Role of Tie2 in maintenance of conventional outflow
Recently, two independent research laboratories have shown that Tie2 is expressed and activated in Schlemm’s canal endothelial cells during development and in the mature vessel. Disruption of the Tie2 pathway in mice by conditional knockout early in postnatal development results in failure of the formation of Schlemm’s canal, associated with increased intraocular pressure (IOP) and with retinal and optic nerve pathology resembling human congenital glaucoma. Tie2 pathway disruption later in postnatal development results in degeneration of Schlemm’s canal with development of increased IOP and retinal and optic pathology reminiscent of primary open angle glaucoma (POAG). Tie2 is most highly expressed in mature Schlemm’s canal inner wall endothelium and disruption of the Tie2 pathway results in increased cell death, or apoptosis, and reduced formation of giant vacuoles consistent with compromised conventional outflow. Activation of Tie2, with razuprotafib (AKB-9778), affects pathways commonly associated with reduction of intraocular pressure. Rhopressa and Vyzulta are recently approved glaucoma drugs which block the Rho pathway and stimulate the eNOS pathway, respectively. Inhibition of VE-PTP should provide both benefits, blocking Rho and stimulating eNOS potentially producing greater IOP reductions with a disease modifying effect on the conventional outflow and Schlemm’s canal.
Development of razuprotafib (AKB-9778) topical drops for treatment of primary open angle glaucoma (POAG)
In both of Aerpio’s completed Phase 2 studies (TIME-2 and TIME-2b) with systemically dosed razuprotafib (AKB-9778), the treatment cohorts exhibited a statistically significant reduction in intraocular pressure (IOP) versus patients receiving placebo. These IOP reductions were detected in individuals with normal ocular pressure in a study not designed to measure IOP changes.
Aerpio has developed a topical ocular formulation of razuprotafib (AKB-9778) and completed a multiple ascending dose (MAD) Phase 1b study in subjects with normal ocular pressures. The primary endpoint in the study is safety and tolerability with an important secondary endpoint measuring the decrease in IOP. Aerpio reported the topline results of this trial in January 2020 and presented the data at Glaucoma 360 conference in February 2020. The data is summarized below.
The Phase 1b trial is a randomized, double-masked study designed to assess increasing concentrations of razuprotafib (AKB-9778) dosed topically as eye drops. The primary outcome of the study is ocular safety and tolerability with change in intraocular pressure (IOP) at Day 7 as a pharmacodynamic outcome. Conjunctival hyperemia and IOP were assessed at 0 (pre-dose), 2, 4, and 8 hours post-dose on Day -1 (baseline), Day 1 (first day of razuprotafib (AKB-9778) dosing) and Day 7 (last day of razuprotafib (AKB-9778) dosing). Results from the first 3 cohorts, each comprising 12 subjects with normotensive eyes (non-glaucoma subjects), were reported on October 10, 2019. Subsequently, results from cohort 4, also comprising 12 subjects with normotensive eyes, were observed to be consistent with those from cohorts 1 through 3.
Based on favorable tolerability and pharmacodynamic findings in these ocular normotensive subjects, Aerpio elected to recruit a fifth cohort of subjects with OHT/POAG on standard of care prostaglandin therapy to assess the safety, tolerability and pilot activity of once-daily razuprotafib (AKB-9778) (40 mg/ml) as an adjunctive therapy. In the fifth cohort 43 patients were recruited with OHT/POAG and baseline IOP measurements between 17 and 27 mmHg while treated with once-daily prostaglandin therapy. Patients were randomized 3:1 to receive either razuprotafib (AKB-9778) (32 subjects) or placebo (11 subjects), administered in the morning for 7 days, while continuing their evening prostaglandin therapy. Conjunctival hyperemia and IOP were assessed in the same manner as described for cohorts 1-4 (see above).
Results from cohort 5 are as follows:
- Subjects in cohort 5 randomized to the active arm exhibited statistically significant decreases in IOP at all post-razuprotafib (AKB-9778) administration time points on both Days 1 and 7 compared with Day -1 baseline values when they were being treated with prostaglandin alone (see Figure 1; Diurnal = mean IOP of 2, 4 and 8 hour time points; ** p < 0.05, *** p < 0.001).
- When the change is placebo-corrected, razuprotafib (AKB-9778) plus prostaglandin versus prostaglandin alone produced a statistically significant decrease in IOP on Day 7 at 0, 4 and 8 hours post dose as compared to placebo (placebo-adjusted data at 0 hrs. -2.26 mmHg, p = 0.007; 2 hrs. -1.24, p = 0.138; 4 hrs. -1.47 mmHg; p = 0.048; 8 hrs. -1.80 mmHg; p = 0.041). We believe these results suggest a persistent IOP-lowering activity from adding razuprotafib (AKB-9778) to standard-of-care prostaglandin therapy.
Topical ocular administration of razuprotafib (AKB-9778) was well tolerated over seven days in cohort 5. In the active arm treated with razuprotafib (AKB-9778) plus prostaglandin, 18.8% of subjects experienced hyperemia compared with 9.1% of subjects in the prostaglandin-alone arm. In all cases, this hyperemia was minimal-to-mild in severity, transient in duration and generally considered non-adverse. There were no reports of conjunctival hemorrhage or pain on instillation during the seven days of dosing.