Aerpio Pharmaceuticals Inc. has "a very different way" of activating Tie2, CEO Joseph Gardner told BioWorld Today. "What I don't know is whether an anti-angiopoietin-2 [Ang2] antibody activates Tie2, and how much activation you would get," he said. "We feel very confident with our approach. Our program is on solid ground scientifically, in terms of the data we have generated and published."

His reference is to the push by Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. and Bayer AG, of Leverkusen, Germany, which last year broadened their work in eye disease with a $130 million agreement to test the former's vascular endothelial growth factor (VEGF) trap Eylea (aflibercept) in combination with the Ang2 antibody nesvacumab in diabetic macular edema (DME). (See BioWorld Today, March 25, 2016.)

Tie2 signaling is responsible for stabilizing blood vessels and maintaining vascular integrity. In diabetic vasculature, especially in back of the eye, Tie2 is down-regulated. There's an activating ligand, Ang1, and inactivating ligand, Ang2. Regeneron and Bayer believe that, by mopping up the antagonist Ang2, they can activate Tie2. The phase II trial with Eylea and nesvacumab (also known as REGN910) started in March of last year, will enroll 304 patients and is expected to finish in October of this year.

Cincinnati-based Aerpio's approach with AKB-9778, on the other hand, targets vascular endothelial protein tyrosine phosphatase (VEPTP), which acts as a negative regulator, or brake, at the Tie2 receptor. Having just raised $40 million by way of a private placement that sold about 8 million shares for $5 each, Aerpio completed a reverse merger with Aerpio Therapeutics Inc. and Aerpio Acquisition Corp., a wholly owned subsidiary of the company. Next, in the second quarter, the company plans to start a 150-patient, double-masked, placebo-controlled, phase IIb trial with once-daily and twice-daily subcutaneous dosing of AKB-9778 to evaluate the safety and efficacy of the treatment in subjects with moderate to severe diabetic retinopathy without DME.

Last June, results from a phase IIa study in DME with AKB-9778 were published in Ophthalmology. "We were primarily looking for changes in anatomy and changes in retinal thickness in the eye that had the DME," Gardner said. "We were able to see a statistically significant benefit of the combination therapy over Lucentis [ranibizumab, Roche Holding AG] alone. That's very exciting because it's a first. Nobody's ever been able to demonstrate that in a DME patient you can make an anti-VEGF drug work better."

AKB-9778's route of administration is also distinct. "The patient surveys give you the obvious result, which is that patients really don't like getting shots in the eye," he said. Phase IIa results showed that the combo of AKB-9778 (dosed at 15 mg twice per day subcutaneously) and injected Lucentis dosed at 0.3 mg intravitreally provided a clinically significant benefit in reduction of macular edema, as measured by central subfield thickness (CST), compared to Lucentis alone at month two (p=0.02) and at end of treatment at month three (p=0.008). In association with the improvement in CST, the dual therapy showed a trend toward improved visual acuity (proportion of patients achieving improvement of at least three lines in visual acuity) when compared to Lucentis alone.

"Non-proliferative diabetic retinopathy patients are currently not even treated with Lucentis," Gardner noted. "We wanted to get in front of the anti-VEGF drugs in the therapy paradigm. This would truly be a change in how diabetic retinopathy patients get treated. And we treat both eyes, so in effect we would lower cost of care in these patients as well. If we can prevent or delay progression to DME, we would reduce the number of those shots that would be required." Aerpio was launched in December 2011 in a spinout transaction from Akebia Therapeutics Inc., a Cincinnati biotech also co-founded by Gardner. (See BioWorld Today, Oct. 5, 2012.)

Current investors of Aerpio participated in the latest offering, including Novartis Venture Fund, Orbimed, Satter Investment Management, Kearny Venture Partners, Venture Investors LLC and Triathlon Medical Ventures. New institutional investors Montrose Capital Partners and Ally-Bridge also came aboard. Raymond James & Associates Inc., National Securities Corp. and Katalyst Securities LLC acted as placement agents in the fundraising.

"The primary focus for the raise and the primary use of funds will be to run a phase IIb study in non-proliferative diabetic retinopathy patients with a dosing duration of one year," Gardner said. "The trial is fully financed all the way through." Partnering strategy for AKB-9778 is "to be determined, but the likely plan would be to seek geographic partners in Europe and Asia. In retina [research] right now, there aren't a lot of well-validated mechanisms like ours out there, and we're the only group that's focused on activating Tie2 via this mechanism that's in the clinic. One would expect that we will get a lot of attention over the next couple of years." As of several years ago, Aerpio owns all of the related intellectual property.

Another candidate in the same space is known as COMP-Ang1, a gene therapy approach based on the adeno-associated virus system for delivery of a modified form of Ang1 to the retina. Researchers at the Dublin City University School of Biotechnology and Queen's University Belfast Center for Experimental Medicine are pursuing the work, with help from laboratories at the University of Utah. It's part of an effort jointly funded by the NIH and research and development institutions in Ireland.