Original articleEnhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression
Section snippets
Methods
This was a phase IIa, randomized, placebo- and sham injection–controlled, double-masked clinical trial conducted at 40 sites in the United States, 36 of which enrolled at least 1 subject. The study was carried out with institutional review board approval. Informed consent for the research was obtained from all subjects, and the study complied with the Declaration of Helsinki and the Health Insurance Portability and Accessibility Act. The study was registered at www.clinicaltrials.gov under the
Subject Disposition
A total of 144 subjects with clinically significant DME and CST >325 μm were enrolled. A total of 93% of subjects (134/144) completed the 12-week active treatment period: 43 subjects (89.6%) in the AKB-9778 monotherapy group, 44 subjects (93.6%) in the ranibizumab monotherapy group, and 47 subjects (95.9%) in the combination group. Of the 134 subjects who remained in the trial through the 12-week primary end point, compliance with subcutaneous study medication dosing was 97.8% across all
Discussion
Tie2 activation renders endothelial cells less responsive to pro-angiogenic and pro-permeability factors, promoting vascular stability. This is a critical function that requires tight regulation that is achieved through titration of an endogenous full agonist, angiopoietin 1, and an endogenous weak partial agonist, angiopoietin 2; and regulation of an endothelial tyrosine phosphatase, VE-PTP. Hypoxia increases the expression of both angiopoietin 2 and VE-PTP, which collaborate to limit Tie2
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Supplemental material is available at www.aaojournal.org.
Members of the TIME-2 study group are listed in the Appendix (available at www.aaojournal.org).
Financial Disclosure(s): The author(s) have made the following disclosure(s): P.A.C.: Consultant – Aerpio Therapeutics, Alimera, Applied Genetic Technologies, Eleven Biotherapeutics, AsclipiX, Genentech/Roche, Kala Pharmaceuticals, Rxi Pharmaceuticals, Akebia, Regeneron, Allegro, Intrexon, RegenX; Institutional grants – AbbVie, Aerpio Therapeutics, Allergan, Genentech/Roche, Genzyme, GlaxoSmithKline, Oxford Biomedica, Regeneron, RegenX, Rxi Pharmaceuticals; Royalties – Graybug; Equity – Alimera, Allegro, Graybug.
A.K.: Grants – Aerpio Therapeutics, Genentech; Personal fees – Genentech, Novartis, Allergan; Nonfinancial support – Genentech, Novartis.
M.S.: Research support and personal fees (Advisory Committee) – Aerpio Therapeutics; Consultant – Genentech, Allergan; Grants − Regeneron, Ampio, Allegro, Stem Cells Inc., Acucela, Optos, Neurotech.
S.P.: Grants – Alcon, Ophthotech, Genentech, Allergan, Regeneron.
D.B.: Consultant – Aerpio Therapeutics, Alcon, Allegro, Allergan, Bausch & Lomb, Bayer, CoDa Therapeutics, ForeSight Biotherapeutics, Erigen Inc., Genentech, GlaxoSmithKline, Neurotech, Notal Vision, Novartis Ophthalmics, Ophthotech, Ohr, Optos, Regeneron, RetroSense Therapeutics, Sun Pharmaceuticals, Stem Cells Inc., ThromboGenics.
B.W., L.G., K.P., M.B.: Employees – Aerpio Therapeutics.
This study was funded by Aerpio Therapeutics, Cincinnati, Ohio.
Author Contributions:
Conception and design: Campochiaro, Withers, Gambino, Peters, Brigell
Data collection: Campochiaro, Khanani, Singer, Patel, Boyer, Dugel, Kherani
Analysis and interpretation: Campochiaro, Kherani, Withers, Gambino, Peters, Brigell
Obtained funding: Not applicable
Overall responsibility: Campochiaro, Kherani, Withers, Gambino, Brigell