Study of the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of BCD-180 in Patients With Axial Spondyloarthritis (LEVENTA)

Inclusion Criteria:

1. Signed Informed Consent Form for participation in the study.

2. Men and women aged >18 years of age at the time of signing the Informed Consent Formfor participation.

3. Positive test result for HLA-B27.

5. Presence of r-axSpA OR nr-axSpA according to the criteria provided below:

• r-axSpA: axSpA diagnosis meets the ASAS 2009 criteria subject to the presenceof radiographic signs of sacroiliitis according to the modified New Yorkcriteria (van der Linden et al. 1984) according to the central review. Subjectswith an established diagnosis of ankylosing spondylitis according to themodified New York criteria may also be included in the study (van der Linden etal. 1984).

• nr-axSpA: axSpA diagnosis meets ASAS 2009 criteria in the absence ofradiographic signs of sacroiliitis according to the modified New York criteria (van der Linden et al. 1984) according to the central review.

5. Active disease at the screening and the randomization visit diagnosed based on bothcriteria:

• ASDAS-CRP ≥2.1

• assessment of the severity of back pain ≥4 on the NRS (BASDAI, question No. 2).

6. For subjects with nr-axSpA: presence of objective MRI signs of sacroiliitis (according to ASAS/OMERACT) as assessed by the central review AND/OR based on hsCRPlevel >1.5 ULN at screening.

7. For subjects with r-axSpA: hsCRP level ˃1.5 ULN at screening.

8. Duration of back pain ≥3 months, age <45 years at the onset of the axSpA-associatedback pain.

9. Meeting at least one of the following criteria based on the Investigator'sassessment:

• Inadequate response to therapy with NSAIDs defined as insufficient response totherapy with NSAIDs at therapeutic doses for at least 4 weeks, or insufficientresponse to therapy with two NSAIDs at the maximum permitted dose with thetotal duration of therapy of at least 4 weeks;

• Contraindications for therapy with NSAIDs;

• Intolerance of therapy with more than one NSAID.

10. For bDMARDs-experienced and/or targeted synthetic DMARD-experienced subjects (tsDMARD): meeting at least one of the following criteria based on theInvestigator's assessment:

• lack and/or loss of efficacy, according to the European Alliance ofAssociations for Rheumatology 2022 (EULAR 2022) recommendations, while ontherapy with adequate doses of bDMARDs or tsDMARDs for ≥12 weeks;

• intolerance of bDMARDs and/or tsDMARDs used for the treatment of axSpA (regardless of treatment duration).

11. For subjects continuing to receive NSAIDs or COX-2 inhibitors: the drug dose shallbe steady for at least 14 days prior to Visit 1/Week 0.

12. For women: negative pregnancy test result at screening (the test is not performed inwomen who have been postmenopausal for at least 2 years or are surgically sterile) .

13. The ability of the subject to follow the Protocol procedures, according to theInvestigator.

14. Willingness of subjects and their sexual partners of childbearing potential to usereliable methods of contraception from the date of signing the ICF, throughout thestudy, and for 8 weeks after the last administration of BCD-180/placebo (infusions)/adalimumab/placebo (subcutaneously). This requirement does not apply tosubjects who have had operative sterilization and women who have been postmenopausalfor more than 2 years.

15. For participants of childbearing potential, from signing the informed consent form,throughout the study, and for 8 weeks after the last dose of BCD-180/placebo (intravenously)/adalimumab/placebo (subcutaneous):

• no egg donation for female subjects;

• no sperm donation for male subjects.

Exclusion Criteria:

1. Refusal to take NSAIDs for the treatment of axSpA for any subjective reasons that donot have a clinical justification.

2. Use of the following medicines/procedures:

• at any time before signing the ICF: total lymphoid irradiation;

• at any time before signing the ICF: bone marrow transplantation, including stemand hematopoietic cell transplantation for any indications;

• at any time before signing the ICF: splenectomy;

• within 8 weeks before signing the ICF: treatment with immunoglobulins;

• within 12 months before signing the ICF: use of immunosuppressants. Exception:glucocorticoids. A subject receiving glucocorticoids may be included in thestudy provided that the daily dose of glucocorticoids is ≤10 mg/day (calculatedwith reference to prednisolone) and was stable for at least 4 weeks prior tothe Randomization Visit.

• within 4 weeks before signing the ICF and during the screening period: use ofsynthetic DMARDs and thiopurines, including, but not limited to: 6-mercaptopurine, azathioprine, and others. Exception: the medicinal products listed below if their dose was stable for 4 weeksbefore signing the ICF and during the screening period:

• oral or parenteral methotrexate at a dose ≤25 mg/week, therapy shall be startedat least 8 weeks before signing the ICF;

• 5-aminosalicylic acid and its derivatives, including sulfasalazine, at a dosenot exceeding 3 g/day, provided that therapy was started at least 8 weeksbefore signing the ICF. Subjects with inflammatory bowel disease (IBD) may betreated with topical 5-aminosalicylic acid at therapeutic doses;

• intra-articular and paraspinal glucocorticoids within 4 weeks prior to theRandomization Visit, intramuscular glucocorticoids within 2 weeks prior tothe Randomization Visit;

• use of alkylating agents at any time within 12 months prior to signing theICF;

• BCD-180 administration at any time before signing the ICF.

