Comparative efficacy and safety of adalimumab biosimilar (BCD-057) and innovator in patients with psoriasis vulgaris. Results of the BCD-057-2/CALYPSO phase III international, multicenter, randomized double-blind clinical trial

The paper gives the results of the phase III clinical trial of adalimumab (ADA) biosimilar, (BCD-057) (BIOCAD, Russia), which demonstrate the clinical equivalence of the biosimilar to the ADA innovator Humira® in patients with moderate and severe psoriasis.
Objective. The BCD-057-2/CALYPSO phase III international, multicenter, randomized double-blind clinical trial of the efficacy and safety of BCD-057 (International Nonproprietary Name (INN): adalimumab, ZAO «BIOCARD», Russia) versus Himura® (INN: adalimumab (OOO «Abbvie») in patients with plaque psoriasis aims to prove the equivalent pharmacokinetics, efficacy, safety, and immunogenicity of these medicines in both direct parallel comparison and subsequent switching from innovator to biosimilar.
Patients and methods. The investigation enrolled 346 adult patients diagnosed with moderate to severe plaque psoriasis lasting at least 6 months. After screening, the patients were randomized in a 1:1 ratio into BCD-057 or Humira® groups. At week 24, the patients taking Humira® were re-randomized 1:1 into a group to continue treatment with the ADA innovator or into that to switch to BCD-057. The primary efficacy endpoint was to estimate the proportion of patients who had achieved a 75% improvement in Psoriasis Area and Severity Index (PASI75) at week 16. The secondary endpoints included the assessment of the time course of changes in the skin, nails, degree of itching, and quality of life at weeks 16 and 24. Safety was evaluated from the incidence of treatment-associated adverse events (AEs), cases of severe toxicity (grades 3–4 AEs according to the Common Terminology Criteria Adverse Event (CTCAE) 4.03), cases of early patient withdrawal due to AEs, as well as cases of toxicity potentially associated with the use of tumor necrosis factor-α inhibitors. Immunogenicity was determined using the validated test of patient serum samples for binding antibodies (BAb) and neutralizing antibodies.
Results and discussion. The per-protocol population for efficacy evaluation included 342 patients. At week 16, the primary endpoint of PASI75 was shown to be achieved by 62.5% (105/168) and 66.46% (109/164) of the patients in the BCD-057 and Himura® groups, respectively; p=0.45). The difference between the groups in PASI75 responses was 3.22% with 95% confidence interval [-14.25%; 6.32%]. The analysis of additional endpoints revealed no significant differences in the efficacy of the biosimilar and innovator. During 24 weeks of the investigation, treatment-associated AEs were recorded in 31.03 and 25.58% of the patients in the BCD-057 and Humira® groups, respectively (p=0.31). The proportion of patients with BAb detected at 16 weeks of the investigation was 25.44 and 24.07% in the BCD-057 and Humira® groups, respectively (p=0.87).
Conclusion. The investigation provided convincing clinical evidence for of the equivalent efficacy, safety, and immunogenicity of BCD-057 and Humira®.

1. Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol. 2015 Jan;27(1):55-62. doi: 10.1093/intimm/dxu102. Epub 2014 Nov 19.

2. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016 Jan;12(1):49-62. doi: 10.1038/nrrheum.2015.169. Epub 2015 Dec 10.

3. Vinay DS, Kwon BS. The tumour necrosis factor/TNF receptor superfamily: therapeutic targets in autoimmune diseases. Clin Exp Immunol. 2011 May;164(2):145-57. doi: 10.1111/j.1365-2249.2011.04375.x. Epub 2011 Mar 14.

4. https://www.drugs.com/history/enbrel.html

5. https://www.drugs.com/remicade.html

6. http://grls.rosminzdrav.ru

7. Nasonov EL, Karateev DE, Satybaldyev AM, et al. Rheumatoid arthritis in the Russian Federation according to Russian arthritis registry data (Communication I). Nauchnoprakticheskaya revmatologiya = Rheumatology Science and Practice. 2015;53(5):472–84. (In Russ.). Doi: 10.14412/1995-4484-2015-472-484

8. Nasonov EL. Biosimilars in rheumatology. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2016;54(6):628-40. (In Russ.). doi: 10.14412/1995-4484-2016-628-640

9. Kay J, Schoels MM, Dö rner T, et al; Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases. Ann Rheum Dis. 2018 Feb;77(2):165-174. doi: 10.1136/annrheumdis-2017-211937. Epub 2017 Sep 2.

10. Nasonov EL. The results of a phase IIIcomparative clinical trial of rituximab (Acellbia® and Mabthera®) in rheumatoid arthritis (the BIORA study). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2016;54(5):510-9. (In Russ.). doi: 10.14412/1995-4484-2016-510-519

11. Karateev DE, Mazurov VI, Zonova EV, et al. Comparative efficacy and safety of infliximab biosimilar (BCD-055) and innovator infliximab in patients with ankylosing spondylitis (results of international, multiple-center, double-blind phase I and phase III clinical studies). Sovremennaya revmatologiya = Modern Rheumatology Journal. 2017;11(3):14-25. (In Russ.). doi: 10/14412/1996-7012-2017-3-14-25

12. Eremeeva A, Fogt S, Chernyaeva E, et al AB0034 Pharmacokinetics and Safety of BCD-057, Adalimumab Biosimilar Candidate, Compared To Humira in Healthy Volunteers (Results of Phase I Clinical Study). Ann Rheum Dis. 2016;75:908

13. https://clinicaltrials.gov/ct2/show/NCT02762955

14. Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005 Mar;64 Suppl 2:ii65-8.

15. Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad Dermatol. 2003 Aug; 49(2):206-12.

16. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf

17. Правила проведения исследований биологических лекарственных средств на территории Евразийского экономического союза, 2016. http://docs.cntd.ru/document/456026116

18. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. February 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM291128.pdf

19. Saurat JH, Stingl G, Dubertret L, et al; CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008 Mar;158(3):558-66. Epub 2007 Nov 28.

20. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheum. 2003 Jan;48(1):35-45.

21. Van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2006 Jul;54(7):2136-46.

22. Nasonov EL, editor. Rossiiskie klinicheskie rekomendatsii. Revmatologiya [Russian clinical guidelines. Rheumatology]. Moscow: GEOTAR-Media; 2017.

23. Kubanova AA, Kubanov AA, Znamenskaya LF, et al. Psoriaz. Klinicheskie rekomendatsii RODVK [Psoriasis. Clinical guidelines of RODVK]. Moscow; 2015. P. 415-70.

24. Hsu L, Snodgrass BT, Armstrong AW. Antidrug antibodies in psoriasis: a systematic review. Br J Dermatol. 2014 Feb;170(2):261-73. doi: 10.1111/bjd.12654.

25. Moots RJ, Xavier RM, Mok CC, et al. The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with ada limumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study. PLoS One. 2017 Apr 27;12(4):e0175207. doi: 10.1371/journal.pone.0175207.

26. European Medicines Agency. Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis. CHMP/EWP/2454/02 corr, 2004. https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-indicated-treatment-psoriasis_en.pdf