Reduction of intraocular pressure by SHP639, a novel C-type natriuretic peptide analog, and its exposure in aqueous humor of normotensive Dutch Belted rabbits and beagle dogs

Abstract

Purpose : SHP639 is a topical 9-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of glaucoma and ocular hypertension. This study assessed SHP639’s impact on intraocular pressure (IOP), aqueous humor (AH) exposure, and its PK/PD relationship in rabbits and dogs.

Methods : For IOP measurements, animals received a single topical dose of 0.03%, 0.1%, 0.3%, or 0.6% SHP639 in one eye and vehicle in the other. IOP was measured pre-dose and from 0.5 to 24 hours post-dose for rabbits, and 1 to 48 hours post-dose for dogs. To assess exposure in AH, another set of animals received a single topical dose of 0.03%, 0.1%, 0.3%, or 0.6% in both eyes. AH was collected at the same timepoints at which IOP and exposure were measured. Plasma was collected to evaluate systemic exposure. Mean AH and plasma SHP639 concentrations were measured by liquid chromatography-mass spectrometry, and the PK parameters were estimated with non-compartmental analysis.

Results : Topical administration of SHP639 resulted in a robust dose-dependent decrease in IOP in both rabbits (Figure 1) and dogs. In rabbits, the maximum mean decrease in IOP ranged from −10.9% for the 0.03% dose to −34.4% for the 0.6% dose. In dogs, maximum mean IOP decreases ranged from −16.5% (0.03% dose) to –26.4% (0.3% dose). The duration of the IOP-lowering effect was 12 hours in rabbits and 48 hours in dogs. SHP639 exposure in AH (both AUC and C_max) was also dose-dependent, with C_max ranging from 0.15 to 93.6 ng/mL (0.03% and 0.6% doses) in rabbits, and from 0.49 ng/mL to 13.8 ng/mL (0.03% and 0.3% doses) in dogs. In both species, exposure in AH correlated well with IOP reduction. The PK/PD profile was fitted to an inhibitory sigmoidal model (Figure 2), and the in vivo EC₅₀ was similar in rabbits (2 ng/mL) and dogs (0.4 ng/mL). Exposure in plasma was only detectable at early timepoints.

Conclusions : In rabbits and dogs receiving a single topical ocular administration of SHP639, a dose-dependent IOP-lowering effect was observed, along with an increase in AH exposure. SHP639 is thus a potent topical IOP reducing agent that shows a strong PK/PD relationship with minimal systemic exposure in these two species.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Figure 1. SHP639 dose-dependent decrease in IOP in rabbits.

 

Figure 2. SHP639 PK/PD profile in rabbits and dogs.