PMID- 27236272 OWN - NLM STAT- MEDLINE DCOM- 20170630 LR - 20220409 IS - 1549-4713 (Electronic) IS - 0161-6420 (Linking) VI - 123 IP - 8 DP - 2016 Aug TI - Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression. PG - 1722-1730 LID - S0161-6420(16)30201-9 [pii] LID - 10.1016/j.ophtha.2016.04.025 [doi] AB - 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 mum 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 mum) compared with the ranibizumab monotherapy group (-110.4+/-17.2 mum; P = 0.008) and was 6.2+/-13.0 mum in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0+/-11.2 mum and 29.2%, respectively, in the combination group versus 392.1+/-17.1 mum 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. CI - Copyright (c) 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. FAU - Campochiaro, Peter A AU - Campochiaro PA AD - Johns Hopkins, Wilmer Eye Institute, Baltimore, Maryland. Electronic address: pcampo@jhmi.edu. FAU - Khanani, Arshad AU - Khanani A AD - Sierra Eye Associates, Reno, Nevada. FAU - Singer, Michael AU - Singer M AD - Medical Center Ophthalmology Associates, San Antonio, Texas. FAU - Patel, Sunil AU - Patel S AD - Retina Research Institute of Texas, Abilene, Texas. FAU - Boyer, David AU - Boyer D AD - Retina Vitreous Associates Medical Group, Beverly Hills, California. FAU - Dugel, Pravin AU - Dugel P AD - Retinal Consultants of Arizona, Phoenix, Arizona; USC Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California. FAU - Kherani, Saleema AU - Kherani S AD - Johns Hopkins, Wilmer Eye Institute, Baltimore, Maryland. FAU - Withers, Barbara AU - Withers B AD - Aerpio Therapeutics, Cincinnati, Ohio. FAU - Gambino, Laura AU - Gambino L AD - Aerpio Therapeutics, Cincinnati, Ohio. FAU - Peters, Kevin AU - Peters K AD - Aerpio Therapeutics, Cincinnati, Ohio. FAU - Brigell, Mitchell AU - Brigell M AD - Aerpio Therapeutics, Cincinnati, Ohio. CN - TIME-2 Study Group LA - eng PT - Clinical Trial, Phase II PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20160526 PL - United States TA - Ophthalmology JT - Ophthalmology JID - 7802443 RN - 0 (AKB-9778) RN - 0 (Angiogenesis Inhibitors) RN - 0 (Aniline Compounds) RN - 0 (Sulfonic Acids) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 2.7.10.1 (Receptor, TIE-2) RN - EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3) RN - ZL1R02VT79 (Ranibizumab) SB - IM MH - Angiogenesis Inhibitors/*therapeutic use MH - Aniline Compounds/*therapeutic use MH - Diabetes Mellitus, Type 1/complications MH - Diabetes Mellitus, Type 2/complications MH - Diabetic Retinopathy/diagnosis/*drug therapy/metabolism MH - Double-Blind Method MH - Drug Therapy, Combination MH - Female MH - Fluorescein Angiography MH - Humans MH - Injections, Subcutaneous MH - Intravitreal Injections MH - Macular Edema/diagnosis/*drug therapy/metabolism MH - Male MH - Middle Aged MH - Ranibizumab/*therapeutic use MH - Receptor, TIE-2/*metabolism MH - Receptor-Like Protein Tyrosine Phosphatases, Class 3/antagonists & inhibitors MH - Sulfonic Acids/*therapeutic use MH - Tomography, Optical Coherence MH - Vascular Endothelial Growth Factor A/*antagonists & inhibitors MH - Visual Acuity EDAT- 2016/05/30 06:00 MHDA- 2017/07/01 06:00 CRDT- 2016/05/30 06:00 PHST- 2016/01/18 00:00 [received] PHST- 2016/04/15 00:00 [revised] PHST- 2016/04/15 00:00 [accepted] PHST- 2016/05/30 06:00 [entrez] PHST- 2016/05/30 06:00 [pubmed] PHST- 2017/07/01 06:00 [medline] AID - S0161-6420(16)30201-9 [pii] AID - 10.1016/j.ophtha.2016.04.025 [doi] PST - ppublish SO - Ophthalmology. 2016 Aug;123(8):1722-1730. doi: 10.1016/j.ophtha.2016.04.025. Epub 2016 May 26.