The Totality of Evidence Supporting the Approval of Adalimumab Biosimilar GP2017

A review article summarized the totality of evidence supporting the approval of the adalimumab biosimilar GP2017 (Hyrimoz; Sandoz) in the United States and Europe.

The totality of evidence refers to the stepwise approach to biosimilar development, a “robust dataset,” the authors said, required for “high confidence in biosimilarity between the proposed biosimilar and its reference medicine.” First, comprehensive analytical and functional assays confirm similarity in structure and function, followed by clinical studies: Pharmacokinetic similarity is investigated in healthy volunteers, and a comparative clinical trial examines efficacy, safety, and immunogenicity in a sensitive patient population.

Adalimumab is a monoclonal antibody targeting tumor necrosis factor (TNF)-α. The reference product (Humira), originally approved by the FDA in 2002, is used to treat immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel diseases (Crohn disease and ulcerative colitis). The adalimumab biosimilar GP2017 was approved in 2018 by both the FDA and European Medicines Agency (EMA) for all indications of the reference product not protected by orphan exclusivity.

The reference adalimumab is available in its original low-concentration formulation. However, the authors noted that a high-concentration, citrate-free formulation developed to reduce injection site pain has become the preferred formulation used in clinical practice. In 2023, a high-concentration, citrate-free formulation of GP2017 was also approved by the FDA and EMA.

Analytical and functional characterization

Analytical studies established primary and higher-order structural similarity, as well as post-translational modifications, of GP2017 to both the US and EU reference products. The reviewers wrote that functional assays demonstrated “a high degree of similarity” in TNF binding affinity, TNF neutralization, and additional attributes relating to the drug’s pharmacologic and biologic activity. According to the authors, TNF binding curves of the reference products and biosimilar were “superimposable” and 3-dimensional structures were “indistinguishable.”

Preclinical studies

Although preclinical studies in animal models are no longer required by the FDA or EMA for biosimilar approval, the authors wrote, “they may be run to address any residual uncertainties or to further support the evidence for biosimilarity.” They noted preclinical studies “were recommended to be included in the data package at the time of initial development” of GP2017. Mean serum concentrations of the biosimilar and reference product were similar following a single dose in rabbits, and similar improvements in arthritis symptoms in response to GP2017 and the reference product were demonstrated in a transgenic mouse model.

Pharmacokinetics in healthy subjects

Pharmacokinetic similarity was demonstrated in a 3-arm phase 1 study comparing the biosimilar to the US and EU reference products in healthy male volunteers. The 90% CIs for the ratios of the geometric least square means of the primary and secondary pharmacokinetic endpoints were within the predefined pharmacokinetic similarity margins. There were also “no relevant differences” in safety, tolerability, and immunogenicity between GP2017 and either reference product. The authors noted that this study also reported similar pharmacokinetic parameters of the biosimilar as delivered by either prefilled syringe or autoinjector. Additionally, a phase 1 pharmacokinetic bridging study established similar pharmacokinetic parameters of the high-concentration, citrate-free formulation of GP2017 to the original biosimilar formulation.

Comparative clinical efficacy trials

Two clinical trials demonstrated biosimilarity of GP2017 to the reference product in safety, efficacy, and immunogenicity. ADACCESS, a confirmatory clinical trial included in both US and EU approval dossiers, “reported no clinically meaningful differences in efficacy, safety or immunogenicity” in patients with chronic plaque psoriasis who were treated with the biosimilar or reference product continually or underwent up to 4 switches. The primary endpoint of this trial was the proportion of patients who achieved a 75% improvement in Psoriasis Activity and Sensitivity Index (PASI) score (PASI 75) at week 16, prior to any switches, and the difference between groups was within the +/- 18% equivalence margin. “Similar and low” rates of adverse events were observed between groups, as well as similar incidence of antidrug antibodies. After switching in a subset of patients, the authors said, “clinical outcomes remained consistent,” and safety and immunogenicity were also similar in all groups.

Another clinical trial, ADMYRA, was conducted “to support worldwide registration purposes” of GP2017, the reviewers said. This trial included patients with moderate to severe RA who had an inadequate response to disease modifying anti-rheumatic drugs. Patients were randomized to receive GP2017 for 48 weeks or undergo a single switch from the reference product to GP2017 at week 24, and continue treatment to week 48. According to the authors, ADMYRA demonstrated efficacy, safety and immunogenicity profiles of GP2017 “matching” the reference product, and “this comparable efficacy was sustained after switching…with no impact on safety and immunogenicity.”

Finally, the reviewers added, patient-reported outcomes and quality of life measures were included in both ADACCESS and ADMYRA, with “comparable improvements” in these measures in biosimilar and reference product groups, “and these outcomes were not affected by treatment switching.” The authors closed saying the totality of evidence they described can assure patients and prescribers that both GP2017 and its high-concentration, citrate-free formulation are “effective alternative adalimumab biosimilars that provide similar efficacy and safety as their reference medicine.”

Reference

Gaylis N, Both C, Lemke L, von Richter O, Yamauchi P. 'Totality of Evidence' approach in the development of GP2017, an approved adalimumab biosimilar. Adv Ther. Published online March 21, 2024. doi:10.1007/s12325-024-02809-w