Inclusion Criteria: * Written consent to participate in the study * Male or female 30 to 80 years of age, inclusive, on the day of enrollment (Day 1) * Body mass index (BMI) ≤ 40 kilograms per meters squared (kg/m2) * Clinical diagnosis of OA of the knee on the American College of Rheumatology criteria (Altman, 1986) with radiologic evidence of OA (K-L Grade 2 or 3 for SAD Phase Cohort A and K-L Grade 2, 3 or 4 for SAD Phase Cohorts B and C and the Expansion Phase) at the index joint at the screening visit * Moderate pain in the index joint * Failed two or more types of conservative therapy for index knee osteoarthritis (e.g., structured exercise programs, topical or oral non-steroidal anti-inflammatory therapies); or failed one prior type of conservative therapy and at least one prior index knee IA treatment (corticosteroid or hyaluronic acid) * Sexually active females and males agree to use highly effective methods of contraception Exclusion Criteria: * Reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease * History of or current infection in the index knee joint * Inability to undergo Magnetic Resonance Imaging (MRI) due to presence of surgical hardware or other foreign body in the index knee * Unstable index knee joint (e.g., torn anterior cruciate ligament, etc.) within 12 months of Screening * Any IA drug/biologic use within 6 months of Screening or 5 half-lives (whichever is longer) (e.g., IA corticosteroid, IA hyaluronic acid, platelet rich plasma injection, stem cells, prolotherapy and amniotic fluid injection, etc.) * Cold or radiofrequency nerve ablation of the index knee within 12 months of Screening * Arthroscopic or open surgery on the index knee within 12 months of Screening or planned/anticipated surgery on the index knee for the study period * Anticipated major surgery during the study period * Laboratory values that meet exclusion criteria * ECG abnormality at Screening or Baseline judged clinically significant * Use of immunomodulators, immunosuppressive, or chemotherapeutic agents within 5 years of Screening * Use of any other investigational drug, biologic or device within 3 months of Screening * Any systemic or local bacterial or viral infection requiring IV antibiotics or antivirals within 4 weeks of Screening or oral antibiotics or antivirals within 2 weeks of Screening * Known allergy or sensitivity to methylprednisolone * Any other clinically significant acute or chronic medical conditions (e.g., bleeding disorder) that, in the judgment of the Investigator, would preclude the use of an IA injection or that could compromise patient safety, limit the patient's ability to complete the study, and/or compromise the objectives of the study Note: Other protocol defined inclusion/exclusion criteria apply.