Adalimumab biosimilars

Fully human IgG1 kappa monoclonal antibody of 1,330 amino acids and about 148 kDa, expressed in Chinese hamster ovary cells. Originally created by phage display, so its sequence is entirely human.

Binds soluble and membrane-bound tumour necrosis factor alpha with high affinity and blocks its interaction with the p55 and p75 TNF receptors. It also lyses TNF-expressing cells in the presence of complement and modulates leukocyte migration markers such as E-selectin, ICAM-1 and VCAM-1.

Given subcutaneously; absolute bioavailability about 64%, peak concentrations around 5 days after a 40 mg dose, terminal half-life about two weeks (range 10 to 20 days). Steady-state trough concentrations of roughly 5 micrograms per mL with 40 mg every other week, higher with concomitant methotrexate, which reduces clearance by about 40%.

40 mg every other week for most adult indications, with induction dosing in Crohn's disease, ulcerative colitis, hidradenitis suppurativa and psoriasis; weight-band dosing in children. Available at 50 mg/mL (original, citrate-buffered) and 100 mg/mL (high-concentration, citrate-free) in pre-filled syringes and pens.

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis
• Ankylosing spondylitis and non-radiographic axial spondyloarthritis
• Psoriatic arthritis
• Plaque psoriasis (adult and paediatric)
• Hidradenitis suppurativa
• Crohn's disease (adult and paediatric)
• Ulcerative colitis
• Non-infectious uveitis (adult and paediatric)

Anti-drug antibodies develop in a minority of patients and reduce exposure and response; methotrexate lowers the rate. Because immunogenicity varies with formulation, comparative immunogenicity is a core part of every adalimumab biosimilar programme, and it is the reason high-concentration citrate-free versions were developed separately from the original 50 mg/mL products.

Humira was first licensed by FDA on 31 December 2002 (BLA 125057) and authorised in the EU on 8 September 2003 (EMEA/H/C/000481), initially for rheumatoid arthritis, with the remaining indications added over the following fifteen years. The EU compound patent expired in October 2018, the point at which the first European biosimilars launched. In the United States, biosimilar entry was governed by settlement agreements with AbbVie and began in January 2023, more than six years after the first FDA biosimilar approval.

Sources: Purple Book (S016), EMA medicines data (S017); patent expiry and US settlement dates from company and press reports (S006, S007).

Adalimumab is the most-biosimilared biologic in the world because Humira was the best-selling prescription medicine for most of a decade and its expiry dates were widely known years in advance. For a developer, the reference product's long clinical record and the number of comparator biosimilars already on the market mean the analytical package is demanding and the comparative clinical study is usually run in plaque psoriasis or rheumatoid arthritis, the two indications regulators have accepted as sensitive models.