Etanercept biosimilars

Dimeric fusion protein of about 150 kDa consisting of the extracellular ligand-binding domain of the human p75 TNF receptor linked to the Fc portion of human IgG1, produced in Chinese hamster ovary cells. It is not an antibody, and its heterogeneity (misfolded and truncated species) makes it one of the harder biosimilars to characterise.

Acts as a soluble decoy receptor, binding TNF alpha and lymphotoxin alpha and preventing them from engaging cell-surface TNF receptors. Unlike the anti-TNF antibodies it does not bind transmembrane TNF stably, which is thought to explain its lack of efficacy in Crohn's disease.

Subcutaneous bioavailability about 60%, peak concentrations around 48 to 60 hours, half-life about 70 hours, so dosing is weekly or twice weekly. Clearance is similar in adults and children when adjusted for body surface area.

50 mg once weekly, or 25 mg twice weekly, in pre-filled syringes and pens; 0.8 mg/kg weekly in children. Some Indian products are supplied as lyophilised powder in 25 mg vials rather than as solution.

• Rheumatoid arthritis
• Juvenile idiopathic arthritis
• Psoriatic arthritis
• Ankylosing spondylitis and non-radiographic axial spondyloarthritis
• Plaque psoriasis (adult and paediatric)

Anti-etanercept antibodies are uncommon and non-neutralising, and do not affect efficacy. Comparative programmes rest on analytical similarity, where the Fc-receptor and complement binding profile and the proportion of misfolded species have to be matched, a pharmacokinetic study in healthy volunteers, and a comparative efficacy study in rheumatoid arthritis or plaque psoriasis.

Enbrel was licensed by FDA on 2 November 1998 (BLA 103795) and authorised in the EU on 2 February 2000 (EMEA/H/C/000262). Samsung Bioepis's Benepali was the first EU biosimilar in January 2016 and Sandoz's Erelzi the first FDA approval in August 2016, but US launches were blocked by Amgen's patents until 2029 under court rulings in 2019 and 2020. India's first product, from Cipla, was imported in 2012 and Intas's domestic Intacept was permitted in 2014.

Sources: Purple Book (S016), EMA medicines data (S017), CDSCO lists (S013, S014); US patent litigation from court records and press reports.

Etanercept is the biosimilar that shows how patents, not science, set the timetable: approved by FDA in 2016, unmarketable in the United States until 2029, while Europe has had four products since 2016 and Benepali took the majority of the market in several countries. For an Indian developer the analytical package is the hurdle; three domestic manufacturers hold permissions and Lupin's product reached the EU through Mylan and now Biocon as Nepexto and Fubelv.