Efficacy and Safety of BCD-085, a Novel Interleukin-17 Inhibitor. Results of Phase II Clinical Trial in Patients with Moderate-to-Severe Plaque Psoriasis

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Abstract

Recent studies on psoriasis confirmed that interleukin-17 (IL-17) plays a crucial role in the progression of the disease. Inhibition of this cytokine leads to significant improvement in the course of the disease. Russian biotechnology company BIOCAD have developed an innovative drug, a monoclonal antibody against IL-17, BCD-085. The main objective of the phase II study was to determine the optimal therapeutic dose of BCD-085 in patients with moderate-tosevere plaque psoriasis. The efficacy, safety, and pharmacokinetics of the drug have also been investigated.

Materials and methods

The study was an international multicenter, comparative, randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of multiple subcutaneous administration of various doses of BCD-085 to patients with moderate to severe plaque psoriasis. Patients were randomized into 4 groups in 1:1:1:1 ratio: group 1 received BCD-085 at a dose of 40 mg, group 2 – 80 mg, group 3 – 120 mg, and group 4 received placebo. Administration of BCD-085/placebo was performed subcutaneously on day 1 at weeks 0, 1, 2, and then on day 1 at weeks 4, 6, 8, 10.

Results

All studied doses of BCD-085 demonstrated significant superiority over placebo and high efficacy in the treatment of plaque psoriasis. PASI 75 at week 12 was reached by 92.68% of patients in group 3 (120 mg of BCD-085), 83.33% in group 2 (80 mg of BCD-085), 80.0% in group 1 (40 mg of BCD-085), and 23.08% in group 4 (placebo) (p < 0.0001). In the course of the study, the dose-dependent effect of the drug was demonstrated. The drug showed favorable safety profile (no cases of serious adverse events or early withdrawal due to adverse events, no cases of adverse events with 4 grade of severity according to CTCAE 4.03). According to the results of pharmacokinetics study, the drug is characterized by a linear increase in serum BCD-085 concentration, reaching its maximum by the end of the first week of observation, and by slow elimination.

Conclusion

BCD-085 showed high efficiency, more than 90% of patients reached PASI 75 by the 12th week of treatment, and a favorable safety profile. Based on the results of the phase II study, the optimal therapeutic dose was 120 mg.

About the authors

A. V. Samtsov

Military Medical Academy of S. M. Kirov of the Ministry of Defence of the Russian Federation, St. Petersburg

Email: fake@neicon.ru
Akademika Lebedeva str., 6, lit. Ж, 194044 Russian Federation

V. R. Khairutdinov

Military Medical Academy of S. M. Kirov of the Ministry of Defence of the Russian Federation, St. Petersburg

Email: fake@neicon.ru
Akademika Lebedeva str., 6, lit. Ж, 194044 Russian Federation

A. L. Bakulev

Saratov State Medical University named after V. I. Razumovsky of the Ministry of Health of the Russian Federation, Saratov

Email: fake@neicon.ru
Bol’shaya Kazach’ya str., 112, 410012 Russian Federation

A. A. Kubanov

State Scientific Centre of Dermatovenereology and Cosmetology of the Ministry of Health of the Russian Federation, Moscow

Email: fake@neicon.ru
Korolenko str., 3, bldg 6, 107076 Russian Federation

A. E. Karamova

State Scientific Centre of Dermatovenereology and Cosmetology of the Ministry of Health of the Russian Federation, Moscow

Email: fake@neicon.ru
Korolenko str., 3, bldg 6, 107076 Russian Federation

A. V. Artem’eva

Closed Joint-stock Company BIOCAD, St. Petersburg

Author for correspondence.
Email: artemevaav@biocad.ru
Svyazi str., 34, lit. A, Strelna, 198515 Russian Federation

