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

Peter A Campochiaro, Arshad Khanani, Michael Singer, Sunil Patel, David Boyer, Pravin Dugel, Saleema Kherani, Barbara Withers, Laura Gambino, Kevin Peters, Mitchell Brigell

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalOphthalmology
DOIs
StateAccepted/In press - Jan 18 2016

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Macular Edema
Vascular Endothelial Growth Factor A
Visual Acuity
Diabetic Retinopathy
Subcutaneous Injections
Placebos
Outcome Assessment (Health Care)
AKB-9778
Intraocular Injections
Ranibizumab
Optical Coherence Tomography
Edema
Clinical Trials
Safety
Injections

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression. / Campochiaro, Peter A; Khanani, Arshad; Singer, Michael; Patel, Sunil; Boyer, David; Dugel, Pravin; Kherani, Saleema; Withers, Barbara; Gambino, Laura; Peters, Kevin; Brigell, Mitchell.

In: Ophthalmology, 18.01.2016.

Research output: Contribution to journalArticle

Campochiaro, Peter A ; Khanani, Arshad ; Singer, Michael ; Patel, Sunil ; Boyer, David ; Dugel, Pravin ; Kherani, Saleema ; Withers, Barbara ; Gambino, Laura ; Peters, Kevin ; Brigell, Mitchell. / Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression. In: Ophthalmology. 2016.
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title = "Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression",
abstract = "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.",
author = "Campochiaro, {Peter A} and Arshad Khanani and Michael Singer and Sunil Patel and David Boyer and Pravin Dugel and Saleema Kherani and Barbara Withers and Laura Gambino and Kevin Peters and Mitchell Brigell",
year = "2016",
month = "1",
day = "18",
doi = "10.1016/j.ophtha.2016.04.025",
language = "English (US)",
journal = "Ophthalmology",
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TY - JOUR

T1 - Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression

AU - Campochiaro, Peter A

AU - Khanani, Arshad

AU - Singer, Michael

AU - Patel, Sunil

AU - Boyer, David

AU - Dugel, Pravin

AU - Kherani, Saleema

AU - Withers, Barbara

AU - Gambino, Laura

AU - Peters, Kevin

AU - Brigell, Mitchell

PY - 2016/1/18

Y1 - 2016/1/18

N2 - 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.

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 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.

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