A Phase 2, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Rosnilimab in Subjects with Moderate to Severe Rheumatoid Arthritis

Prior treatment

• Subject has history of inflammatory joint disease other than RA including, but not limited to, gout, systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis (e.g., ankylosing spondylitis, nonradiographic axial spondyloarthritis), reactive arthritis, overlap connective tissue disease syndromes, scleroderma, polymyositis, dermatomyositis, or any arthritis with onset prior to age 17 years. A subject with a history of Sjogren's Syndrome secondary to RA may be enrolled in the study.
• Subject has any factors that, in the Investigator’s opinion, would predispose the subject to develop an infection, including, but not limited to: a. Subject has any evidence of active infection (e.g., bronchopulmonary, urinary, or gastrointestinal) that required systemic antibacterial, antifungal, or antiviral therapy within 4 weeks before Day 1.; b. Subject has any open, draining, or infected skin wounds or ulcers within 3 months before Day 1; c. Subject has a history of chronic or recurrent infectious disease, including but not limited to, chronic renal infections, chronic chest infections (e.g., bronchiectasis), recurrent urinary tract infections (e.g., recurrent pyelonephritis or chronic nonremitting cystitis), and deep fungal infections (e.g., mucocutaneous candidiasis) within 6 months before Day 1; d. Subject has a history of an opportunistic infection (e.g., Pneumocystis carinii, aspergillosis, or mycobacteria other than TB) or parasitic infections (e.g., helminths, protozoa, Trypanosoma cruzi) within 12 weeks before Day 1.; e. Subject has a history of recurrent herpes zoster or 1 or more episodes of disseminated herpes zoster.; f. Subject has a history of 1 or more episodes of disseminated herpes simplex (including eczema herpeticum).
• Subject has a known or suspected congenital or acquired immunodeficiency state, or condition that would compromise the subject’s immune status (e.g., previous recipient of an organ transplant which requires continued immunosuppression, history of splenectomy).
• Subject had surgery within 4 weeks of Day 1 or plans to have surgery that, in the opinion of the Investigator, would interfere with the study.
• Subject has a history of clinically significant drug or alcohol abuse in the 12 months before Day 1, or other factors limiting the ability to cooperate or comply with the study protocol, as determined by the Investigator.
• Subject is not able to tolerate SC drug administration.
• The subject had prior exposure to a PD-1 or PD-L1 agonist, antagonist, or modulator.
• The subject is receiving any of the therapies listed in Table 3 within the washout period specified in the table
• Subject has been treated with intravenous, subcutaneous, intra-articular, intramuscular, intrabursal, intratendon sheath, and/or trigger point/tender point corticosteroids in the 8 weeks immediately before Day 1.
• Subject must have discontinued all high-potency opiates as defined in Table 3 at least 1 week prior to the first dose of study treatment on Day 1.
• Subject has received or plans to initiate during the study any of the following prescribed medications or therapies within the specified period: a. Immunomodulatory biologic agents (including investigational biologics) received within 8 weeks or 5 half-lives (whichever is longer) immediately before Day 1; b. Live or live-attenuated vaccines within 12 weeks before the first dose of study treatment on Day 1. Note: Currently authorized nonlive and nonlive-attenuated vaccines, including COVID-19 vaccines (e.g., RNA-based vaccines, protein-based vaccines, and nonreplicating viral-vector-based vaccines) are allowed during the study.