T. V. Korotaeva

Research Institute of Rheumatogy named after V. A. Nasonova, Moscow

Email: fake@neicon.ru
Kashirskoe shosse, 34A, 115522 Russian Federation

References

  1. Кубанов А. А., Зырянов С. К., Белоусов Д. Ю. Клинико-экономический анализ эффективности применения биологических препаратов для лечения псориаза. Качественная клиническая практика. 2015;(3):34– 42. [Kubanov A. A., Zyryanov S. K., Belousov D. Yu. Kliniko-ehkonomicheskij analiz ehffektivnosti primeneniya biologicheskih preparatov dlya lecheniya psoriaza. Kachestvennaya klinicheskaya praktika. 2015;(3):34–42.]
  2. Lowes M. A., Suárez-Fariñas M., Krueger J. G. Immunology of Psoriasis. Annu. Rev. Immunol. 2014;32:227–255.
  3. Krueger J. G. The Immunologic Basis for the Treatment of Psoriasis with New Biologic Agents. J. Am. Acad. Dermatol. 2002;46(1):1–23.
  4. Weger W. Current Status and New Developments in the Treatment of Psoriasis and Psoriatic Arthritis with Biological Agents. Br. J. Pharmacol. 2010;160(4):810–820.
  5. FDA. Information for Healthcare Professionals: Cimzia (Certolizumab Pegol), Enbrel (Etanercept), Humira (Adalimumab), and Remicade (Infliximab). September 4, 2008.
  6. Gaffen S. L., Jain R., Garg A. V., Cua D. J. The IL-23–IL-17 Immune Axis: from Mechanisms to Therapeutic Testing. Nat. Rev. Immunol. 2014;14(9):585–600.
  7. Lowes M. A., Russell C. B., Martin D. A. et al. The IL-23/T17 Pathogenic Axis in Psoriasis is Amplified by Keratinocyte Responses. Trends Immunol. 2013;34(4):174–181.
  8. Griffiths C. E., Strober B. E., van de Kerkhof P. et al. Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis. N. Engl. J. Med. 2010;362(2):118–128.
  9. Reich K., Puig L., Paul C. et al. One-Year Safety and Efficacy of Ustekinumab and Results of Dose Adjustment after Switching from Inadequate Methotrexate Treatment: the TRANSIT Randomized Trial in Moderate-to-Severe Plaque Psoriasis. Br. J. Dermatol. 2014;170(2):435–444.
  10. Fellner C. More Biologic Therapies Expected to Treat Advanced Plaque Psoriasis. P. T. 2016;41(6):388–390.
  11. Miossec P. Update on Interleukin-17: a Role in the Pathogenesis of Inflammatory Arthritis and Implication for Clinical Practice. RMD Open. 2017;3(1):e000284.
  12. Langley R. G., Elewski B. E., Lebwohl M. et al. Secukinumab in Plaque Psoriasis – Results of Two Phase 3 Trials. N. Engl. J. Med. 2014;371(4):326–338.
  13. Griffiths C. E., Reich K., Lebwohl M. et al. Comparison of Ixekizumab with Etanercept or Placebo in Moderate-to-Severe Psoriasis (UNCOVER-2 and UNCOVER-3): Results from Two Phase 3 Randomised Trials. Lancet. 2015;386(9993):541–551.
  14. Farahnik B., Beroukhim K., Abrouk M. et al. Brodalumab for the Treatment of Psoriasis: A Review of Phase III Trials. Dermatol. Ther. (Heidelb.) 2016;6(2):111–124.
  15. Malakouti M., Brown G. E., Wang E. et al. The Role of IL-17 in Psoriasis. J. Dermatolog. Treat. 2015;26(1):41–44.
  16. Насонов Е. Л. Новые возможности фармакотерапии имму- новоспалительных ревматических заболеваний: фокус на ингибиторы интерлейкина 17. Научно-практическая ревматология. 2017;55(1):68–86. [Nasonov E. L. Novye vozmozhnosti farmakoterapii immunovospalitel'nyh revmaticheskih zabolevanij: fokus na ingibitory interlejkina 17. Nauchnoprakticheskaja revmatologija. 2017;55(1):68–86.]
  17. Zhu S., Qian Y. IL-17/IL-17 Receptor System in Autoimmune Disease: Mechanisms and Therapeutic Potential. Clin. Sci. 2012;122(11):487– 511. Martin D. A., Towne J. E., Kricorian G. et al. The Emerging Role of IL-17 in the Pathogenesis of Psoriasis: Preclinical and Clinical Findings. J. Invest. Dermatol. 2013;133(1):17–26.
