Ixekizumab for the Management of Refractory Non-Infectious Uveitis: A Proof-of-Concept Study

Inclusion Criteria:

1. At least 18 years of age
2. Diagnosis of non-infectious intermediate, posterior, panuveitis, or chronic steroiddependent anterior uveitis
3. Failure of at least one classic synthetic DMARD including Methotrexate, Mycophenolate,Cyclosporin, Azathioprine, Cyclophosphamide, and/or at least one anti-TNF agentincluding Adalimumab, Infliximab, Etanercept, Golimumab or Certolizumab
4. Active disease at screening visit
5. At least 1 of the following parameters in at least one eye:

• active inflammatory chorioretinal and/or inflammatory retinal vascular lesions
• ≥ 1+ vitreous haze (Nussenblatt criteria)
• ≥ 2+ anterior chamber cells (National Eye Institute/Standardization of UveitisNomenclature criteria)
• Cystoid macular edema, seen on optical coherence tomography and/or fluoresceinangiography
• FA leakage pattern deemed by investigators to be suggestive of activeintermediate, posterior, and panuveitis, including optic disc, retinal vascular,and macular leakages
• Active snowbanking

Exclusion Criteria:

• The presence of only acute anterior uveitis.
• Serpiginous choroidopathy
• Subject with prior inadequate response to high-dose oral corticosteroids (> 60 mg ofprednisone)
• Subject with confirmed or suspected infectious uveitis
• Patients with intraocular pressure of ≥ 25 mmHg or evidence of optic nerve injury
• Corneal or lens opacity that precludes adequate ophthalmic evaluation.
• Patients likely to undergo cataract surgery during the duration of the trial.
• Patients with Best Corrected Visual Acuity (BCVA) less than 20 letters (EarlyTreatment Diabetic Retinopathy Study)
• Dose of concomitant immunosuppressive therapy at the baseline visit:
• Methotrexate (MTX) ˃ 25 mg per week
• Cyclosporine ˃ 4 mg/kg per day
• Mycophenolate mofetil ˃ 3 grams per day or an equivalent drug to mycophenolatemofetil (e.g. mycophenolic acid) at an equivalent dose approved by the medicalmonitor.
• Azathioprine ˃ 175 mg per day
• Tacrolimus (oral formulation) > 8 mg per day
• If entering the study on 1 concomitant immunosuppressive therapy, dose has beenincreased within the last 28 days prior to Baseline visit.
• Subject has received Retisert® (implant) within 3 years prior to the Baseline visit orthat has had complications related to the device. Subject has had Retisert® (implant)removed within 90 days prior to the Baseline visit or has had complications related tothe removal of the device
• Subject has received intraocular or periocular corticosteroids within 30 days prior toBaseline visit
• Subject with proliferative or severe non-proliferative diabetic retinopathy orclinically significant macular edema due to diabetic retinopathy
• Subject with neovascular/wet age-related macular degeneration
• Subject with abnormality of vitreo-retinal interface (i.e., vitreomacular traction,epiretinal membranes, etc.) with the potential for macular structural damageindependent of the inflammatory process, deemed macular pathology is deemed by aretinal specialist to be a potential cofounder of patient's visual acuity reduction
• Subject with severe vitreous haze that precludes visualization of the fundus at thebaseline visit
• Subject has received Ozurdex® (dexamethasone implant) within 6 months prior to thebaseline visit
• Subject has received intravitreal anti-VEGF therapy within 45 days of the Baselinevisit for Lucentis® (ranibizumab) or Avastin® (bevacizumab) or within 60 days of theBaseline visit for anti-VEGF Trap (aflibercept)
• Subject has received intravitreal methotrexate within 90 days prior to the Baselinevisit
• Subject on systemic carbonic anhydrase inhibitor within 1 week prior to Screeningvisit
• Subject with macular edema as the only sign of uveitis
• Subject with a history of scleritis
• Subject with intolerance to high-dose oral corticosteroids (equivalent of oralprednisone 1 mg/kg/day or 60 to 80 mg/day)
• Subject on cyclophosphamide within 30 days prior to the Baseline visit
• Participation in other investigational drug or device clinical trials within 30 daysprior to Day 0 or planning to participate in other investigational drug or deviceclinical trials within 180 days following 48 weeks after day 0. This includes bothocular and non-ocular clinical trials
• Major surgery within 8 weeks prior to screening or planned major surgery within 6months following randomization
• Treatment with intravenous gamma globulin or plasmapheresis during the course of thetrial
• Immunization with a live/attenuated vaccine within 4 weeks prior to baseline
• History of severe allergic or anaphylactic reactions to human, humanized monoclonalantibodies
• Prior history of Crohn's Colitis or Ulcerative Colitis
• Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (includeuncontrolled diabetes mellitus) or gastrointestinal disease (including complicateddiverticulitis, liver disease or peptic ulcer disease)
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterialor other infections (including but not limited to tuberculosis and atypicalmycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungalinfections of nail beds)
• Any major episode of infection requiring hospitalization or treatment with IVantibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior toscreening
• Active tuberculosis (TB) requiring treatment within the previous 3 years. Patientsshould be screened for latent TB and, if positive, treated following local practiceguidelines prior to initiating trial. Patients treated for tuberculosis with norecurrence in 3 years are permitted
• Primary or secondary immunodeficiency (history of or currently active)
• Evidence of active malignant disease, malignancies diagnosed within the previous 5years (including hematological malignancies and solid tumors, except basal andsquamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that hasbeen excised and cured)
• Pregnant women or breast-feeding mothers
• Patients with reproductive potential not willing to use an effective method ofcontraception
• History of alcohol, drug, or chemical abuse within 1 year prior to screening.
• Serum creatinine > 1.6 mg/dL (141 μmol/L) in female patients and > 1.9 mg/dL (168 μmol/L) in male patients. Patients with serum creatinine values exceeding limits maybe eligible for the study if their estimated glomerular filtration rates (GFR) are >30.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upperlimit of normal (ULN)
• Total Bilirubin > 1.5 ULN
• Platelet count < 100 x 109/L (100,000/mm3)
• Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
• White Blood Cells < 3.0 x 109/L (3000/mm3)
• Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3)
• Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)
• Positive Hepatitis BsAg, or Hepatitis C antibody