Phase 1 safety study of intravitreal (ITV) Anti-High Temperature Requirement A1 (aHtrA1), a novel serine protease inhibitor, in patients with Geographic Atrophy (GA)

Abstract

Purpose : The secreted protease HtrA1 is active in the retina and can potentially degrade extracellular matrix proteins and proteins involved in the visual cycle. Inhibiting HtrA1 is hypothesized to slow progression of GA lesion growth. The Phase 1 study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ITV aHtrA1 following single and multiple doses in patients with GA secondary to age-related macular degeneration.

Methods : In the single ascending dose stage (SAD), a single ITV injection of aHtrA1 was given in 5 dose-escalation cohorts ranging 1–20 mg, with patients followed for 12 weeks (wks; n=15). The second stage evaluated the maximum tested dose, 20 mg, administered every 4 wks (q4w) for 3 doses, with patients followed to wk 20 (n=13). Primary outcome measures were safety and tolerability. Exploratory outcome measures included aqueous and serum PK and assessment of the PD effect of aHtrA1 in aqueous humor as measured by inhibition of Dickkopf-related protein 3 (DKK3) cleavage, an HtrA1 substrate.

Results : ITV aHtrA1 was well tolerated at single doses up to 20 mg ITV and multiple doses of 20 mg q4w in patients with GA. No dose-limiting toxicities were observed. No ocular serious adverse events (AEs) or systemic or ocular AEs were reported related to ITV aHtrA1. Based on serum and aqueous humor PK data, the half-life for vitreal elimination of aHtrA1 was 4.8 days, estimated by a population PK model. Dose-dependent inhibition of DKK3 cleavage by aHtrA1 was observed in the SAD cohorts. Higher aHtrA1 doses yielded longer duration of HtrA1 inhibition; DKK3 cleavage inhibition was sustained for ≥8 wks after a single 20 mg ITV dose. In the multiple dose stage, DKK3 cleavage remained inhibited throughout the treatment period. Following the last dose of aHtrA1 at wk 8, inhibition was maintained through Day 112 (8 wks after the last dose), with an upward trend towards baseline levels by Day 133 (11 wks after the last dose).

Conclusions : ITV aHtrA1 was well tolerated with an acceptable safety profile at the maximum tested dose, 20 mg q4w Χ 3 doses. Furthermore, a sustained PD effect suggesting potential for ≥8 wks of target inhibition with the 20mg dose was observed in the aqueous humor as measured by inhibition of DKK3 cleavage. A Phase 2 study evaluating ITV aHtrA1 efficacy is currently in progress.

This is a 2020 ARVO Annual Meeting abstract.