Results from TIME-2, a phase IIA study, support further development of combination treatment with subcutaneous injection of the Tie2 activator, AKB-9778 (Aerpio Therapeutics), plus intravitreous (IVT) anti-VEGF injection for diabetic macular edema.
Seattle-Results from TIME-2, a phase IIA study, support further development of combination treatment with subcutaneous injection of the Tie2 activator, AKB-9778 (Aerpio Therapeutics), plus intravitreous (IVT) anti-VEGF injection for diabetic macular edema (DME), as well as the development of non-IVT therapy for the treatment of diabetic retinopathy.
Speaking at ARVO 2016, Arshad Khanani, MD, noted that multiple therapeutic approaches to regulate Tie2 activity are under development. AKB-9778 is the only Tie2 targeted compound in clinical trials that has completed a phase II randomized, placebo-controlled study in the setting of retinal disease.
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“TIME-2 provides proof of concept for treatment of diabetic eye disease, both DME and diabetic retinopathy, by activation of Tie2 through inhibition of vascular endothelial-protein tyrosine phosphatase (VE-PTP) mediated by AKB-9778,” said Dr. Khanani, who is in private practice, Reno, NV.
Dr. Khanani explained that Tie2 is a transmembrane receptor expressed on vascular endothelial cells that exists in an activated state in normal healthy vasculature.
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In diabetic vasculature, Tie2 is deactivated, which leads to vascular destabilization and leakage. AKB-9778 acts by inhibiting VE-PTP, which is the most critical negative downregulator of Tie2.
TIME-2 was a double-masked, double-dummy trial that randomized 144 patients with DME and central subfield thickness (CST) ≥325 µm measured by spectral domain OCT to subcutaneous injection of AKB-9778 15 mg BID plus monthly sham IVT injection; AKB-9778 15 mg BID plus IVT ranibizumab 0.3 mg (Lucentis, Genentech); or ranibizumab 0.3 mg monotherapy plus placebo subcutaneous injection. Patients were treated for 3 months and then observed for 2 more months.
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The three study groups were well-balanced in their baseline characteristics; a high proportion of patients enrolled had received prior anti-VEGF treatment.
Change from baseline CST was analyzed as the main outcome measure, and the results showed a highly statistically significant difference favoring the combination treatment group versus ranibizumab monotherapy (-163.8 ± 24.3 µm versus -109.2 ± 17.2 µm, respectively).
In addition, the proportion of patients achieving and maintaining a dry retina (CST ≤300 µm) was also highest in the combination treatment group.
Due to its short duration, TIME-2 was not powered to show a statistically significant difference between study groups for improvement in visual acuity. Nevertheless, the data showed a trend favoring combination treatment, Dr. Khanani said.
An analysis examining changes in diabetic retinopathy severity score (DRSS) showed the percentage of study eyes achieving a 2-step or greater improvement from baseline was equal across the three treatment groups.
Most interestingly, fellow eyes of patients treated with AKB-9788 also showed significant improvement in DRSS that was equal to the study eyes for the group treated with combination therapy.
AKB-9778 was well tolerated and not associated with any clinically significant abnormalities in findings from physical examination or laboratory tests.
Ocular and non-ocular adverse events were similar across the study groups. Two patients in both the AKB-9778 monotherapy and combination groups developed a serious adverse event, but all were deemed by the investigator to be unrelated to treatment, Dr. Khanani said.