title: Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression.
abstract: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME).
  
  
  
  A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial.
  
  
  
  Subjects (n = 144) with decreased vision from DME and central subfield thickness (CST) ≥325 μm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites.
  
  
  
  Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID) + monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB-9778 15 mg BID + monthly 0.3 mg ranibizumab; or (3) ranibizumab monotherapy: subcutaneous placebo injections BID + monthly 0.3 mg ranibizumab. Best-corrected visual acuity (BCVA) and CST were measured at baseline and every 4 weeks.
  
  
  
  Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS).
  
  
  
  At week 12, mean change from baseline CST was significantly greater in the combination group (-164.4±24.2 μm) compared with the ranibizumab monotherapy group (-110.4±17.2 μm; P = 0.008) and was 6.2±13.0 μm in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0±11.2 μm and 29.2%, respectively, in the combination group versus 392.1±17.1 μm and 17.0%, respectively, in the ranibizumab monotherapy group. Mean change from baseline BCVA (letters) was 6.3±1.3 in the combination group, 5.7±1.2 in the ranibizumab monotherapy group, and 1.5±1.2 in the AKB-9778 monotherapy group. The percentage of study eyes that gained ≥10 or ≥15 letters was 8.7% and 4.3%, respectively, in the AKB-9778 monotherapy group, 29.8% and 17.0%, respectively, in the ranibizumab monotherapy group, and 35.4% and 20.8%, respectively, in the combination group. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a ≥2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events.
  
  
  
  Activation of Tie2 by subcutaneous injections of AKB-9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone.
authors.affiliation: Johns Hopkins, Wilmer Eye Institute, Baltimore, Maryland. Electronic address: pcampo@jhmi.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.affiliation: Sierra Eye Associates, Reno, Nevada.
authors.forename: Arshad
authors.initials: A
authors.lastname: Khanani
authors.affiliation: Medical Center Ophthalmology Associates, San Antonio, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Singer
authors.affiliation: Retina Research Institute of Texas, Abilene, Texas.
authors.forename: Sunil
authors.initials: S
authors.lastname: Patel
authors.affiliation: Retina Vitreous Associates Medical Group, Beverly Hills, California.
authors.forename: David
authors.initials: D
authors.lastname: Boyer
authors.affiliation: Retinal Consultants of Arizona, Phoenix, Arizona; USC Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Pravin
authors.initials: P
authors.lastname: Dugel
authors.affiliation: Johns Hopkins, Wilmer Eye Institute, Baltimore, Maryland.
authors.forename: Saleema
authors.initials: S
authors.lastname: Kherani
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Barbara
authors.initials: B
authors.lastname: Withers
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Laura
authors.initials: L
authors.lastname: Gambino
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Kevin
authors.initials: K
authors.lastname: Peters
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Brigell
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003930:Diabetic Retinopathy / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007279:Injections, Subcutaneous; D058449:Intravitreal Injections; D008269:Macular Edema / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab / Q000627:therapeutic use*; D042787:Receptor, TIE-2 / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000037:antagonists & inhibitors; D013451:Sulfonic Acids / Q000627:therapeutic use*; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014792:Visual Acuity
chemical_list: C000598564:AKB-9778; D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; D013451:Sulfonic Acids; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D000069579:Ranibizumab