Phase IIa Proof-of-Concept Study to Investigate the Efficacy, Safety, and Tolerability of FBL-MTX in Patients with Rheumatoid Arthritis

Prior treatment

• Positive result in drugs-of-abuse and ethanol tests.
• Use of a depot injection or an implant of any drug (except for contraceptives) within the previous 6 months.
• Previous treatment with any of following: a) oral or injectable gold within 4 weeks prior to Day 1; b) sulfasalazine within 4 weeks prior to Day 1; c) azathioprine within 4 weeks prior to Day 1; d) D penicillamine within 4 weeks prior to Day 1; e) cyclosporine within 8 weeks prior to Day 1; f) MTX within 4 weeks prior to Day 1; g) leflunomide within 8 weeks prior to Day 1 or a minimum 4 weeks prior to Day 1, if after 11 days of standard cholestyramine therapy; h) any cytotoxic agent, including chlorambucil, cyclophosphamide, nitrogen mustard, and other alkylating agents; i) any JAK inhibitor or other small molecule immunomodulator; j) potent Pg-p inducer (e.g. rifampin, phenytoin, carbamazepine, and St. John's wort) within 3 weeks prior to Day 1; k) metamizole and other hematotoxic drugs, anticonvulsants, and 5-fluorouracil within 4 weeks prior to admission; l) substances that may have adverse effects on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine) within 4 weeks prior to Day 1.
• Participation in any clinical trial within the previous 4 weeks or 5 half-lives of the investigational medicinal product (IMP).
• Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months.
• Positive Interferon-Gamma Release Assay (IGRA), in the previous 3 months, unless the patient received previous treatment for tuberculosis (with documented evidence) or presents conditions and is willing to initiate latent tuberculosis treatment (to guarantee, at least, 4 weeks of treatment before baseline).
• Positive result in drugs-of-abuse and ethanol tests.

Other illness

• Known hypersensitivity / allergy reaction to MTX or any of the excipients.
• History of liver impairment (Child-Pugh B or C).
• Any other condition that the Investigator considers to render the participant unsuitable for the study.
• Any recent disease or condition or treatment that, according to the Investigator, would put the participant at undue risk due to study participation.
• Any other condition that the Investigator considers to render the participant unsuitable for the study period.
• Known severe hypersensitivity reaction to any other drug.
• Any medical condition (e.g., gastrointestinal, renal or hepatic, including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (e.g., cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or participant safety.
• History of drug or alcohol abuse.
• Resting heart rate < 50 bpm in ECG.

Lab values

• Estimated renal creatinine clearance (CLCr) below the lower limit of normal range (60 mL/min), based on CLCr calculation by the Cockcroft-Gault formula and normalized to an average body surface area of 1.73 m2
• History of short QT syndrome, long QT syndrome, or clinically significant cardiac arrhythmia.
• Family history of sudden death before 40 years old, short, or long QT syndrome.

Other

• Systolic Blood Pressure (SBP) < 90 mmHg and/or Diastolic Blood Pressure (DBP) <45 mmHg.
• SBP > 160 mmHg and/or DBP > 95 mmHg.
• Veins unsuitable for IV puncture on either arm (for patients in the pharmacokinetics group).
• If woman of childbearing potential (WOCBP), positive pregnancy test.
• If woman, she is breast-feeding.
• If WOCBP, positive urinary pregnancy test.
• Baseline QTcF interval > 450 msec if man or > 470 msec if woman, or < 350 msec.

• Free written informed consent prior to any procedure required by the study.
• If under oral corticosteroid therapy (≤ 10mg per day of prednisone or equivalent), must be able to be on a stable regimen from at least 4 weeks before baseline up to up to EoS.
• Eligible to start treatment with an immunomodulator.
• No clinically relevant diseases other than RA captured in medical history.
• No clinically relevant findings other than RA-related captured on physical examination.
• No clinically relevant abnormalities on vital signs.
• No clinically relevant abnormalities on 12-lead ECG.
• No clinically relevant abnormalities on clinical laboratory tests.
• No evidence of clinically significant active infection.
• Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab).
• Negative results from either the hepatitis B or C serology based on hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, total hepatitis B core antibody (IgM will be measured if total anti-hepatitis B core antibody is positive), and hepatitis C virus (HCV) antibody (anti-HCVAb) markers, except for vaccinated subjects or subjects with past resolved hepatitis.
• Willingness to accept and comply with all study procedures and restrictions.
• A female participant is eligible if she meets one of the following criteria: a) is of non-childbearing potential; or b) is of childbearing potential and agrees to use an highly effective contraceptive method from at least 4 weeks prior to admission to study period until at least 6 months after the last investigational product administration.
• A male participant who is sexually active with a female partner of childbearing potential (pregnant or non-pregnant) must use contraception (condom) from admission until at least 90 days following the last investigational product administration.
• A male participant must ensure that his non-pregnant female partner of childbearing potential agrees to consistently and correctly use for the same period a highly effective method of contraception
• A male participant must be willing not to donate sperm from admission until 90 days following the last investigational product administration.
• At least moderately active disease, as defined by DAS28-CRP >3.2, including: a) Tender joint count (TJC) ≥ 4 b) Swollen joint count (SJC) ≥ 4 c) C-Reactive protein (CRP) ≥ upper limit of normal; d) Documented history of positive RA factor and/or cyclic citrullinated peptide antibody test.
• DMARD-naïve RA patient or RA patient with an inadequate response or intolerance to oral MTX.
• Male or female participant ≥ 18 years, at the time of signing the informed consent.
• Body mass index (BMI) of 18.5 to 35.0 kg/m2, inclusive.
• Diagnosis of RA according to the 2010 classification criteria of the ACR/EULAR, with a Total Score ≥ 6/10.
• At least moderately active disease, as defined by DAS28-CRP >3.2 at Screening and Baseline, including: a) Tender joint count (TJC) ≥ 4; b) Swollen joint count (SJC) ≥ 4; c) C-Reactive protein (CRP) ≥ upper limit of normal; d) Documented history of positive RA factor and/or cyclic citrullinated peptide antibody test.
• Chest X-ray performed in the previous 3 months not suggestive of tuberculosis.
• If under NSAIDs therapy, must be able to be in a stable dosing regimen from at least 2 weeks before baseline up to EoS.