A Dose Escalation Study to Assess Safety, Tolerability and Pharmacokinetics of ASP2409 Following a Single Intravenous Dose in Patients With Rheumatoid Arthritis on Methotrexate

This is a dose-escalation study. Sequential cohorts of subjects will receive increasing doses of ASP2409 or matching placebo.

Subjects in all cohorts will stay confined in the unit for 3 days. All subjects will have scheduled outpatient visits and be followed for a minimum of 90 days.

Inclusion criteria

• Subject weighs at least 50 kg.
• Subject has a body mass index (BMI) of ≤ 35 kg/m2.
• Subject's 12-lead electrocardiogram (ECG) results are normal at Screening and Day -1 or, if abnormal, the abnormality is not clinically significant
• Female subject must be either:

• Of non-childbearing potential:

• post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
• documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening).
• Or, if of childbearing potential:

• must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1.
• must use two forms of birth control (at least one of which must be a barrier method) starting at Screening and throughout the Treatment and Observation Period, and for ≥ 120 days after final study drug administration.
• Acceptable forms include:

• Established use or oral, injected or implanted hormonal methods of contraception.
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/ cream/suppository.
• Female subject must not be breastfeeding at Screening or during the Treatment and Observation period and for ≥ 120 days after final study drug administration.
• Female subject must not donate ova starting at Screening and throughout the Treatment and Observation period and for ≥ 120 days after final study drug administration.
• Male subject must not donate sperm starting at Screening and throughout the Treatment and Observation period and for at least ≥ 120 days after final study drug administration.
• Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the Treatment and Observation period and for ≥ 120 days after final study drug administration.
• Subject has Rheumatoid Arthritis (RA) that was diagnosed according to the 1987 revised criteria of the American College of Rheumatology (ACR) ≥ 6 months prior to Screening.
• Subject meets the ACR 1991 revised criteria for Global Functional Status in RA, Class I, II or III at Screening.
• Subject MUST be on concomitant methotrexate (MTX):

• for ≥ 3 months prior to study drug infusion, AND
• at a stable dose (10 - 25 mg/week) for ≥ 28 days prior to study drug infusion and throughout the study.
• Subjects on the following medications must remain on a stable regimen: non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, hydroxychloroquine (Plaquenil®), sulfasalazine, oral corticosteroids (≤ 10 mg of prednisone, or equivalent, daily) or low dose opioids (≤ 30 mg of oral morphine, or equivalent, daily) for

≥ 28 days prior to Screening and remain so throughout the Treatment and Observation Period. (The start of Plaquenil and sulfasalazine must be ≥ 2 months prior to study drug infusion.)

• Subject is highly likely to comply with the protocol and complete the study.

Exclusion criteria

• Subject has an ongoing clinically significant systemic disease such as uncompensated heart failure, uncontrolled diabetes mellitus, severe hepatic failure or severe pulmonary disease.
• Subject has a history of any malignancy except for adequately-treated, non-melanoma skin cancer and adequately-treated in-situ cervical cancer.
• Subject has a history of severe allergic or anaphylactic reactions.
• Subject has a history of consuming more than 14 units of alcoholic beverages per week or has a history of alcoholism or drug/chemical/substance abuse within past 6 months prior to Screening (Note: one unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits).
• Subject has a positive test for alcohol or drugs of abuse (excluding drugs prescribed to subject) at Screening or Day -1.
• Subject has/had a viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to Day -1.
• Subject has a past history of serious opportunistic infection.
• Subject is known positive for human immunodeficiency virus (HIV) antibody.
• Subject has a positive tuberculosis (TB) skin test or Quantiferon Gold test at Screening.
• Subject has a positive test for hepatitis C antibody, or positive test for hepatitis B surface antigen (HBsAg), or positive hepatitis B core antibody at Screening.
• Subject's laboratory test results at Screening:

• alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), are ˃ 2 times the upper limit of normal, AND/OR
• are outside the normal limits and considered by the Investigator to be clinically significant with regard to the remaining per-protocol laboratory tests.
• Subject received any live or live attenuated vaccine within 30 days prior to study drug infusion.
• Subject received any systemic immunosuppressant agent, other than (MTX) or stable steroid regimen, within 2 months prior to study drug infusion.
• Subject has previously received any antibody or therapeutic biologic product within 56 days or 5 half-lives, whichever is longer, prior to study drug infusion.
• Subject has previously participated in any interventional clinical study or has received an experimental agent within 56 days or 5 half-lives, whichever is longer, prior to study drug infusion.
• Subject is participating in another clinical trial or has participated in another dose group of the current trial.
• Subject has had any significant blood loss, donated one unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to clinic admission on Day -1.
• Subject has taken Orencia® (abatacept), Nulojix® (belatacept) or any other CTLA4-Ig molecule.
• Subject has any other condition which precludes the subject's participation in the trial.
• Subject has a history of prolonged QT syndrome.