Other illness

• Subject has signs, symptoms, or current diagnosis of severe, progressive, or uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic (other than RA), or psychiatric conditions or metabolic disturbances, as determined by the Investigator, at Screening or Day 1.
• Subject had a cardiac hospitalization, myocardial infarction, or unstable cardiovascular disease (e.g., unstable angina, rapid atrial fibrillation, or clinically significant arrythmia), as determined by the Investigator, within 3 months of Day 1.
• Subject meets New York Heart Association criteria for Class III or higher congestive heart failure at Screening or Day 1.
• Subject has as a history of lymphoproliferative disease (including lymphoma) or monoclonal gammopathy of undetermined significance, or signs and symptoms suggestive of possible lymphoproliferative disease (e.g., lymphadenopathy or splenomegaly) as determined by the Investigator.
• Subject has a history of malignancy or cervical intraepithelial dysplasia within 5 years before Day 1 (except for squamous and basal cell carcinomas of the skin). See Appendix 12 for region-specific requirements.
• Subject has a history of any significant drug allergy or reaction to polysorbate 80 (a component of the study treatment formulation) or any other inactive ingredients (excipients) in the study treatment formulation.
• Subject has a history of severe allergic or anaphylactic reaction to human, humanized, chimeric, or murine mAb
• Subject tests positive for any of the following at Screening: a. Hepatitis C antibody with positive hepatitis C RNA; b. Hepatitis B surface antigen (HBsAg); c. Human immunodeficiency virus (HIV) 1 or HIV 2 (determined by testing algorithm depicted in Appendix 11)
• Subjects with a negative hepatitis B surface antigen (HBsAg-), positive hepatitis B core antibody (HBcAb+), and negative hepatitis B surface antibody (HBsAb-) at Screening will require additional reflexive testing for hepatitis B virus DNA (see Appendix 2) and cannot be randomized if hepatitis B virus DNA is detectable.
• The subject has a history of an inadequate response, loss of response, or intolerance to any combination of 3 or more bDMARD/tsDMARD classes. For this study, bDMARD classes are defined as 1) TNFα inhibitors (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab), 2) B-cell inhibitors (e.g., belimumab, rituximab), 3) selective costimulatory modulators (e.g., abatacept), 4) IL-1 inhibitors (e.g., anakinra), and 5) IL-6 inhibitors (e.g., sarilumab, tocilizumab). Targeted synthetic DMARD classes include but are not limited to: 1) JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib, filgotinib).

Lab values

• Subject meets any of the following laboratory criteria at Screening: a. Hemoglobin <9 g/dL; b. White blood cell count <2.5 × 10^9/L ; c. Platelets < 100 × 10^9/L; d. Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73 m2; e. ALT or AST > 2 × upper limit of normal (ULN); f. Total bilirubin > 1.5 × ULN. Subjects with Gilbert’s disease who have serum bilirubin < 3 × ULN may be included.
• Subject has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstances that might, in the opinion of the Investigator, confound the results of the study, interfere with the subject’s ability to comply with the study procedure, or make participation in the study not in the subject’s best interest.

Other

• Subject is a pregnant or lactating woman, or a woman who intends to become pregnant during the study.
• Subject has fibromyalgia which, in the opinion of the Investigator, will interfere with the assessment of tender or swollen joints.
• Subject is currently enrolled in another clinical study.
• The subject has Class IV RA according to 1991 Revised Criteria for the Classification of Global Functional Status in Rheumatoid Arthritis (Hochberg 1992) at Screening or Day 1.

