Biosimilars in psoriasis: What can we expect?

Summary Biosimilars are biotechnologically processed drugs whose amino acid sequence is identical to the original biopharmaceutical. They are of considerable clinical, economical, and health care interest. As patents for biologicals used to treat psoriasis expire, biosimilars will become more and more important within the field of dermatology. The patents for the two top-selling drugs (adalimumab and etanercept) will terminate in the next few years. Applications for biosimilars will presumably be submitted to the EMA and the FDA for all patent-free biologicals. Both regulatory bodies have issued guidelines on the assessment of bioequivalence, as well as the benefits and risks of biosimilars. While the preclinical requirements of the FDA and EMA are largely comparable, the formal requirements for clinical bioequivalence, including clinical efficacy and safety, differ markedly. Therefore, from a medical and health care perspective before biosimilars enter the market, specific evidence-based regulatory conditions need to be created and fulfilled. Only then biosimilars can be a less expensive option for a large number of patients, providing them with substances of the same value. Adequate, unequivocal proof of their bioequivalence, quality, and related patient safety should have priority over any ostensible economic benefits.

Background The advent of biologicals was a revolution in the treatment of psoriasis, just as they once revolutionized the treatment of rheumatoid arthritis. The use of approved second-line therapies – adalimumab, etanercept, infliximab, and ustekinumab in the treatment of psoriasis, and golimumab in the treatment of psoriatic arthritis – has led to unparalleled success in moderate-to-severe psoriasis and psoriatic arthritis. For a specific group of psoriasis patients, they are now a permanent standard of treatment that conforms to guidelines [1, 2]. Yet, although they are extremely useful, biologicals have not been widely used in the cases of psoriasis [2]. One explanation may be a lack of knowledge among many dermatologists about their use. Another perhaps more important reason is their high cost. There is also a significant economic risk for

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the prescribing physician in Germany, should a formal error occur. In other countries, the use of biologicals is restricted by local, regional, and national drug budgets. These countries, like Germany, have an interest in drugs which may present biosimilar alternatives after the patents for biologicals expire. In recent years, such drugs, which are known as biosimilars, have been used for certain indications and treatments [3]. These include erythropoietin preparations and growth hormones [4]. The question – which was already raised, and controversially discussed, when biosimilars were introduced – is to what extent a structurally similar, imitation drug could really possess the identical efficacy and safety as the original [5]. Depending on the manufacturing processes used, variation in clinically relevant properties may occur which affect these substances and later monoclonal antibodies. In 2004, the European Medicines Agency (EMA), and much later, the

© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1204

Review Article  Biosimilars in psoriasis

U.S. Food and Drug Administration (FDA), formulated regulatory requirements for the evaluation of biosimilars on the basis of preclinical data and clinical features. In coming years, biosimilars will enter the market as the patents on biologicals used to treat psoriasis expire. There is the need to clarify what this means in terms of health care regulatory issues and for dermatology. The present article aims to describe the future introduction of biosimilars for the treatment of psoriasis and psoriatic arthritis based on published data and regulatory requirements.

Biosimilars – equals among equals? Biosimilars are specially approved, imitation drugs. The therapeutic protein is produced using recombinant technology, and is structurally similar (biosimilar) to the original; in terms of its pharmacological effect on the receptor, its mechanism of action is identical to the original (reference drug) [6]. Compared to most chemically synthesized drugs, biosimilars have a high molecular weight and a highly complex molecular structure. Despite an identical amino acid sequence, the tertiary and quaternary structure may be heterogeneous. This has an impact on the effectiveness as well as safety and efficacy profiles of biological agents. Clearly, biosimilars must be treated differently from generic copies of chemically synthesized drugs. There is thus a high level of agreement to be found between the regulatory measures of the FDA and the EMA in regard to evaluating preclinical data. Yet there are significant differences between the FDA and EMA concerning the rules governing the evaluation of clinical bioequivalence. The FDA requires clear factual information, based on the results of clinical studies, in support of bioequivalence. For the EMA, evidence of pharmacokinetic and pharmacodynamic equivalence is sufficient; only in uncertain cases additional evidence of clinical bioequivalence, based on randomized clinical studies, is a requirement [7]. Both regulatory organs recommend non-interventional safety trials (post-marketing surveillance studies) after biosimilars go on the market.

