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The Totality of Evidence Supporting Adalimumab Biosimilar AVT02


A review article described the totality of evidence supporting the approval of the adalimumab biosimilar AVT02 (Simlandi; Alvotech) for all approved indications of the reference product, Humira.

A review article described the totality of evidence supporting the approval of the adalimumab biosimilar AVT02 (Simlandi; Alvotech) for all approved indications of the reference product, Humira. AVT02 demonstrated biosimilarity to Humira in structure, function, and pharmacokinetics. A comparative clinical trial in patients with psoriatic arthritis found no clinically meaningful differences in efficacy, safety, and immunogenicity, the authors reported.

“Totality of evidence” refers to the stepwise approach of evaluating biosimilarity between a proposed biosimilar and the originator product it references. Biosimilars have an identical amino acid sequence to their reference products, however, the authors noted, there is “inherent variability” because biologics are manufactured using living cells. The stepwise approach includes comparative analytical assessments assessing structure and in vitro biological activity of the biosimilar molecule, comparative clinical pharmacokinetics (PK) and/or pharmacodynamics (PD) in healthy subjects, and finally a comparative clinical trial evaluating efficacy, safety, and immunogenicity in an indication of the reference product.

injectable pen | Image credit: Orawan - stock.adobe.com

Image credit: Orawan - stock.adobe.com

Adalimumab is a monoclonal antibody targeting tumor necrosis factor (TNF)-α, used to treat several autoimmune and inflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. The biosimilar AVT02 references the high-concentration, citrate-free formulation of the reference product. The authors noted this formulation offers advantages over the higher-volume formulation, as it is “more patient-friendly with less injection site-related pain.” AVT02 was approved by the FDA in February 2024.

“High similarity” in Structure and Post-Translational Modifications

Analytical studies compared adalimumab AVT02 to both the US and EU reference products. The amino acid sequence is identical, with “high similarity” in primary structure and post-translational modifications. Differences in post-translational modifications (glycation, afucosylation, and deamidation) as well as oxidation and C-terminal heterogeneity were detected but did not affect biological activity of the antibody and were considered not clinically meaningful.

Similarly, the distribution of charge variants differed between AVT02 and the reference product, however, “these differences did not lead to any detectable decrease in biological activity or function,” the authors wrote.

Biological activity was assessed based on mechanisms of action involving both the antigen-binding fragment and Fc region of the antibody. AVT02 was similar to the reference product in assays measuring binding to and inhibition of both soluble and transmembrane TNF. High similarity was also demonstrated in assays indicating antibody-dependent cell-mediated cytotoxicity. The authors also noted that AVT02 demonstrated similarity in assays particularly relevant to reference adalimumab’s mechanisms or proposed mechanisms in inflammatory bowel disease.

Similar Pharmacokinetics Profiles Between AVT02 and Reference Adalimumab

Pharmacokinetics of AVT02 were compared to both the US and EU reference products in 390 healthy subjects following a single subcutaneous dose. Primary pharmacokinetic parameters were maximum concentration (Cmax), area under the serum concentration–time curve from time zero to the time of the last quantifiable concentration (AUC0–t), and area under the serum concentration–time curve from time zero extrapolated to infinity (AUC0–inf). Pairwise comparisons to both US and EU reference products for all primary pharmacokinetic parameters were within the predefined margins for biosimilarity. The authors added that further support for pharmacokinetic similarity was provided by the comparative clinical trial in psoriatic arthritis, in which there was “no clinically meaningful difference” in pharmacokinetic parameters and trough concentrations between AVT02 and the reference product.

Comparative Clinical Efficacy and Safety Trial in Psoriatic Arthritis

In line with FDA and European Medicines Agency guidelines, the comparative clinical efficacy and safety trial was conducted in psoriatic arthritis, deemed to be the most sensitive patient population for detecting differences between the biosimilar and reference product, because of its high placebo-adjusted response rate. Furthermore, this indication was selected as the most sensitive for detecting differences in safety and immunogenicity ”since patients are usually treated with biologic monotherapy, without the potential adverse events and impact on the immunogenicity of concomitant medication,” the authors wrote.

The 54-week, randomized, double-blind, parallel-group study included 412 adult participants randomized to receive either the biosimilar or EU reference product every other week. At week 16, patients on the reference product were rerandomized to undergo a switch to AVT02 or remain on the reference product up to week 48. The primary efficacy endpoint, percent improvement in the Psoriasis Area Severity Index (PASI) score from baseline to week 16, was similar in the 2 groups, at 89% in the biosimilar group and 87% in the reference product group. Furthermore, secondary efficacy endpoints and subgroup analyses based on antidrug antibody status also showed no clinically meaningful differences between groups.

Safety data was assessed from five clinical trials. According to the authors, no clinically meaningful differences between AVT02 and either the US or EU reference product in safety profiles were observed after a single administration in healthy subjects, and the safety results in noncomparative and comparative clinical trials were “in line with the known safety profile of the [reference product] and did not reveal any unexpected signals.” They added that the frequency of injection site reactions and injection site pain rates were similar to those of the reference product “supporting the attributes of the new high-concentration citrate-free formulation.”

The incidence of immunogenicity in the pharmacokinetic study was high, the authors said, “as expected in healthy participants and well known for the [reference product],” and was similar between groups. In the comparative clinical trial in psoriatic arthritis, immunogenicity was also similar between biosimilar and reference product groups, and antidrug antibodies (ADAs) and neutralizing antibodies (nAbs) were detected in most participants “irrespective of treatment.” Additionally, there was no difference in adalimumab serum trough concentrations between the biosimilar and reference product in subgroups with or without ADAs or nAbs.

Altogether, the authors concluded, “the totality of evidence described demonstrates the biosimilarity of AVT02 to the [reference product], thereby fulfilling the scientific and regulatory requirements for high-concentration formulation of AVT02 as a biosimilar.”


McClellan JE, Ómarsdóttir S, Roy N, Berger V, Michel C, Berti F. The totality of evidence approach in the development of AVT02 (adalimumab), a biosimilar to Humira. Ther Adv Chronic Dis. 2024;15:20406223231223286. doi:10.1177/20406223231223286

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