3. Vaccination with any vaccines within 12 weeks prior to signing the ICF.

4. Documented presence of one or more of the listed conditions:

• within 8 weeks before signing the ICF and during the screening period:exacerbated IBD (attack of Crohn's disease or exacerbation (relapse, attack) ofulcerative colitis), severe, generalized, pustular, exudative, psoriasis of thehands and feet;

• acute uveitis within less than 2 weeks prior to signing the ICF and during thescreening period. Clarification: for subjects with IBD: IBD therapy must be stable for 8 weeks priorto signing the ICF. For subjects with psoriasis: topical products may be used.

5. A current diagnosis or a history of a severe immunodeficiency of any origin.

6. A diagnosis of HIV infection, hepatitis B, hepatitis C.

7. The following laboratory test results at screening:

• Transaminase (ALT and/or AST) activity >1.5×ULN;

• ALP activity >1.5×ULN;

• WBC count <3.0 cells×109/L;

• Neutrophil count <1.5 cells×109/L;

• Lymphocyte count <0.8 cells×109/L;

• Platelet count <100 cells × 109/L;

• Hemoglobin level <100 g/L;

• Serum blood creatinine >ULN.

8. Clinically significant thyroid disease and/or clinically significant deviation ofthe TSH level from the reference values at screening.

9. Diagnosis of active or latent tuberculosis, including a history of tuberculosis .

10. Major surgery within 4 weeks prior to signing the ICF or major surgery planned forthe period of participation in the study.

11. Documented diagnosis of infectious mononucleosis within 8 weeks prior to signing theICF and during the screening period, any active infection or recurrent infectionwithin 4 weeks prior to signing the ICF and during the screening period, includingfever ≥38°C at the Randomization Visit.

12. Documented diagnosis of any other chronic infection that, in the opinion of theinvestigator, can increase the risk of infectious complications.

13. Severe infectious diseases (requiring hospitalization, parenteral use ofantibacterial, antimycotic or antiprotozoal drugs) within 8 weeks prior to signingthe ICF and during the screening period.

14. Systemic antibacterial, antimycotic or antiprotozoal therapy within 8 weeks prior tosigning the ICF and during the screening period.

15. Epileptic seizures, a history of seizures.

16. A history of or current (at the time of signing the ICF and during the screeningperiod) significant uncontrolled neuropsychiatric disorders, severe depressionand/or suicide attempts, a risk of suicide and/or any psychiatric illness that, inthe opinion of the investigator, may pose an excessive risk to the subject or havean impact on the subject's ability to follow the protocol.

17. Known (including from historical data) alcohol or drug dependence, psychoactivesubstance or drug abuse, evidence of alcohol/drug dependence or current abuse that,in the investigator's opinion, is a contraindication to AS therapy or limitstreatment adherence.

18. The following diseases:

• at screening and/or in the past and at the Randomization Visit: non-axSpAinflammatory joint disease (including rheumatoid arthritis, gout, psoriaticarthritis, Lyme disease, etc.),

• at screening and/or at the Randomization Visit: reactive arthritis,

• at screening and/or in the past and at the Randomization Visit: systemicautoimmune diseases (including systemic lupus erythematosus, systemicscleroderma, inflammatory myopathy, mixed forms of inflammatory connectivetissue diseases, overlap syndrome, etc.). Exception: the following subjects may be included in the study:

• eligible patients with psoriasis;

• diagnosed with IBD, at the stage of remission without the need for systemictherapy;

• with uveitis associated with axSpA, except for subjects with severe visualimpairment or with sight in one eye, subjects with corneal opacity, significantcataract, posterior capsule opacity, or posterior synechia in the studied eyeof such severity that makes assessment of uveitis severity insufficient orimpossible. Clarification: the study may include subjects with prior acuteuveitis 2 weeks after the resolution, including those receiving topicaltherapy, including intra-bulbar administration of glucocorticoids.

19. Comorbidities (including, but not limited to, metabolic, hematological, renal,hepatic, pulmonary, neurological, endocrine, cardiac, infectious, gastrointestinaldisorders), including disorders ongoing at the time of screening, which, in theopinion of the investigator, may affect the course of radiographic axSpA, theresults of assessment of its symptoms, or create an unacceptable risk to the subjectfrom study therapy.

20. Known allergy or intolerance to any component of the test drug, premedication drugsused in this clinical study. For bDMARDs and/or tsDMARD-naive subjects: knownallergy or intolerance of any components of adalimumab.

21. For bDMARDs and/or tsDMARD-naive subjects: contraindications for the use ofadalimumab.

22. A history of angioedema.

23. Fibromyalgia, or other conditions associated with chronic pain .

24. Lymphoproliferative diseases or malignancies with a remission duration of less than 5 years, with the exception of cured basal cell carcinoma and cervical cancer insitu.

25. Pregnancy, pregnancy planning (including pregnancy of female sexual partners of malestudy subjects) less than 8 weeks after the last administration of BCD-180/placebo (intravenously)/adalimumab/placebo (subcutaneous), breastfeeding.

26. Contraindications to MRI.

27. Simultaneous participation in other clinical studies, as well as previousparticipation in other clinical studies less than 3 months before signing the ICF,prior participation in this study.

Exception: subjects who dropped out of this study at screening.