Psoriasis vulgaris – unlimited potential for ­innovation? With a prevalence of 2.5 %, and a high disease burden, psoriasis vulgaris has a significant socio-economic impact [8]. There is a high burden of disease for patients, given the generally severely impaired quality of life, as well as treatment refractory disease and frequent side effects. There is still no permanent cure for psoriasis. Suppression of disease signs and the systemic inflammatory response are sufficient to allow patients to remain symptom-free for long periods of

time; accompanying diseases may also be treated. In recent years, biological agents have been shown to have greater efficacy and tolerability compared to traditional systemic therapies [9]. Biologicals can be highly effective, even in recalcitrant disease. Although they are not first-line treatments, they are expressly recommended for use in “high-need patients” if all other available and approved systemic agents, including methotrexate (MTX) and cyclosporine, are ineffective, not tolerated, or cannot be taken due to pre-existing disease [1]. Biologicals are thus an indispensable “second-line” therapy for the treatment of moderate-to-severe psoriasis. By and large, biologicals do not have any toxic chemical/ pharmacological adverse effects (AE). Most related side effects are due to the specific biological properties of a given preparation, and result from neutralization of the biological activity of their target molecules, such as TNF-α or IL-12/ IL-23. After the U.S. patents for etanercept (2012), adalimumab (2016), and infliximab (2014) expire, it will not be long before biosimilars become available for the treatment of psoriasis (Table 1). Numerous pharmaceutical companies, especially in Asia, have already developed biosimilar drugs, some based on evidence from controlled clinical trials [10]. There is the obvious, if ostensible, idea of using a biosimilar for the same benefit but with lower treatment costs; thus in a cost minimization process, the appropriate preparation would be determined exclusively by price [11]. Even if only partly successful, biosimilars would then significantly lower drug costs and lead to a re-structuring of the pharmaceutical market. A limitation, from an economic standpoint, is the potential risk due to new side effects and reduced efficacy [12].

Biological characteristics of biosimilars and their consequences The proteins in biologicals, and thus biosimilars, are formed by protein folding, which leads to a complex three-dimensional structure [6]. During the biotechnological manufacturing process, batch-to-batch variability in the tertiary and quaternary structure may occur, even within a single production line [6, 13]. Switching production sites and conditions have often had a negative effect on the stability and quality of biologicals (Table 2) (according to [7]). This occurred, for instance, when efalizumab (Raptiva®), a biological specifically designed to treat psoriasis, was manufactured at a new facility. Although it was within the same company, it led to such immense differences in the drug’s biological characteristics that the FDA ordered a new phase III study to assess bioequivalence [14]. Clinically relevant variations within the production of the identical agent have also been reported for other biological preparations such as erythropoietin; this can affect protein characteristics, for

© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1204

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Review Article  Biosimilars in psoriasis

Table 1  Patent approvals and expiration dates for biologicals used in psoriasis, as well as published development of biosimilars for these substances (modified according to Dörner T. and colleagues [7] and U.S. sources (www.fda.gov and www.uspto.gov/patents)). Agent

Infliximab

Etanercept

Adalimumab

Golimumab

Ustekinumab

Brand name

Remicade®

Enbrel®

Humira®

Simponi ®

Stelara®

Description

Chimeric human/ Human mouse monoclonal TNFR2-Fcγ1 IgG1κ antibody fusion protein

Human ­monoclonal IgG1κ antibody

Human ­monoclonal IgG1κ antibody

Human ­monoclonal IgG1κ antibody

Specificity

TNF-α

TNF-α, ­lymphotoxin

TNF-α

TNF-α

p40 subunit of ­IL-12, IL-23

Indication based on EU approval

RA, PsA, AS, MC, CU, Ps

RA, PsA, AS, JIA, Ps, pedPs

RA, PsA, AS, MC, Ps

RA, PsA, AS

Ps

Indication based on EU approval for children

Biosimilars in psoriasis: what can we expect?

Biosimilars are biotechnologically processed drugs whose amino acid sequence is identical to the original biopharmaceutical. They are of considerable ...
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