Study of an Anti-TLR4 mAb in Rheumatoid Arthritis

Randomized, Placebo-Controlled, Double Blind, Multicenter Phase 2 Study to Explore Tolerability, Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Intravenous Multiple Infusions of NI-0101, an Anti-Toll Like Receptor 4 Monoclonal Antibody in Patients With Rheumatoid Arthritis

This is a Phase 2, PoC, randomized, placebo-controlled, double blind, international multicentre study to explore the effect of a new antibody to treat patients with Rheumatoid Arthritis

The study foresees the randomization of at least 81 moderate to severe, ACPA positive, RA patients who are inadequate responders to MTX, in two double blind arms (NI-0101:placebo, with a ratio of 2:1). Patients will receive NI-0101 or placebo infusions up to a maximum of 6 administrations (every two weeks for 12 weeks). All patients will continue receiving a stable dose of MTX. After 12 weeks, patients will enter the follow up period with monthly visits for a minimum of 12 weeks.

Inclusion Criteria:

• Male and female patients
• Age >= 18 years old
• BMI: < 30 and > 18
• Diagnosis of RA according to 2010 ACR/EULAR criteria and with a disease duration of at least 6 months since diagnosis
• Patient must present with active RA, characterized by at least 6 swollen joints out of 66 assessed and 6 tender joints out of 68 assessed and by the presence of synovitis (measured by ultrasound) in at least one of the 6 swollen joints
• C-reactive protein (CRP) level > 0.7 mg/dL or if the CRP level is between 0.3 mg/dL and 0.7 mg/dL (included) then patient must also present an ESR > 30mm/hr
• Patients must have received MTX treatment for at least 3 months and have been on a stable dose of MTX for at least 6 weeks prior to start of screening
• ACPA-positive RA patients
• Women must be postmenopausal (> 12 months without menses) or surgically sterile or using two effective contraception methods for at least 4 weeks prior to the randomization date and agree to continue contraception for the duration of their participation in the study (until the end of follow up period)
• Sexually active male patients must use a barrier method of contraception during the course of the study (and until the end of the follow up period)
• Patients must give written informed consent for study participation

Exclusion Criteria:

• A documented history of an autoimmune disease other than RA by ACR classification, or Sjögren syndrome
• Administration of cytotoxic drugs and immune suppressants (other than MTX) within 3 months prior to screening
• Previous multiple administrations of any biological DMARD or targeted synthetic DMARD
• Known primary immunodeficiency
• Pregnant or breastfeeding women
• Suspicion of active or latent tuberculosis
• HIV, HCV, HBV infection
• Infection reported during screening not recovered 72h prior to first dose
• History of anaphylactic reactions to any protein therapeutics or excipients
• Any history of malignancy, excluding cured basal or squamous cell carcinoma of the skin, or cervical in situ carcinoma
• Clinically significant cardiac disease requiring medication, such as congestive heart failure, unstable angina, myocardial infarction within 6 months prior to randomization
• Moderate to severe renal insufficiency, clinically relevant liver function test abnormalities or pancytopenia
• Major psychiatric or neurological disorder