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

A Randomized, Double-Blind, Placebo-Controlled Clinical Study of the Efficacy and Safety of BCD-180 in Patients With Active Axial Spondyloarthritis

The aim of the study is to evaluate the efficacy, safety, immunogenicity, pharmacokinetics and pharmacodynamics of a fixed dose of study drug (BCD-180) in comparison with placebo in patients with active axial spondyloarthritis (axSpA). The study will include HLA-B27+ patients with radiographic (r-axSpA) and non-radiographic (nr-axSpA) who had no response to prior therapy with non-steroidal anti-rheumatic drugs (NSAIDs), have not received biologic disease-modifying anti-rheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), and subjects with insufficient efficacy and/or loss of efficacy on bDMARDs and/or tsDMARDs.

Subjects meeting the eligibility criteria will be randomized in 2 groups:bDMARDs and/or tsDMARD naive subjects and bDMARDs and/or tsDMARD experienced subjects will be randomized independently of each other.

bDMARDs and tsDMARD-naive subjects (naïve) will be randomized into 3 groups:

• BCD-180 (naïve);
• Placebo (naïve);
• Adalimumab.

bDMARDs and/or tsDMARD experienced subjects (exp) will be randomized into 2 groups:

• BCD-180 (exp);
• Placebo (exp).

After the primary endpoint assessment all subjects will be switched to BCD-180.

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 Form for participation.

3. Positive test result for HLA-B27.

4. 4. 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 presence of radiographic signs of sacroiliitis according to the modified New York criteria (van der Linden et al. 1984) according to the central review. Subjects with an established diagnosis of ankylosing spondylitis according to the modified New York criteria may also be included in the study (van der Linden et al. 1984).
   • nr-axSpA: axSpA diagnosis meets ASAS 2009 criteria in the absence of radiographic 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 both criteria:

   • 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 hsCRP level >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-associated back pain.

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

   • Inadequate response to therapy with NSAIDs defined as insufficient response to therapy with NSAIDs at therapeutic doses for at least 4 weeks, or insufficient response to therapy with two NSAIDs at the maximum permitted dose with the total 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 the Investigator's assessment:

    • lack and/or loss of efficacy, according to the European Alliance of Associations for Rheumatology 2022 (EULAR 2022) recommendations, while on therapy 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 shall be 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 in women 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 the Investigator.

14. Willingness of subjects and their sexual partners of childbearing potential to use reliable methods of contraception from the date of signing the ICF, throughout the study, and for 8 weeks after the last administration of BCD-180/placebo (infusions)/adalimumab/placebo (subcutaneously). This requirement does not apply to subjects who have had operative sterilization and women who have been postmenopausal for 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 do not 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 stem and 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 the study provided that the daily dose of glucocorticoids is ≤10 mg/day (calculated with reference to prednisolone) and was stable for at least 4 weeks prior to the Randomization Visit.
   • within 4 weeks before signing the ICF and during the screening period: use of synthetic 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 weeks before signing the ICF and during the screening period:

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

   • 5-aminosalicylic acid and its derivatives, including sulfasalazine, at a dose not exceeding 3 g/day, provided that therapy was started at least 8 weeks before signing the ICF. Subjects with inflammatory bowel disease (IBD) may be treated with topical 5-aminosalicylic acid at therapeutic doses;

     • intra-articular and paraspinal glucocorticoids within 4 weeks prior to the Randomization Visit, intramuscular glucocorticoids within 2 weeks prior to the Randomization Visit;
     • use of alkylating agents at any time within 12 months prior to signing the ICF;
     • 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) of ulcerative colitis), severe, generalized, pustular, exudative, psoriasis of the hands and feet;
   • acute uveitis within less than 2 weeks prior to signing the ICF and during the screening period.

   Clarification: for subjects with IBD: IBD therapy must be stable for 8 weeks prior to 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 of the 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 for the period of participation in the study.

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

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

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

14. Systemic antibacterial, antimycotic or antiprotozoal therapy within 8 weeks prior to signing 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 screening period) significant uncontrolled neuropsychiatric disorders, severe depression and/or suicide attempts, a risk of suicide and/or any psychiatric illness that, in the opinion of the investigator, may pose an excessive risk to the subject or have an impact on the subject's ability to follow the protocol.

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

18. The following diseases:

    • at screening and/or in the past and at the Randomization Visit: non-axSpA inflammatory joint disease (including rheumatoid arthritis, gout, psoriatic arthritis, 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: systemic autoimmune diseases (including systemic lupus erythematosus, systemic scleroderma, inflammatory myopathy, mixed forms of inflammatory connective tissue 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 systemic therapy;
    • with uveitis associated with axSpA, except for subjects with severe visual impairment or with sight in one eye, subjects with corneal opacity, significant cataract, posterior capsule opacity, or posterior synechia in the studied eye of such severity that makes assessment of uveitis severity insufficient or impossible. Clarification: the study may include subjects with prior acute uveitis 2 weeks after the resolution, including those receiving topical therapy, including intra-bulbar administration of glucocorticoids.

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

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

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

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 in situ.

25. Pregnancy, pregnancy planning (including pregnancy of female sexual partners of male study 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 previous participation 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.