  18. Rouvier E., Luciani M. F., Mattéi M. G. et al. CTLA-8, Cloned from an Activated T Cell, Bearing AU-Rich Messenger RNA Instability Sequences, and Homologous to a Herpesvirus Saimiri Gene. J. Immunol. 1993;150(12):5445–5456.
  19. Elloso M. M., Gomez-Angelats M., Fourie A. M. Targeting the Th17 Pathway in Psoriasis. J. Leukoc. Biol. 2012;92(6):1187–1197.
  20. Yilmaz S. B., Cicek N., Coskun M. et al. Serum and Tissue Levels of IL-17 in Different Clinical Subtypes of Psoriasis. Arch. Dermatol. Res. 2012;304(6):465–469. Yan K. X., Fang X., Han L. et al. Foxp3+ Regulatory T Cells and Related Cytokines Differentially Expressed in Plaque vs. Guttate Psoriasis Vulgaris. Br. J. Dermatol. 2010;163(1):48–56.
  21. Miossec P., Kolls J. K. Targeting IL-17 and Th17 Cells in Chronic Inflammation. Nat. Rev. Drug Discov. 2012;11(10):763–776.
  22. Burchill M. A., Nardelli D. T., England D. M. et al. Inhibition of Interleukin-17 Prevents the Development of Arthritis in Vaccinated Mice Challenged with Borrelia burgdorferi. Infect. Immun. 2003;71(6):3437–3442.
  23. Mangan P. R., Su L. J., Jenny V. et al. Dual Inhibition of Interleukin-23 and Interleukin-17 Offers Superior Efficacy in Mouse Models of Autoimmunity. J. Pharmacol. Exp. Ther. 2015;354(2):152–165.
  24. Reszke R., Szepietowski J. C. Secukinumab in the Treatment of Psoriasis: an Update. Immunotherapy. 2017;9(3):229–238.
  25. Hofstetter H. H., Ibrahim S. M., Koczan D. et al. Therapeutic Efficacy of IL-17 Neutralization in Murine Experimental Autoimmune Encephalomyelitis. Cell Immunol. 2005;237(2):123–130.
  26. Genovese M. C., Van den Bosch F., Roberson S. A. et al. LY2439821, a Humanized Anti–Interleukin-17 Monoclonal Antibody, in the Treatment of Patients With Rheumatoid Arthritis. Arthritis Rheum. 2010;62(4):929–939.
  27. Waite J. C., Skokos D. Th17 Response and Inflammatory Autoimmune Diseases. Int. J. Inflam. 2012;2012:819467.
  28. FDA. Pharmacology Review(s). Application Number: 125504Orig1s000. 2013.
  29. Ekimova V., Ulitin A., Evdokimov S. et al. High Affinity Anti-IL17A Monoclonal Antibody. Poster presentation. PEGS 2015. Unpublished data.
  30. Федеральный закон «Об обращении лекарственных средств» от 12.04.2010 № 61-ФЗ. [Federal'nyj zakon "Ob obrashhenii lekarstvennyh sredstv" ot 12.04.2010 N 61-FZ.]
  31. FDA, Guidance for Industry S6 Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (May 2012) as adopted by FDA at 77 Fed. Reg. 29665, 29666 (May 18, 2012).
  32. Guidelines on the Quality, Safety, and Efficacy of Biotherapeutic Protein Products Prepared by Recombinant DNA Technology.
  33. Patent WO2016048188 Publication Date 2016-03-3 High Affinity and Aggregatively Stable Antibodies on the Basis of Variable Domains Vl and a Derivative VНН. Ulitin A., Evdokimov S., Solovyev V. et al.
  34. Chernyaeva E., Eremeeva A., Galustyan A. et al. Pharmacokinetics, Safety and Tolerance of BCD-085, a Novel IL-17 Inhibitor, Based on the Results of Phase 1 Clinical Study in Healthy Volunteers. Ann. Rheum. Dis. 2016;75:429.
  35. Papp K. A., Langley R. G., Sigurgeirsson B. et al. Efficacy and Safety of Secukinumab in the Treatment of Moderate-to-Severe Plaque Psoriasis: a Randomized, Double-Blind, Placebo-Controlled Phase II DoseRanging Study. Br. J. Dermatol. 2013;168(2):412–421.
  36. Leonardi C., Matheson R., Zachariae C. et al. Anti-Interleukin-17 Monoclonal Antibody Ixekizumab in Chronic Plaque Psoriasis. N. Engl. J. Med. 2012;366(13):1190–1199.

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Copyright (c) 2017 Samtsov A.V., Khairutdinov V.R., Bakulev A.L., Kubanov A.A., Karamova A.E., Artem’eva A.V., Korotaeva T.V.

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