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Review
. 2024 Jan 19:15:20406223231223286.
doi: 10.1177/20406223231223286. eCollection 2024.

The totality of evidence approach in the development of AVT02 (adalimumab), a biosimilar to Humira

Joseph E McClellan  1 , Sesselja Ómarsdóttir  2   3 , Nivedita Roy  4 , Verena Berger  5 , Cecilia Michel  6 , Fausto Berti  6
Affiliations
Review

The totality of evidence approach in the development of AVT02 (adalimumab), a biosimilar to Humira

Joseph E McClellan et al. Ther Adv Chronic Dis. .

Abstract

The development of a biosimilar is based on comparative structural, physicochemical, functional and clinical assessments. The sum of these analyses encompasses the 'totality of evidence', which demonstrates no clinically meaningful differences between the biosimilar and the reference product (RP). Once biosimilarity has been established, provided there is suitable scientific justification, clinical data may be extrapolated to other indications of the RP. AVT02 has been developed as a biosimilar to high-concentration, low-volume Humira (adalimumab), an anti-tumour necrosis factor-alpha monoclonal antibody approved for various chronic inflammatory indications. The totality of evidence for AVT02 is described, supporting its approval as an adalimumab biosimilar for all approved indications globally. Analytical similarity assessments using mass spectrometry methods demonstrated identical amino acid sequences for AVT02 and the RP, with high similarity in terms of primary structure, post-translational modifications and higher-order structural attributes. The mechanism of action was assessed by various cell-based potency assays and binding assays, and the results demonstrated that AVT02 is highly similar to the RP. No clinically meaningful differences in terms of purity, potency and safety were observed, and minor differences in a few physiochemical attributes did not impact the in vitro biologic activity and were not considered clinically relevant. Clinical similarity was demonstrated by comparing the pharmacokinetic, efficacy, safety and immunogenicity profiles of AVT02 with those of the RP. Clinical studies supported similar pharmacokinetic and comparable immunogenicity profiles between AVT02 and the RP in healthy participants and participants with moderate-to-severe chronic plaque psoriasis, with no new safety signals detected. The totality of evidence described demonstrates the biosimilarity of AVT02 to the RP, thereby fulfilling the scientific and regulatory requirements for AVT02 as a high-concentration biosimilar for the treatment of chronic plaque psoriasis and all approved indications of the RP.

Keywords: adalimumab; biosimilar; chronic plaque psoriasis; extrapolation of indications; totality of evidence.

Plain language summary

Demonstrating the high similarity between the biosimilar AVT02 (adalimumab) and Humira, supporting AVT02 to be used to treat all conditions currently treated with Humira Biosimilars are drugs that have similar quality, effectiveness, and safety profiles to an already approved biological drug, which is referred to as the ‘reference product (RP)’. Although biosimilars have identical amino acids (the building blocks that make up proteins) to the RPs, they are manufactured in living cells which leads to a small amount of natural variability. Therefore, extensive testing is required to confirm that a biosimilar is highly similar to the RP. The ‘totality of evidence’ is a set of tests to demonstrate that there are no meaningful differences between the biosimilar and the RP, in other words, that there is ‘biosimilarity’ between the biosimilar and RP. Once biosimilarity has been proven, the biosimilar may be used to treat all the diseases currently treated with the RP, without the need for separate clinical trials in each disease. AVT02 has been developed as a biosimilar to Humira, an antibody approved for various chronic inflammatory diseases such as chronic plaque psoriasis (PsO). A step-by-step approach was used to show biosimilarity of AVT02 to Humira. This included clinical studies (in healthy individuals and participants with moderate to severe chronic PsO) and non-clinical studies (comparisons of the chemistry of the drugs and how they work in the body). Clinical studies in healthy individuals and participants with PsO showed that AVT02 and Humira were taken up and degraded by the body in a similar way, peoples’ immune response to the two drugs were similar, and both drugs had similar side effects. No clinically meaningful differences in the purity, effectiveness, and safety of AVT02 compared with Humira were seen. The evidence demonstrates the biosimilarity of AVT02 to Humira and supports the use of AVT02 to treat all conditions which are currently treated with Humira.

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Figures

Figure 1.
Figure 1.
Overview of known and purported mechanisms of action for adalimumab: (a) sTNF-adalimumab trimer complexes, (b) reverse signalling, (c) CDC and (d) ADCC. ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; sTNF, soluble tumour necrosis factor.
Figure 2.
Figure 2.
Overview of PK similarity assessment of adalimumab primary PK (AVT02-GL-101, PK population). Results are based on an analysis of variance with treatment and stratification factors as fixed effects. The data were logarithmically transformed prior to the analysis and then transformed back for the result presentation. *90% CI: FC method: p values for stages 1 and 2 data were recalculated using a range of limits (instead of 0.8 and 1.25) until the combined p value for the FC test equalled 0.05 – these final limits provided the 90% CI for the combined geometric mean ratio. AUC0–inf, area under the serum concentration–time curve from time zero (pre-dose) extrapolated to infinity; AUC0–t, area under the serum concentration–time curve from time zero (pre-dose) to the time of the last quantifiable concentration; CI, confidence interval; Cmax, maximum concentration; FC, Fisher’s combination; PK, pharmacokinetic; RP, reference product.
Figure 3.
Figure 3.
Mean serum concentration–time profiles of adalimumab by treatment group on (a) linear and (b) semi-logarithmic scales (AVT02-GL-101, PK population). The lower limit of quantitation = 7.5 ng/ml. Concentrations reported as below the limit of quantitation are set to zero for the calculation of summary statistics. Mean concentration values of zero are excluded from printing on the log concentration scale. PK, pharmacokinetic; RP, reference product.
Figure 4.
Figure 4.
LS mean (±SE) of percent improvement from baseline in PASI score by visit – FAS through (a) week 16 and (b) week 50 (AVT02-GL-301). Missing percent improvement in PASI is imputed using LOCF method for subjects with post-baseline assessment. BL, baseline; FAS, full analysis set; LOCF, last observation carry-forward; LS, least squares; PASI, Psoriasis Area and Severity Index; SE, standard error.
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