Efficacy and Safety of RPH-104 for Resolution and Prevention of Recurring Attacks in Adult Subjects With Familial Mediterranean Fever With Resistance to or Intolerance of Colchicine

• Presence of voluntarily signed and dated ICF to participate in this study.
• Verified diagnosis of familial Mediterranean fever (FMF) based on Tel HaShomer diagnostic criteria (Pras M., 1998) or the criteria developed by the Eurofever /Pediatric Rheumatology International Trials Organization (PRINTO) expert group (2019);
• Presence of at least one mutation in Mediterranean fever gene (MEFV) exon 10 (results of the study performed earlier at any time may be provided or a respective test should be performed during the screening);
• Presence (at screening onset) of data on history of at least one (on average) disease attack per month throughout the last 3 months (Ozen et al., 2020);

• Presence of at least one of the below-mentioned (at screening onset) documented data confirming:

  • resistance to colchicine at the maximum tolerable therapeutic dose (up to 3 mg/day) confirmed by at least one monthly attack (on average) despite the therapy specified within at least 3 last months. Colchicine administration will be continued at stable dose if it is not associated with unacceptable adverse reactions;
  • intolerance of therapeutic or subtherapeutic doses of colchicine (unacceptable adverse reactions); Colchicine dose should be stable for at least 5 days before patient enrollment into the study (prior to screening onset).
• Ability and willingness of the subject, according to the reasonable Investigator's judgment, to attend the study site at all scheduled visits, undergo the study procedures and follow the Protocol requirements including subcutaneous (SC) injections by qualified site personnel;
• Consent of female subjects of childbearing potential defined as all females with physiological potential to conceive (except for those with absolute termination of menses to be determined retrospectively after 12 months of natural amenorrhea, i.e. amenorrhea with relevant clinical status, e.g. appropriate age) to use highly effective contraception throughout the study starting from the screening (signed ICF) and for at least 8 weeks after the study treatment completion (discontinuation); and negative pregnancy test (serum test for human chorionic gonadotropin (HCG)).

or Consent of the sexually active men subjects to use highly effective contraception throughout the study starting from the screening (signed ICF) and for at least 8 weeks after the study treatment completion (discontinuation).

A highly effective method of contraception is defined as follows:

• complete abstinence: if it corresponds to the preferred and conventional lifestyle of the female subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation method) and interrupted coitus are not considered acceptable contraceptive methods;
• female sterilization: surgical bilateral ovariectomy (with/without hysterectomy) or tubal ligation at least 6 weeks prior to the study treatment initiation. In case of ovariectomy only the female reproductive status should be verified by further hormonal test;
• male sterilization (with documented absence of sperm in ejaculate post vasectomy) at least 6 months for screening. Vasectomized male partner should be the only partner of the participating female subject;

• combination of two of the following methods (a+b or a+c or b+c):

  а) oral, injection or implanted hormonal contraceptives; in case of oral contraceptives the female subjects should administer the same product for at least 3 months prior to the study treatment;

  b) intrauterine device or contraceptive system;

  с) barrier methods: condom or occlusive cap (diaphragm or cervical cap / vaginal fornix cap) with spermicidal foam/gel/film/cream/vaginal suppository.

  • Presence of active FMF attack at Visit 1 (Day 0) lasting for not more than 2 days before Visit 1 defined as simultaneous development of clinical and serological signs of the attack including:
• Physician Global Assessment (PGA) score ≥ 2 supposing mild, moderate or severe activity of the disease (i.e. clinical signs), and
• CRP level > 10 mg/L (i.e. serological signs).

Exclusion criteria:

• Hypersensitivity to the study product (RPH-104) and/or its components/excipients.
• Administration of live (attenuated) vaccines less than 3 months prior to Day 0 (treatment initiation) and/or necessity to use such vaccine within 3 months after the study product RPH-104 treatment completion (discontinuation). Live attenuated vaccines include viral vaccines against: measles, rubella, parotitis, varicella, rotavirus, influenza (as nasal spray), yellow fever, poliomyelitis (oral polio-vaccine); tuberculosis vaccine (BCG), typhoid (oral typhoid fever vaccine) and camp fever (epidemic typhoid vaccine). Immunocompetent family members should refuse to use oral polio-vaccine throughout the subject's participation in the study.

