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CLINICAL TRIAL DOWNLOAD: Subcutaneous Administration Targeting the Tie2 Pathway

A study of AKB-9778 failed to meet its primary endpoint.

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In March, Aerpio Pharmaceuticals announced top-line data from its phase 2b TIME-2b study, designed to assess the efficacy and safety of its lead candidate, AKB-9778, for patients with moderate to severe nonproliferative diabetic retinopathy (NPDR). AKB-9778 is a small-molecule vascular endothelial protein tyrosine phosphatase (VE-PTP) inhibitor targeting the Tie2 pathway. Results from the study showed that AKB-9778 administered subcutaneously twice daily did not meet the study’s primary endpoint of an improvement of 2 or more steps in diabetic retinopathy severity score (DRSS) compared to placebo. The percentage of patients achieving the primary endpoint was 9.6% in the study group and 3.8% in the placebo group (P=.270). Here we ask several retina specialists to weigh in on the results.

J. Fernando Arevalo, MD PhD, Edmund F. and Virginia B. Ball Professor of Ophthalmology; chairman, Department of Ophthalmology, Johns Hopkins Bayview Medical Center; Retina Division, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland

The data from TIME-2b confirm that complications of diabetic retinopathy are multifactorial. Although the Tie2 pathway may play an important role for the treatment of diabetic complications, it is not the only pathway, and combination treatments targeting different pathways are needed. Tie2 activation may be important, but alone, it may be insufficient to treat diabetic complications. Even though secondary endpoints were encouraging, I don’t give those the same weight as the primary endpoint, which was not met. Finally, my sense is that even though subcutaneous administration has the appeal that could treat both eyes with one administration, it may not be as effective as intravitreal injections.

Elias Reichel, MD, professor, vice chair, and director of the vitreoretinal service, New England Eye Center, Boston, Massachusetts

While subcutaneous administration of AKB-9778 did not show a statistically significant benefit in showing a 2-step improvement in DRSS among study subjects with moderate to severe nonproliferative diabetic retinopathy, there was a trend favoring this intervention. The real “flash in the pan” in this phase 2 trial was that 2 prespecified secondary endpoints, urine albumin-creatinine ratio and intraocular pressure, demonstrated encouraging benefits from this systemic therapy. Activation of the Tie2 pathway may play an important role in the kidney complications of diabetes and, surprisingly, may be an exciting target for open-angle glaucoma.

Nathan C. Steinle, MD, partner, California Retina Consultants

AKB-9778 is being investigated as a subcutaneous injection for the treatment of nonproliferative diabetic retinopathy and as an eye drop for the treatment of glaucoma. AKB-9778 binds to and inhibits VE-PTP, a regulator of Tie2.

I had several patients in the latest Aerpio trial for diabetic retinopathy, and the interest in the trial mainly stemmed from the ability to offer an alternative treatment to intravitreal injections. The novel delivery method (subcutaneous injections daily or BID vs placebo for 48 weeks) was well tolerated and represented a potential alternative for patients that were averse to serial intravitreal injections. Unfortunately, the study did not show statistically significant regression in diabetic retinopathy vs placebo, but it did show potential benefits regarding systemic renal function.

Given the strength of the recent PANORAMA trial results and past results from the RISE and RIDE studies and Protocol S, it appears the bar has been set extremely high by anti-VEGF intravitreal injections in the treatment of diabetic retinopathy. The search for intravitreal injection alternatives will undoubtedly continue. RP