title: Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2.
abstract: OBJECTIVE
  AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME).
  
  
  METHODS
  Open-label, dose-escalation clinical trial.
  
  
  METHODS
  Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks.
  
  
  METHODS
  Patients were seen weekly during a 4-week treatment period for safety assessments, best-corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral-domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks.
  
  
  METHODS
  Safety assessments, change from baseline BCVA, and change from baseline CST.
  
  
  RESULTS
  All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 μm in 5 patients and by 50 to 100 μm in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA.
  
  
  CONCLUSIONS
  No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator.
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: pcampo@jhmi.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Raafay
authors.initials: R
authors.lastname: Sophie
authors.affiliation: Center for Retina and Macular Disease, Winter Haven, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Tolentino
authors.affiliation: Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati School of Medicine, Cincinnati, Ohio.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Miller
authors.affiliation: Charlotte Eye, Ear, Nose & Throat Associates, Charlotte, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Browning
authors.affiliation: Retina Vitreous Associates Medical Group, Beverly Hills, California.
authors.forename: David S
authors.initials: DS
authors.lastname: Boyer
authors.affiliation: Ophthalmic Consultants of Boston, Boston, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Heier
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Laura
authors.initials: L
authors.lastname: Gambino
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Barbara
authors.initials: B
authors.lastname: Withers
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Brigell
authors.affiliation: Aerpio Therapeutics, Cincinnati, Ohio.
authors.forename: Kevin
authors.initials: K
authors.lastname: Peters
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007279:Injections, Subcutaneous; D008269:Macular Edema / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D042787:Receptor, TIE-2 / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000037:antagonists & inhibitors*; D013451:Sulfonic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology
chemical_list: C000598564:AKB-9778; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D042787:Receptor, TIE-2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3