Enhanced Benefit in Diabetic Macular Edema From AKB-9778 Tie2 Activation Combined With Vascular Endothelial Growth Factor Suppression

Ophthalmology. 2016 Aug;123(8):1722-1730. doi: 10.1016/j.ophtha.2016.04.025. Epub 2016 May 26.

Abstract

Purpose: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME).

Design: A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial.

Participants: 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.

Methods: 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.

Main outcome measures: Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS).

Results: 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.

Conclusions: 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.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Aniline Compounds / therapeutic use*
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 2 / complications
  • Diabetic Retinopathy / diagnosis
  • Diabetic Retinopathy / drug therapy*
  • Diabetic Retinopathy / metabolism
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Fluorescein Angiography
  • Humans
  • Injections, Subcutaneous
  • Intravitreal Injections
  • Macular Edema / diagnosis
  • Macular Edema / drug therapy*
  • Macular Edema / metabolism
  • Male
  • Middle Aged
  • Ranibizumab / therapeutic use*
  • Receptor, TIE-2 / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / antagonists & inhibitors
  • Sulfonic Acids / therapeutic use*
  • Tomography, Optical Coherence
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Visual Acuity

Substances

  • AKB-9778
  • Angiogenesis Inhibitors
  • Aniline Compounds
  • Sulfonic Acids
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Receptor, TIE-2
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Ranibizumab