Effectiveness and safety of BCD180, anti-TRBV9⁺ T-lymphocytes monoclonal antibody in patients with active radiographic axial spondyloarthritis: 36-week results of double-blind randomized placebo-controlled phase II clinical study ELEFTA

The aim – to evaluate the clinical effectiveness, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of seniprutug (BCD-180) in patients with radiographic active axial spondyloarthritis (r-axSpA, or ankylosing spondylitis).
Subjects and methods. 260 patients with active r-axSpA and inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) were randomized into three groups: seniprutug (BCD-180) at doses of 5 mg/kg or 7 mg/kg, or placebo. BCD-180 was administered on weeks 0–12–36. Patients in the placebo group were switched to BCD-180 at a dose of 5 mg/kg at week 24 and continued therapy at week 36. The primary endpoint was the proportion of patients achieving 40% improvement by Assessment in Spondyloarthritis International Society scale (ASAS40) at week 24. Secondary endpoints were proportion achieving ASAS20/40, improvement of 5 out of 6 criteria of ASAS (ASAS5/6), ASAS partial remission, clinically important improvement in ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score with C-reactive protein) (ASDAS-CII) and major improvement in ASDAS-CRP (ASDAS-MI). The dynamics of the disease activity status according to ASDAS-CRP, the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) indices, as well as the dynamics of laboratory markers (C-reactive protein anderythrocyte sedimentation rate (ESR)) were analyzed. Safety was assessed by the frequency and profile of adverse events (AEs) and adverse reactions (ARs).
Results. The proportion of patients achieving ASAS40 at week 24 with seniprutug (BCD-180) at the dose of 7 mg/kg and 5 mg/kg was 51.4% and 40.8%, respectively, compared with 24% in the placebo group (p=0.0012 and p=0.0417, respectively). Analysis of secondary endpoints showed that in patients with r-axSpA, BCD-180 at both study doses was significantly superior to placebo at week 24 in the following measures: decrease in the proportion of subjects with very high disease activity (ASDAS-CRP>3.5) achieving ASDAS-CII, ASAS20, ASAS5/6. A statistically significant decrease in the ASDAS-CRP, BASDAI, BASFI indices, as well as the concentration of CRP and ESR were demonstrated. Tolerability of seniprutug therapy was assessed as acceptable. Infusion reactions were the most common observed adverse events, the vast majority of which were mild to moderate in severity according to CTCAE 5.0 (Common Terminology Criteria for Adverse Events) and developed predominantly during the first administration. The proportion of patients with binding antibodies was 5.1%. However, no neutralizing antibodies were detected.
Conclusion. Seniprutug (BCD-180) demonstrated superiority over placebo in clinical efficacy with a favorable safety profile and low immunogenicity as a treatment of r-axSpA.

1. Erdes ShF, Badokin VV, Bochkova AG, Bugrova OV, Gaidukova IZ, Godzenko AA, et al. On the terminology of spondyloarthritis. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2015;53(6):657-660 (In Russ.) doi: 10.14412/1995-4484-2015-657-660

2. Baraliakos X, Kiltz U, Peters S, Appel H, Dybowski F, Igelmann M, et al. Efficiency of treatment with non-steroidal antiinflammatory drugs according to current recommendations in patients with radiographic and non-radiographic axial spondyloarthritis. Rheumatology (Oxford). 2017;56(1):95-102. doi: 10.1093/rheumatology/kew367

3. Fragoulis GE, Siebert S. Treatment strategies in axial spondyloarthritis: What, when and how? Rheumatology (Oxford). 2020;59(Suppl 4):iv79-iv89.

4. Ramiro S, Nikiphorou E, Sepriano A, Ortolan A, Webers C, Baraliakos X, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis. 2023;82(1):19-34.

5. Walsh JA, Saffore CD, Collins EB, Ostor A. Clinical and economic benefit of advanced therapies for the treatment of active ankylosing spondylitis. Rheumatol Ther. 2023;10(5):1385-1398.

