Efficacy and Safety of RPH-104 Treatment in Patients With Recurrent Pericarditis

Inclusion Criteria:

• Voluntarily signed and dated Informed Consent Form for participation in the study.

• Recurrent pericarditis diagnosis.

• ≥ 1 pericarditis episodes experienced prior to screening has met ≥ 2 of thefollowing 4 criteria, in the Investigator's opinion and based on the documentedavailable data, according to 2015 European Society of Cardiology (ESC) Guidelinesfor the Diagnosis and Management of Pericardial Diseases:

• Pericarditic chest pain

• Pericardial rub

• New widespread ST-segment elevation/PR-segment depression according to ECGfindings

• Pericardial effusion (new or worsening)

• Presents with at least the third episode of pericarditis during screening (i.e., atleast the second pericarditis recurrence following the first pericarditis episode),and within ≤ 7 days prior to and including RI baseline (first administration ofstudy drug) has at least two of the following signs: 1) ≥ 1 day with NRS pain score ≥ 4 (without any other potential causes for the increase in the pain intensity); 2)CRP ≥ 1 mg/dL, (without any other potential causes for the CRP elevation); 3) new orprogression of existing pericardial effusion during the diastole as demonstrated byechocardiography; 4) evidence of new widespread ST-elevation (ST segment or T waveratio in lead v6 > 0.25) or PR depression on ECG. Each sign must be presented eitheron the same day or separated by no more than 7 days from the other sign.

• NSAIDs and/or colchicine and/or CS (in any combination), if used, at stable doselevels for at least 3 days prior to and including RI baseline before RPH-104administration.

• If using NSAIDs and/ or colchicine and/or CS at RI baseline, is willing and able, inthe opinion of the investigator, to taper and discontinue these drugs no later thanWeek 12 of the RI period.

• The patient's ability and willingness (in the reasonable opinion of theInvestigator) to come to the study site for all scheduled visits, to undergo allstudy procedures and comply with the protocol requirements, including consent tosubcutaneous injections by qualified personnel of the study site.

• Consent of women of childbearing potential (defined as all women physiologicallyable to become pregnant) to use highly effective contraceptive methods throughoutthe study, starting from the beginning of the screening (signing of the InformedConsent Form) and for at least 8 weeks after discontinuation of the study drug; anda negative pregnancy test result (serum test for chorionic gonadotropin).

OR

Consent of sexually active male subjects to use highly effective contraceptive methods throughout the study, starting from the beginning of the screening and for at least 8 weeks after discontinuation of the study drug.

Highly effective methods of contraception include the following:

1. complete abstinence (if it agrees with the preferable and usual lifestyle of thepatient). [Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods of contraception];

2. sterilization: bilateral removal of the ovaries (with or without removal of theuterus) or tubal ligation at least 6 weeks before the start of the study therapy. Ifonly the ovaries have been removed, the reproductive status of the woman should beconfirmed by subsequent hormone tests;

3. sterilization of the male partner at least 6 weeks before the start of the studytherapy (with proper documentation of the absence of sperm cells in the ejaculateafter vasectomy) [in female subjects, the sexual partner after vasectomy should bethe only partner];

4. use of a combination of any two of the following (a+b or a+c, or b+c):

5. the use of oral, injectable or implanted hormonal contraceptives; in the caseof oral contraceptives, women should consistently use the same drug for aminimum of 3 months prior to the initiation of the study treatment;

6. placement of an intrauterine device (IUD) or intrauterine system (IUS);

7. barrier methods of contraception: a condom or occlusive cap (diaphragm orcervical/vault caps) and spermicidal foam/gel/film/cream/vaginal suppository.

Exclusion Criteria:

