Abstract
Purpose :
To assess the effect of subcutaneous injections (sc) of 15 mg of AKB-9778 BID either as monotherapy (MT) or as combination therapy with ranibizumab (RBZ) on macular edema in subjects with DME.
Methods :
This was a phase 2A, randomized, double-masked, double-dummy trial. 144 patients with DME and central subfield thickness (CST) ≥ 325 µm measured by SD-OCT were enrolled at 36 US sites. Patients were randomized to receive: 1. AKB-9778 MT (sc AKB-9778 15 mg BID + monthly sham IVT injection); 2. AKB-9778+RBZ (sc AKB-9778 15mg BID + monthly IVT injection of 0.3 mg RBZ); or 3. RBZ MT (sc placebo injection BID + monthly IVT injection of 0.3 mg RBZ). The treatment period was 3 months followed by 2 months of observation. The main outcome measure was change from baseline in CST (by ANCOVA with baseline CST as covariate). Other assessments included BCVA, clinical eye examination, 7-field fundus photographs, fluorescein angiogram, physical examination, vital signs, safety laboratory tests, PK assessments, and adverse event reporting.
Results :
The mean change from baseline CST at end of treatment was 6.2±88.4 µm in the AKB-9778 MT group, -109.2±17.2 µm in the RBZ MT group, and -163.8±24.3 µm in the AKB-9778+RBZ group (p=0.008 compared to RBZ MT). Mean CST at month 3 was 339.9±11.2 µm with 29.2% of eyes ≤ 300 µm in the AKB-9778+RBZ group versus 391.2±17.2 µm with 17.0% of eyes ≤ 300 µm in the RBZ MT group. The mean change from baseline BCVA was 1.5±1.2 letters in the AKB-9778 MT group, 5.7±1.2 letters in the RBZ MT group, and 6.3±1.3 letters in the AKB-9778+RBZ group. The percentage of eyes that gained ≥10 letters was 8.7% in the AKB-9778 MT group, 29.8% in the RBZ MT group, and 35.4% in the AKB-9778+RBZ group. In the RBZ MT group, 4.2% of qualified fellow eyes showed ≥2-step reduction in diabetic retinopathy severity score, compared to 11.4% of such eyes in the AKB-9778 groups.
AKB-9778 was well tolerated, with no treatment group differences in serious AEs, severe AEs, or in clinically significant abnormalities in physical examination, ophthalmology examination or laboratory tests.
Conclusions :
These results demonstrate that Tie2 activation by subcutaneously administered AKB-9778 in combination with anti-VEGF therapy enhances the effect of anti-VEGF therapy on diabetic macular edema.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.