6. Juanola X, Ramos MJM, Belzunegui JM, Fernández-Carballido C, Gratacós J. Treatment failure in axial spondyloarthritis: Insights for a standardized definition. Adv Ther. 2022;39(4): 1490-1501.

7. Deodhar A, Yu D. Switching tumor necrosis factor inhibitors in the treatment of axial spondyloarthritis. Semin Arthritis Rheum. 2017;47(3):343-350.

8. Del Vescovo S, Venerito V, Iannone C, Lopalco G. Uncovering the underworld of axial spondyloarthritis. Int J Mol Sci. 2023;24(7):6463. doi: 10.3390/ijms24076463

9. Garrido-Mesa J, Brown MA. T cell repertoire profiling and the mechanism by which HLA-B27 causes ankylosing spondylitis. Curr Rheumatol Rep. 2022;24(12):398-410.

10. Komech EA, Pogorelyy MV, Egorov ES, Britanova OV, Rebrikov DV, Bochkova AG, et al. CD8+ T cells with characteristic T cell receptor beta motif are detected in blood and expanded in synovial fluid of ankylosing spondylitis patients. Rheumatology (Oxford). 2018;57(6):1097-1104.

11. Faham M, Carlton V, Moorhead M, Zheng J, Klinger M, Pepin F, et al. Discovery of T cell receptor β motifs specific to HLAB27-positive ankylosing spondylitis by deep repertoire sequence analysis. Arthritis Rheumatol. 2017;69(4):774-784.

12. Komech EA, Koltakova AD, Barinova AA, Minervina AA, Salnikova MA, Shmidt EI, et al. TCR repertoire profiling revealed antigen-driven CD8+ T cell clonal groups shared in synovial fluid of patients with spondyloarthritis. Front Immunol. 2022;13:973243.

13. Yang X, Garner LI, Zvyagin IV, Paley MA, Komech EA, Jude KM, et al. Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides. Nature. 2022;612(7941):771-777. doi: 10.1038/s41586-022-05501-7

14. Britanova OV, Lupyr KR, Staroverov DB, Shagina IA, Aleksandrov AA, Ustyugov YY, et al. Targeted depletion of TRBV9(+) T cells as immunotherapy in a patient with ankylosing spondylitis. Nat Med. 2023;29(11):2731-2736.

15. Israelson MA, Stepanov AV, Staroverov DB, Shagina IA, Misorin AK, Evstratieva AV, et al. Testing of monoclonal antibodies against the T-cell receptor associated with ankylosing spondylitis. Bulletin of RSMU. 2018;(5):83-92 (In Russ.) doi: 10.24075/brsmu.2018.064

16. European Medicines Agency. Guideline on the clinical investigation of medicinal products for the treatment of axial spondyloarthritis. EMA/CPMP/EWP/4891/03 Rev. 1, Corr. 1. 2017. URL: https://www.ema.europa.eu/en/clinical-investigationmedicinal-products-treatment-axial-spondyloarthritis#currenteffective-version-section (Accessed: 24th December 2021).

17. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, BurgosVargas R, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: A guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68(Suppl 2):ii1-ii44.

18. Maksymowych WP, Inman RD, Salonen D, Dhillon SS, Krishnananthan R, Stone M, et al. Spondyloarthritis Research Consortium of Canada magnetic resonance imaging index for assessment of spinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2005;53(4):502-509.

19. van der Heijde D, Lie E, Kvien TK, Sieper J, van den Bosch F, Listing J, et al. ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(12):1811-1818.

20. Gaydukova IZ, Rebrov AP, Poddubnyi DA. Efficacy and safety of intravenous methylprednisolone in the treatment of patients with active ankylosing spondylitis: Results of a 12-week, prospective, open-label, pilot (METALL) study. Terapevticheskii arkhiv. 2015;87(5):47-52 (In Russ.)