• Hypersensitivity to the study drug (RPH-104), and/or itscomponents/excipients
• History of severe allergic or anaphylactic reactions to human, humanizedor murine monoclonal antibodies or fusion proteins.
• Pericarditis secondary to: a) tuberculosis (TB); b) postthoracic blunttrauma; c) myocarditis; d) systemic autoimmune diseases (systemic lupuserythematosus, rheumatoid arthritis, systemic sclerosis, etc.; Still'sdisease and familial Mediterranean fever are not considered as autoimmunediseases); e) neoplastic, purulent, or radiation etiologies.
• Is currently receiving CS at a dose of > 60 mg/day prednisone (orequivalent).
• Prior therapy with:
• rilonacept - less than 6 weeks prior to the baseline assessment (Day 0 of run-in treatment period);
• canakinumab - less than 12 weeks prior to the baseline assessment (Day 0 of run-in treatment period);
• anakinra - less than 5 days prior to the baseline assessment (Day 0of run-in treatment period);
• Tumor necrosis factor (TNF) inhibitors, Interleukin 6 (IL-6)inhibitors, Janus kinase inhibitors - less than 12 weeks prior to thebaseline assessment (Day 0 of run-in treatment period);
• immunosuppressive agents (azathioprine, cyclosporine, mycophenolate,mofetil, tacrolimus, sirolimus, mercaptopurine) - within 24 weeksprior to the baseline assessment (Day 0 of run-in treatment period),methotrexate - less than two weeks prior to the baseline assessment (Day 0 of run-in treatment period),
• any other biological preparations less than 5 half-lives prior to thetreatment initiation (Day 0 of run-in treatment period).
• The use of a live (attenuated) vaccine within 3 months prior to Day 0 ofthe RI treatment period and/or the need to use this type of a vaccinewithin 3 months after the discontinuation of the study drug. Liveattenuated vaccines include vaccines against viral infections such asmeasles, rubella, mumps, chickenpox, rotavirus, influenza (in the form ofa nasal spray), yellow fever, polio (oral polio vaccine); vaccines againsttuberculosis (BCG), typhoid (oral typhoid vaccine) and typhus (epidemictyphoid vaccine) vaccines. Patient's immunocompetent family members shouldrefrain from administration of a polio vaccine during the patient'sparticipation in the study.
• Conditions or signs that, according to the Investigator, indicateimpairment (weakening) of the immune response in the patient and/orsignificantly increase the risk of the use of immunosuppressive therapy,including, but not limited to, the following conditions at the screening:
• active bacterial, fungal, viral (including COVID-19) or protozoalinfection;
• opportunistic infections and/or Kaposi's sarcoma;
• chronic bacterial, fungal or viral infection requiring systemicantimicrobial therapy;
• HIV-infection, hepatitis B or C (patients with treated hepatitis Cand negative Polymerase chain reaction (PCR) tests after 3 and 6months are regarded as cured from hepatitis C and can be included inthis study); within 6 months prior to the beginning of the screeningperiod:
• disseminated herpes zoster infection, herpetic encephalitis,meningitis and other non-self-limiting infections caused by herpesviruses;
• A history of active tuberculosis or the presence of risk factors or signsindicating the presence of active or latent infection caused by M.tuberculosis, including but not limited to, the following:
• living in specific conditions that increase the risk of contacts withtuberculosis-infected patients, such as prisoners, gathering ofhomeless people etc. within a year before the beginning of thescreening period;
• work experience in a healthcare setting with unprotected contactswith patients having high risk of tuberculosis or patients withtuberculosis within a year prior to the beginning of the screeningperiod;
• close contact, i.e. being in the same room (at home or in anotherconfined environment) for an extended period of time (days or weeksrather than minutes or hours) with a person with active pulmonarytuberculosis within a year prior to the beginning of the screeningperiod;
• test results indicating active tuberculosis or latent infectioncaused by M. tuberculosis: positive result of QuantiFERON-TB/T-SPOTtest.TB during the screening period; findings of chest X-ray exam intwo views confirming pulmonary tuberculosis during the screeningperiod.
• The presence of any other significant comorbidities (cardiovascular,nervous, endocrine, urinary tract, gastrointestinal tract, liver, bloodclotting disorders, autoimmune diseases, etc.) or conditions that may, inthe reasonable opinion of the Investigator, adversely affect theparticipation and well-being of the study subject and/or distort theevaluation of the study results.
• Uncontrolled diabetes mellitus.
• History of organ transplant, or the need for transplant surgery at thebeginning of the screening period, or elective transplant surgery duringthe study.
• The presence of any malignancies during the screening period or within 5years prior to its initiation, except for non-metastatic basal cell andsquamous cell skin cancer after complete resection or carcinoma in situ ofany type following complete resection.
• Mental disorders that, in the reasonable opinion of the Investigator, mayaffect the patient's participation in the study or his/her ability tocomply with the Protocol procedures.
• Pregnancy or breast-feeding.
• History of abuse of alcohol or psychoactive substances as assessed by theInvestigator.
• Severe renal impairment (creatinine clearance by Cockcroft-Gault formula <30 mL/min at screening.
• Presence of any of the following laboratory abnormalities at screening:
• Absolute neutrophil count <1.5 х 10^9/L,
• White blood cells (WBC) count <3 х 10^9/L,
• Platelet count <100 х 10^9/L,
• Hemoglobin ≤ 80 g/L,
• Glycated hemoglobin (HbA1c) ≥ 8%,
• Alanine transaminase (ALT) and/or Aspartate aminotransferase (AST) ≥ 3.0 х Upper limit of normal (ULN),
• Total bilirubin >1.5 х ULN (except for cases of documented Gilbert'ssyndrome).
• Concomitant participation in other clinical studies at the beginning ofthe screening or the use of any unapproved (investigational) medicinalproducts within 4 weeks or 5 half-life periods (whichever is longer) up tothe baseline assessment (Day 0 of the run-in treatment period).
• Prior participation in this clinical study (if at least one dose of thestudy drug was administered). Subjects that are deemed not eligible can berescreened at the discretion of the Investigator.