• Subject is an adult male or female ≥ 18 years when the subject signs the ICF.
• A female subject who is a women of childbearing potential (WOCBP; defined below) must have a negative serum pregnancy test result at the Screening visit (Visit 1) and a negative urine pregnancy test result on Day 1 (Visit 2) prior to administration of study treatment, and must agree to use a highly effective method of birth control from the first dose of study treatment on Day 1 until at least 24 weeks after the last dose of study treatment. A WOCBP is defined as a woman who is between menarche and at least 12 months postmenopausal and who is not surgically or chemically sterilized (e.g., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; tubal ligation or occlusion are not considered acceptable methods of surgical sterilization so do not qualify women as of non-childbearing potential). Postmenopausal is defined as amenorrheic for at least 12 months, and, if aged < 60 years, have a serum follicle-stimulating hormone (FSH) level > 20 mIU/L. Women who are taking hormone replacement therapy do not have to have FSH assessments, but the amenorrhea before starting hormone replacement therapy must have been naturally occurring (i.e., spontaneous) and accompanied by an appropriate clinical profile (e.g., age appropriate with a history of vasomotor symptoms). Note: If a female subject’s childbearing potential changes after start of the study (e.g., a woman who is not heterosexually active becomes active or a premenarchal woman experiences menarche), she must begin practicing a highly effective method of birth control as soon as possible and until at least 24 weeks after the last dose of study treatment.
• Female subjects must agree to refrain from donating ova during the study and for at least 24 weeks after the last dose of study treatment.
• Male subjects must wear a condom when engaging in any activity that allows for passage of ejaculate to another person and use condoms plus spermicide from the first dose of study treatment on Day 1 until at least 150 days (duration of relevant exposure plus the duration of sperm cycle) after the last dose of study treatment if sexually active with a female partner who is a WOCBP. Male subjects should also be advised of the benefit for a female sexual partner who is a WOCBP to use an additional highly effective method of contraception as condoms may occasionally fail to prevent pregnancy
• Male subjects must agree to refrain from donating sperm during the study and for at least 150 days (duration of relevant exposure plus the duration of sperm cycle) after the last dose of study treatment.
• Subject is willing to participate, is not prohibited from participating by any local laws or regulations (e.g. persons under court protection, persons not affiliated to a social security system, protected adults), and is capable of giving voluntary written informed consent, which must be personally signed and dated by the subject and obtained prior to the initiation of any Screening or study-specific procedures.
• Subject is willing to comply with all study procedures and lifestyle considerations and must be available for the duration of the study.
• Subject has a clinical diagnosis of active RA based on the ACR/EULAR 2010 classification criteria (Aletaha 2010) for ≥3 months before Day 1.
• Subject is judged by the Investigator to be in good health (except for RA) based on the subject’s medical history and the results of the subject’s laboratory test results, physical examination, and 12-lead ECG results at Screening and/or Day 1.
• Subject has a positive test result for RF or antibodies to CCP at Screening.
• Subject has moderate to severe RA defined as the presence of ≥6 tender joints (excluding the distal interphalangeal joints; based on TJC68) and ≥6 swollen joints (excluding the distal interphalangeal joints; based on SJC66) at Screening and Day 1.
• Subject has a hs-CRP ≥3 mg/L at Screening.
• Subject must be receiving treatment with at least 1, but not more than 2, of the following csDMARDs for at least 3 months before Screening and be on stable dosages for at least 8 weeks immediately before Day 1 and throughout the study: a. Methotrexate 15 to 25 mg/week or ≥10 mg/week in subjects who cannot tolerate methotrexate at ≥15 mg/week (Subjects taking methotrexate must also be on a 5-mg/week or higher dosage of oral folic/folinic acid prior to Day 1); b. Leflunomide ≤20 mg/day; c. Sulfasalazine ≤3000 mg/day; d. Hydroxychloroquine ≤400 mg/day; e. Chloroquine ≤250 mg/day
• Subject must meet the following tuberculosis (TB) screening criteria: a. Has no history of active or latent TB before Screening or has a known history of latent TB, and the subject i. Has completed appropriate treatment for latent TB before Day 1, or ii. Is receiving or will receive treatment for latent TB that is well tolerated, was or will be initiated at least 14 days prior to Day 1, and will continue or complete during study participation Note: It is the responsibility of the Investigator to verify and document the adequacy of previous or concurrent anti-TB treatment based on current local TB treatment guidelines; b. Has no signs or symptoms suggestive of active TB upon review of the subject’s medical history and/or physical examination c. Has had no recent close contact with a person with active TB, based on information provided by the subject; d. Has a negative QuantiFERON®-TB test result obtained during Screening prior to Day 1 Note: A QuantiFERON-TB test is not required during Screening for subjects with a known history of latent TB who have previously completed, are currently receiving, or plan to initiate appropriate TB treatment as described in Inclusion Criterion 8a. Note: A subject with a newly identified positive QuantiFERON-TB Screening test result must undergo an evaluation to rule out active TB, initiate appropriate treatment for latent TB (according to current local guidelines), and receive and tolerate at least 14 days of therapy prior to being allowed to enter the study under Inclusion Criterion 8a. Note: A subject whose first screening QuantiFERON-TB test result is indeterminate may have the test repeated once. A second indeterminate QuantiFERON-TB test result requires that the subject screen fail;
• Subject has no abnormalities suggestive of a malignancy (e.g., neoplasm) or current active or latent infection, including TB based on a report from a qualified radiologist of a chest X-ray or computerized tomography (CT) scan performed within 6 months before Day 1. If a chest X-ray or CT scan was not performed and read by a qualified radiologist within 6 months before Day 1, chest X-rays (posterior-anterior and lateral views) must be performed and read by qualified radiologist during Screening and before Day 1;