Adalimumab is the most commonly prescribed biological and is approved for rheumatoid arthritis as well as psoriasis, psoriatic arthritis, along with Crohn’s and ulcerative colitis. Its patent life terminated in 2016 in the US [1]. However, in the US AbbVie has stated that, although the composition of matter patent covering Humira expired in December 2016, non-composition of matter patents covering Humira expire no earlier than 2022. The company has therefore made settlement agreements with Amgen and Samsung Bioepis, delaying the launch of biosimilars until January 2023 [2, 3].
Multiple adalimumab biosimilars have been and are in development. The first adalimumab biosimilar approved was ABP501 developed by Amgen as Amjevita in the US and Amgevita/Solymbic in Europe in 2016.
BI 695501 is an adalimumab biosimilar approved by the US Food and Drug Administration and the European Medicines Agency as Cyltezo in 2017 based on the totality of the evidence [4, 5]. Extensive structural and functional analyses were conducted comparing BI 695501 to originator adalimumab demonstrating that the biosimilar was highly similar in structure notwithstanding minor differences that had no impact on function of the molecule. Multiple assays were performed evaluating functional attributes such as ADCC, CDC and FcGamma binding, which demonstrated the equivalence between the biosimilar and the originator biological based on pre-specified criteria established by the regulatory agencies. Pharmacokinetic studies in healthy volunteers demonstrated the equivalence of the biosimilar to the originator in parameters such as AUC and Cmax [6].
A phase III randomized clinical trial was conducted in patients with active rheumatoid arthritis on stable methotrexate who were randomized to BI 695501 or Humira in a double-blind, parallel-group, equivalence study [7]. At Week 24, patients were re-randomized to continue on BI 695501 or Humira, or switch from Humira to BI 695501. The co-primary endpoints were the percentage of patients achieving American College of Rheumatology 20% response criteria (ACR20) at Weeks 12 and 24. Further efficacy and safety endpoints and immunogenicity were assessed up to Week 58.
Of the 645 patients that were randomized, 67.0% and 67.1% (90% CI: -0.9 to 12.7) of patients receiving BI 695501 (n = 324) and Humira (n = 321), respectively, achieved ACR20 at Week 12. At Week 24 the corresponding values were 69.0% and 64.5% (95% CI: -3.4 to 12.5). These differences were within pre-specified margins (Week 12 90% CI: -12 to 15%; Week 24 95% CI:-15 to 15%), demonstrating therapeutic bioequivalence. At Week 24, 593 patients were re-randomized. Up to Week 48, the mean change from baseline in Disease Activity Score 28-erythrocyte sedimentation rate and ACR20/ACR50/ACR70 response rates were similar across the switched (n = 147), continuous BI 695501 (n = 298), and continuous Humira (n = 148) groups. Similar immunogenicity [anti-drug antibodies (ADAs), ADA titres and neutralizing antibodies] was seen between BI 695501 and Humira (to Week 24), and across re-randomized groups (to Week 48). Safety and tolerability profiles were similar between groups.
Cyltezo is not commercially available at this time. Boehringer Ingelheim is currently engaged in patent litigation with AbbVie. Boehringer Ingelheim also intends to seek approval for an auto-injector of Cyltezo, as another delivery option for patients.
Conflict of interest
Several of the authors of the research paper [7] reported conflict of interest, including having received funding from Boehringer Ingelheim or being employees of Boehringer Ingelheim. For full details of the authors’ conflict of interest, see the research paper [7].
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References
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2. GaBI Online - Generics and Biosimilars Initiative. Amgen’s adalimumab biosimilar will only be launched in US in 2023 [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Jun 22] Available from: www.gabionline.net/Biosimilars/News/Amgen-s-adalimumab-biosimilar-will-only-be-launched-in-US-in-2023
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4. GaBI Online - Generics and Biosimilars Initiative. FDA approves adalimumab biosimilar Cyltezo [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Jun 22]. Available from: www.gabionline.net/Biosimilars/News/FDA-approves-adalimumab-biosimilar-Cyltezo
5. GaBI Online - Generics and Biosimilars Initiative. EC approval for adalimumab biosimilar Cyltezo [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Jun 22]. Available from: www.gabionline.net/Biosimilars/News/EC-approval-for-adalimumab-biosimilar-Cyltezo
6. Wynne C, Altendorfer M, Sonderegger I, et al. Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE®-PK) in healthy subjects. Expert Opin Investig Drugs. 2016;25(12):1361-70.
7. Cohen SB, Alonso-Ruiz A, Klimiuk PA, et al. Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomised VOLTAIRE-RA equivalence study. Ann Rheum Dis. 2018;77(6):914-21.
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