Elsevier

Ophthalmology

Volume 123, Issue 8, August 2016, Pages 1722-1730
Ophthalmology

Original article
Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression

https://doi.org/10.1016/j.ophtha.2016.04.025Get rights and content

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.

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

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