A Two-Stage Study of the Efficacy, Safety, Pharmacokinetics, Pharmacodynamics and Immunogenicity of Various Doses of Levilimab When Administered Intravenously and Subcutaneously to Healthy Subjects and Subjects With Active Rheumatoid Arthritis

This is a two-stage study of efficacy, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of various doses of levilimab when administered intravenously and subcutaneously to healthy subjects and subjects with active rheumatoid arthritis resistant to methotrexate monotherapy.

Aim of the Stage 1 is to study the tolerability, safety, immunogenicity, and main pharmacokinetic and pharmacodynamic parameters of levilimab after its single subcutaneous or intravenous administration at ascending doses to healthy subjects.

Aim of the Stage 2 is to confirm the efficacy and safety of levilimab 648 mg IV Q4W in combination with methotrexate and levilimab 324 mg SC Q2W in combination with methotrexate in subjects with active rheumatoid arthritis, resistant to methotrexate monotherapy.

Stage 1: there are 3 dose levels and 5 cohorts. The subjects will be followed up for up to 71 days after the IP administration.

Stage 2: the main period of the study (Weeks 0-24) is blinded; study subjects will receive levilimab with placebo. At Week 24 the study will become open-label and all subjects will continue to receive levilimab. At week 28 patients who achieved the RA remission at week 24 will be switched to maintenance therapy of levilimab and will receive it through Week 52. Subjects who do not achieve remission at Week 24, will continue to receive levilimab from Week 28 to Week 52 inclusive corresponding to their treatment group.

Eligibility Criteria:
Inclusion Criteria (stage 1):

1. Signed Informed Consent Form for participation in the study.
2. Malegender.
3. Age 18-45 inclusive at the time of signing the ICF.
4. Healthy status confirmed by the history, physical examination, and laboratory parameters.
5. The absence of a history and signs of alcohol abuse or substance addiction at the time of signing the ICF, and a negative alcohol saliva screening test in combination with a negative urine drug test.
6. The ability of the subject to follow the Protocol procedures, according to the Investigator.
7. The readiness of the subject and their sexual partners with a childbearing potential to use reliable contraceptive measures from the date of signing the informed consent form throughout the study period and for 4 weeks after the administration of the investigational product. This requirement does not apply to the subjects and their partners who have undergone operative sterilization or the female partners of a subject who have been menopausal for more than 2 years.
8. Readiness not to drink alcohol within 24 hours prior to and 70 days after the administration of the investigational product.

Inclusion Criteria (stage 2):

1. Signed ICF for participation in the study.
2. Men and women aged ≥ 18 on the ICF signing day.
3. Rheumatoid arthritis that meets the ACR 2010 criteria, confirmed not less than 24 weeks before the ICF signing date. In the event that a subject has been diagnosed with rheumatoid arthritis in accordance with the ACR 1987 criteria, the physician-investigator must confirm the diagnosis in accordance with the ACR 2010 criteria during the screening period, with this information included in the primary documentation, if this has not been done previously and is not documented.
4. Methotrexate therapy during the 12 weeks prior to the ICF signing date.
5. Use of methotrexate at a stable dose during the 4 weeks prior to the ICF signing date (the methotrexate dose should be 15-25 mg per week, methotrexate dose of 10 mg may be used in case of intolerability/toxicity of a higher dose).
6. Failure of methotrexate when used over the 12 weeks before the ICF signing date (according to the Investigator).
7. Swollen joint count ≥ 6 (out of 66); tender joint count ≥ 6 (out of 68).
8. The presence of at least one of three criteria: 1) CRP ≥ 10 mg/L, 2) ESR ≥ 28 mm/h (Westergren method / capillary photometry), 3) morning stiffness that lasts longer than 45 minutes.
9. The ability of the subject to follow the Protocol procedures, according to the Investigator.
10. The readiness of the subject and their sexual partners with a childbearing potential to use reliable contraceptive measures from the date of signing the informed consent form throughout the study period and for 4 weeks after the administration of the last dose of the investigational product. This requirement does not apply to the subjects and their partners who have undergone operative sterilization or females who have been menopausal for more than 2 years.