• Conditions or signs which, according to the investigator, evidence impaired (reduced) immune response and/or significantly increase the risk of immunomodulating therapy including (but not limited to):

  • active bacterial, fungal, viral or protozoal infection at screening onset;
  • opportunistic infections and/or Kaposi's sarcoma at the screening period onset;
  • chronic bacterial, fungal or viral infection requiring systemic therapy with parenteral products at the main screening period onset;
  • human immunodeficiency (HIV), hepatitis B (HBV) or C (HCV) viral infections;

• Active tuberculosis (TB) in the history or risk factors or signs evidencing active or latent infection with M. Tuberculosis including (not limited to) the following:

  • living in specific conditions increasing the risk of contact with tuberculosis such as detention facilities, in crowded areas of person of no fixed abode, etc. within the last year before the main treatment period;
  • working in a medical institution with unprotected contact with subjects under high risk of tuberculosis or subjects with tuberculosis within the last year until the main therapy period;
  • close contact, i.e. confinement to a place (home or another confined area) for a long period of time (several days or weeks, not minutes or hours) with a subject with active pulmonary tuberculosis within the last year until the main therapy period;
  • results of examinations indicating active or latent infection with M. Tuberculosis: positive QuantiFERON-TB / T-Spot TB test at screening; chest X-ray/chest CT findings confirming pulmonary tuberculosis during screening.
• Any other relevant concomitant diseases (cardiovascular, nervous, endocrine, urinary, gastrointestinal, hepatic disorders, coagulation disorders, other autoimmune diseases, etc.) or conditions which, according to the investigator's judgment, may affect the subject's participation or well-being in the study and/or distort assessment of the study results.
• History of organ transplantation or necessity in transplantation at the screening onset.
• Any malignancies during the screening period or for 5 years before screening except for non-metastatic basal cell and squamous cell skin cancer after total resection or in situ carcinoma of any type after total resection.
• Pregnancy or breastfeeding.
• History of alcohol or psychoactive substance abuse according to the investigator's evaluation.
• Severe renal failure: creatinine clearance (ClCr) calculated using Cockcroft-Gault formula \< 30 mL/min.

• Prior therapy with:

  • rilonacept - less than 6 weeks prior to Day 0 of the study;
  • canakinumab - less than 12 weeks prior to Day 0 of the study;
  • anakinra - less than 72 hours prior to Day 0 of the study;
  • rituximab - less than 24 weeks prior to Day 0;
  • tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 inhibitors and other biologics - less than 6 weeks or 5 half-life periods (whichever is longer) prior to Day 0 of the study;
  • immunosuppressive drugs (azathioprine, leflunomide, dapsone, cyclosporine, mycophenolate mofetil, tacrolimus, sirolimus, mercaptopurine methotrexate, etc.) - less than 4 weeks or 5 half-lives (whichever is longer) prior to Day 0 of the study. In the case of administration of leflunomide, the completion of a course of elimination with cholestyramine should be documented;
  • intravenous (IV) immunoglobulin (Ig) - less than 8 weeks prior to Day 0;
  • use of any other biologic less than 5 half-life periods prior to Day 0 of the study;
  • IV administration of glucocorticoids less than 1 week (since the end of treatment) prior to Day 0 of the study;
  • intramuscular, intra-articular or peri-articular administration of glucocorticoids less than 4 weeks prior to Day 0;
  • systemic therapy with oral glucocorticoids at doses > 0,2 mg/kg/day equivalent to the prednisolone dose on Day 0;
  • changes in the glucocorticoids dose/dosage regimen within at least 4 weeks prior to screening.

• Any of the deviations in the laboratory tests below:

  • absolute neutrophil count \< 1.5 x 10\^9/L (1500 /mm\^3),
  • White blood cell (WBC) count \< 3 x 10\^9/L (\<3000/mm\^3),
  • platelet count \< 100 \^9/L (\<100000/mm\^3 or \<100000×10\^6/L),
  • alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≥ 2 x upper limits of normal (ULN) if at the screening ALT, AST ≥ 2 x ULN but \< 3 ULN, retest is allowed,
  • bilirubin > 1.5 x ULN (except for documented cases of Gilberts syndrome).
• Parallel participation in other clinical studies at the screening onset or administration of any unauthorized (investigational) products less than 4 weeks or 5 half-life periods (whichever is longer) before Visit 1 (treatment initiation).
• Previous participation in this clinical study, in case of passing the randomization procedure.