High retinal and low systemic exposure of EXN407 eye drops in humans, a new topical therapeutic for the treatment of diabetic macular edema (DME)

Abstract

Purpose : Serine-Arginine Rich Protein kinase-1 (SRPK1) inhibitors inhibit angiogenic VEGF (VEGF-A₁₆₅a) isoform production in vitro and in vivo, and reduce retinal and choroidal neovascularisation in vivo. This makes them candidates for topical treatment for ocular vascular diseases such as exudative age related macular degeneration and DME. Low systemic availability would be an advantage to avoid potential non-ocular effects. EXN407, a potent SRPK1 inhibitor has been shown in non human primates (NHP) as eye drops to reach effective concentrations in the retina, reduce VEGF-A₁₆₅a isoforms, and be rapidly cleared from plasma. The purpose of this study was to confirm the systemic pharmacokinetic profile of EXN407 in people with DME.

Methods : 48 patients with mild centre-involved DME were recruited to clinical trial NCT04565756. EXN407 was administered to 3 patients/ dose strength at 0.5, 1 or 1.5mg/ml b.i.d. for 3 days. Blood samples were taken at 15 min, 30min, 1hr, 2hr, 3hr and 4hr after an eye drop on day 3. 23 patients self administered 1.5mg/ml EXN407 eye drops bi-daily for 85 days, and blood samples taken at 15 min, 30min, 1hr, 2hr, 3hr and 4hr after an eye drop on day 8. No results were available for one patient. EXN407 was measured by mass spectroscopy. These data were compared with results from NHP study after 21 days b.i.d of dosing up to 1.5mg/ml (Batson et al 2019).

Results : Plasma EXN407 C_max was dose dependent in the 3 patient groups. At 0.5mg/ml, all results were below lower limit of quantification (LLOQ, 50pg/ml). At 1mg/ml, results were below LLOQ for 2/3 particpants, and 57pg/ml in remainder. At 1.5mg/ml, below LLOQ in 1 patient, mean ±SEM 83±25pg/ml for the other two. In the 22 patients treated with 1.5mg/ml EXN407 5 were below LLOQ and the mean C_max was 88±41pg/ml These values are comparable to those in non human primates studies, when appropriately scaled. Moreover, values for the 1.5 mg/ml strength at days 3 and 8 were similar, indicating an absence of systemic accumulation.

Conclusions : EXN407, while having high retinal exposure, exhibits very low systemic exposure, with a maximal plasma concentration well below the levels required for efficacy (C_max free concentration <0.001% in vitro IC₅₀), indicating that the effect of EXN407 on retinopathy and macular thickness is due to local topical, not systemic, action.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.