Exclusion Criteria (Stage 1):

1. A history of treatment with the products containing monoclonal antibodies to interleukin 6 or its receptor.
2. A History of severe hypersensitivity reactions (angioneurotic edema, anaphylaxis, or multiple drug allergy).
3. Known allergy or intolerance to monoclonal antibody drugs (murine, chimeric, humanized, or fully human) or any other components of the investigational product.
4. Major surgery within 30 days before the signing of the ICF.
5. Severe infections (including those that required hospitalization or parenteral antibacterial, antiviral, antimycotic, or antiprotozoal agents) within 6 months before signing the ICF.
6. Use of systemic antibacterial, antiviral, antimycotic, or antiprotozoal agents within 2 months before signing the ICF.
7. More than 4 episodes of respiratory infections over the past 6 months before signing the ICF.
8. Impossibility to insert a venous catheter for blood sampling (for example, due to skin disease at venipuncture sites).
9. A history of fever over 40 °C.
10. A history of increased levels of hepatic transaminases above 2.5 x ULN.
11. Epileptic seizures, a history of seizures.
12. Depression, suicidal ideations/attempts at the screening or in the history.
13. Regular oral or parenteral administration of any medicinal products, including over-the-counter drugs, vitamins and dietary supplements, within less than 2 weeks before signing the ICF.
14. Use of medicinal products, including over-the-counter drugs, with a pronounced effect on hemodynamics, liver function, etc. (barbiturates, omeprazole, cimetidine, etc.) within 30 days before signing the ICF.
15. Use of medicinal products that affect the immune status (cytokines and their inducers, glucocorticoid hormones, etc.) within 2 months before signing the ICF.
16. BCG vaccination, vaccination with live attenuated vaccines and with any other vaccines within 12, 8 and 4 weeks before signing the ICF, respectively, as well as during screening.
17. Standard laboratory and investigation abnormalities.
18. Smoking over 10 cigarettes a day.
19. Consumption of more than 10 units of alcohol per week (1 unit of alcohol is equivalent to ½ L of beer, 200 mL of wine or 50 mL of spirits) or a history of alcoholism, drug addiction, or drug abuse.
20. Donation of 450 mL or more of blood or plasma within 2 months prior to signing the ICF.
21. Participation in clinical trials of medicinal products within 2 months before signing the ICF or concurrent participation in other clinical trials.
22. Previous participation in the same clinical trial (excluding subjects who dropped out at screening and did not receive the IP).

Exclusion Criteria (Stage 2):

1. Previous exposure to tocilizumab or other monoclonal antibodies to the interleukin 6 / interleukin 6 receptor.
2. Previous therapy with Janus kinase inhibitors.
3. Previous exposure to rituximab or other products that cause depletion or suppression of B cell activity.
4. Felty's syndrome (regardless of form).
5. The functional status of the subject is class IV according to the ACR 1991 classification.
6. Known allergy or intolerance to any component of the study drug.
7. Concomitant treatment with the following products:

   * the need for prednisolone or its equivalent at an oral dose of more than 10 mg/day;
   * the need for oral prednisolone or its equivalent at a dose of ≤10 mg/day if this dose was not stable during the last 4 weeks before signing the ICF (patients who received topical glucocorticoids can be included in the study);
   * the need for NSAID use if the NSAID dose was not stable during the last 4 weeks before signing the ICF (the patients who occasionally received NSAIDs for fever or allergic syndrome in case of intercurrent diseases can be included);
   * the use of alkylating agents at any time within 12 months before signing the ICF;
   * intra-articular administration of glucocorticoids within 4 weeks before signing the ICF;
   * vaccination with live or attenuated vaccines at any time within 8 weeks before signing the ICF;
   * the use of leflunomide within 8 weeks before signing the ICF;
   * therapy with TNF-α inhibitors or T cell co-stimulation blockers within 8 weeks before signing the ICF.
8. Patients with any of the following laboratory findings at screening:

   * the content of hemoglobin in the blood \< 80 g/L;
   * the number of leukocytes in the blood \< 3.0 × 109/L;
   * the number of platelets in the blood \< 100 × 109/L;
   * the number of neutrophils in the blood \< 2 × 109/L;
   * AST and ALT levels ≥ 1.5 × ULN approved in the laboratory;
   * serum creatinine ≥ 1.7 × ULN approved in the laboratory.
9. Positive pregnancy urine test in women at screening (the test is not performed in women who have been menopausal for at least 2 years or who have undergone operative sterilization; any of these conditions must be documented).
10. A confirmed diagnosis or a history of the severe immunodeficiency of any other nature.
11. Diagnosis of HIV infection, hepatitis B, C.
12. Diagnosis of tuberculosis, including a history of tuberculosis.
13. Latent forms of tuberculosis (positive Diaskintest® or positive result of the QuantiFERON®-TB Gold test or T-SPOT.TB test, in the absence of radiographic signs of pulmonary tuberculosis).
14. A history of or current herpes zoster.
15. Documented chickenpox within less than 30 days before signing the ICF.
16. The confirmed diagnosis of another chronic infection (for example, invasive mycoses, histoplasmosis, etc.), which can increase the risk of infectious complications in the opinion of the Investigator.