A Phase 1b/2a Open-Label, Multiple-Ascending Dose Cohort Study to Assess the Safety, Tolerability, Pilot Efficacy, Pharmacokinetics and Pharmacodynamic Effects of 28-Day Repeat Subcutaneous Doses of AKB-9778 in Subjects with Diabetic Macular Edema

Abstract

Purpose: Although VEGF inhibitors have provided a significant advance in treatment of clinically significant DME, many patients remain inadequately treated. AKB-7998 activates the TIE2 pathway to restore retinal vascular integrity in the presence of elevated ANG2 and VEGF levels. This study was designed to evaluate the safety and efficacy of 28 day BID subcutaneous dosing of AKB-9778 in patients with clinically significant DME.

Methods: Twenty-four DME patients with central retinal subfield thickness (CRT) of > 325 μm and ETDRS acuity < 74 letters participated in the study. Patients were included if they had not been treated for DME in the study eye for > 28 days prior to baseline. Cohorts of 6 patients each were treated with 5 mg, 15 mg, 22.5 mg and 30 mg of AKB-9778 delivered subcutaneously BID for 28 days. Patients were observed for an additional 56 days. Ophthalmic exams including OCT and BCVA, physical exams, blood chemistry and hematology were obtained weekly. Pharmacokinetic samples were obtained at multiple time points post-dosing on Day 1 and Day 14.

Results: All dose levels of AKB-9778 were well tolerated. There were no serious adverse effects or deaths and no changes in clinical labs or hematology were observed. Subcutaneous injections were well tolerated. A transient, generally asymptomatic reduction in blood pressure was observed at the 22.5 and 30 mg doses. One patient in each of these dose groups discontinued from the study after the first dose due to vasovagal events. Pharmacokinetics showed dose proportional increase in exposure with a tmax of 15 - 30 minutes and a half-life of ~1 hour. The 5 mg dose did not improve visual acuity or CRT. At doses of 15 mg or greater, after 1 month of treatment, 7/18 patients had reduction in CRT of > 50 μm and 12/18 patients gained 5 or more letters of visual acuity.

Conclusions: The present study shows that subcutaneous dosing of AKB-9778 is safe and well tolerated through 28 days of dosing at levels up to 30 mg BID. Reduction of DME and corresponding increase of visual acuity were observed at doses of 15 mg and above. The results suggest that TIE2 activation may be effective in the treatment of DME.

Keywords: 499 diabetic retinopathy • 700 retinal neovascularization • 505 edema