Development of biosimilars for rheumatology

In 2012, worldwide sales for the top three selling tumour necrosis factor (TNF) inhibitors reached US$20 billion. These biological treatments for arthritis are costing patients between US$10,000–US$30,000 per year making the need for lower cost biosimilars clear.

There are currently no biosimilar monoclonal antibodies (mAbs) or soluble receptor constructs (cepts—large, intricate proteins with unique tertiary and quaternary structures that are inherently difficult to replicate) approved by EMA or FDA for treatment of rheumatic diseases, although randomized controlled trials are complete or ongoing, see Table 1 [1]. EMA is, however, reviewing two applications for marketing authorization of infliximab biosimilars, one of which is thought to come from South Korean biotechnology company Celltrion, which has already received approval for its product for rheumatoid arthritis and autoimmune diseases from the regulatory authorities in Korea [2].

Table 1: Biosimilars under development for treatment of rheumatic diseases

Reference biological	Manufacturer	Prospective biosimilar	Stage of development	Indication
Trials ongoing in highly regulated markets (defined by EMA and FDA)
Adalimumab	Boehringer Ingelheim (Germany)	BI695501	Phase I completed (New Zealand)	Healthy subjects
Etanercept	Hanwha Chemical (South Korea)	HD203	Phase III (South Korea)	RA
Etanercept	LG Life Sciences (South Korea)	LBEC0101	Phase I completed (South Korea)	Healthy subjects
Etanercept	Mycenax Biotech (Taiwan)	TuNEX	Phase III (Japan and South Korea)	RA
Infliximab	Celltrion (South Korea)	CT-P13	Approved (South Korea)/ Phase 3 complete (EU) RA; AS/RA Phase I complete (EU, South Korea)	AS
Rituximab	Boehringer Ingelheim	BI 695500	Phase III (Argentina, EU, New Zealand, Norway, Peru, Ukraine, USA)	RA
Rituximab	Celltrion (South Korea)	CT-P10	Phase I (South Korea)	RA
Rituximab	Merck	MK8808	Phase I (EU)	RA
Rituximab	Pfizer (USA)	PF-05280586	Phase II (USA)	RA
Rituximab	Samsung	SAIT 101	Trials halted	RA
Rituximab	Sandoz Pharmaceuticals (Switzerland)	GP2013	Preclinical (ACR2012) Phase II (EU, Argentina)	RA
Rituximab	Teva Pharmaceutical Industries (Israel)	TL011	Phase II completed (EU) Phase III halted	RA
Trials on-going in less regulated markets
Rituximab	Boehringer Ingelheim	BI 695500	Phase III (Brazil, Guatemala, Russian Federation)	RA
Rituximab	Merck	MK8808	Phase I (Belarus)	RA
Rituximab	Sandoz Pharmaceuticals (Switzerland)	GP2013	Phase II (Brazil, India) RA	RA
Preclinical
Etanercept	Avesthagen (India)	Avent	Preclinical
Etanercept	Protalix Biotherapeutics (Israel)	PRX-106	Preclinical
RA: rheumatoid arthritis; AS: ankylosing spondylitis.

Legislation that regulates the manufacture, registration and approval of biosimilars varies considerably between different countries, and ‘copy biologicals’ approved in less highly regulated markets may not follow the same strict requirements as is required in Europe by EMA.

Biosimilars, as with all biologicals, are complex molecules to produce, and uncertainties surrounding the exact regulatory requirements have led some companies to suspend their development. This, however, has not put off others and, with patent expiries looming, rheumatologists should expect biosimilars to be with them very soon.

Conflict of interest
Most of the authors of the research article had received study support and/or consultancy fees from both generics and originator drug manufacturers. The research article was a result of the roundtable on ‘Biosimilars for the treatment of rheumatic diseases’, Berlin, Germany, 25 April 2012, which was made possible by an unrestricted educational grant from F. Hoffmann-La Roche. The sponsor had no involvement in the roundtable agenda or development of the manuscript.

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