Aerpio Pharmaceuticals acknowledged the failure of its lead pipeline candidate in a Phase IIb trial in patients with moderate to severe non-proliferative diabetic retinopathy (NPDR), triggering a selloff by investors that sent the company’s shares plunging by more than 70% in early market trading.

AKB-9778 failed the Phase IIb TIME-2b trial (NCT03197870) by missing its primary endpoint, the percentage of patients with an improvement of two or more steps in the diabetic retinopathy severity score (DRSS) in the study eye compared to placebo following 48 weeks of treatment.

That percentage was 9.6% for patients who were dosed with AKB-9778 twice daily, compared with 3.8% for patients dosed with placebo. When all “qualified” eyes were assessed—both study eyes and fellow eyes that met the inclusion/exclusion criteria—the percentages were 8.6% for AKB-9778 twice daily patients, and 2.7% for placebo patients.

The double-masked, placebo-controlled, multi-center trial enrolled 167 patients who were randomized to receive 48 weeks of treatment with either AKB-9778 15 mg subcutaneously once daily (and placebo subcutaneously once daily), AKB-9778 15 mg subcutaneously twice daily, or placebo subcutaneously twice daily.

During the 48-week treatment period, Aerpio said, the rates of progression to sight-threatening complications, including diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR) were similar between treatment groups.

Aerpio highlighted positive results in several of the TMIE-2b trial’s secondary endpoints that it said were consistent with outcomes in its Phase IIa TIME-2 trial of AKB-9778 in diabetic macular edema (NCT02050828). These included changes in the urine albumin to creatinine ratio (UACR), a measure of kidney function, and in intraocular pressure (IOP). UACR was prospectively included in TIME-2a based on a post-hoc analysis of the biomarker in TIME-2.

Drop formulation planned

As a result of the secondary outcome results, Aerpio said, it plans to advance a topical drop formulation of AKB-9778 into clinical development and expects to launch a Phase Ib study in the second quarter of this year, with results anticipated by year’s end.

“While we are disappointed in the primary endpoint results of this study, we are nevertheless encouraged by the fact that several other promising findings observed in our prior three-month Phase IIa trial have been prospectively confirmed in this one-year trial,” Aerpio CEO Stephen Hoffman, MD, PhD, said in a statement.

However, investors responded to the clinical setback of AKB-9778 by sending Aerpio’s shares down about 72% from Friday’s closing price of $4.25, to $1.20 in early trading at 9:48 a.m.

AKB-9778 is a small molecule inhibitor of vascular endothelial protein tyrosine phosphatase (VE-PTP), an important negative regulator of the Tie2 pathway, a key regulator of vascular stability, in diseased blood vessels. AKB-9778 is designed to bind to and inhibit the intracellular catalytic domain of VE-PTP that inactivates Tie2, as decreased Tie2 activity contributes to vascular instability in many diseases, including diabetes.

According to Aerpio, AKB-9778 activates the Tie2 receptor irrespective of extracellular levels of its binding ligands, angiopoietin-1 (agonist) or angiopoietin-2 (antagonist) and may be the most efficient pharmacologic approach to maintain normal Tie2 activation. AKB-9778 is being developed as a subcutaneous injection for the treatment of non-proliferative diabetic retinopathy and as an eyedrop formulation for the treatment of glaucoma.

The most common adverse events with higher incidence in the AKB-9778 BID group were dizziness of 10.9% versus 7.0% in the placebo arm, and headache of 10.9% compared to placebo of 3.5%. There was one patent death in the study’s placebo group.

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