Abstract
Purpose :
NCX 470 is a new molecular entity comprised of the prostamide bimatoprost and the nitric oxide (NO)-donating moiety 6-(nitrooxy)-hexanoic acid. NCX 470 is more effective than equimolar bimatoprost in lowering intraocular pressure (IOP) in rabbit, dog, and non-human primate models of ocular hypertension and glaucoma. Here we report the 28-day ocular toxicity study in Beagle dogs performed as part of the IND-enabling program for the First-in-Human phase 2 dose-response clinical study (NCT03657797) of NCX 470 in ocular hypertensive and glaucoma patients.
Methods :
Beagle dogs (3 males and 3 females/group) were treated with NCX 470 (0.0138%, 0.042%, 0.1%, or vehicle) in both eyes twice daily (4h apart) with 30 μL/eye for 28 consecutive days. Mortality, morbidity, body weight, and food consumption were evaluated. Ocular observations were made using a modified Draize scale. Ophthalmoscopy and slit lamp examinations were performed according to a modified Hackett-McDonald scoring scale. Electrocardiograms, blood pressure, IOP, and electroretinograms were recorded. Clinical pathology was assessed. Serial blood samples were collected up to 24h after the first daily dose on day 1 and day 28 for the determination of plasma concentrations of NCX 470 and metabolites by a validated LC/MS-MS method.
Results :
Topical bilateral ocular dosing of NCX 470 up to 0.1% to Beagle dogs twice daily for 28 consecutive days in a GLP compliant study did not result in any systemic or ocular adverse findings. Thus, the no-observed-adverse-effect-level (NOAEL) was established at the highest dose tested (0.1% twice daily). As described for bimatoprost, ocular findings of conjunctival discharge and hyperemia were observed in all groups receiving NCX 470. In addition, NCX 470 induced miosis and IOP reduction. Specifically, on treatment day 27 at 1.0-1.5h after the first daily dose the mean IOP±SEM were: 19.8±0.4, 16.3±0.6, 14.4±0.8, & 14.7±0.4 mmHg for vehicle, NCX 470 0.0138%, 0.042%, & 0.1%, respectively. Systemic exposure of NCX 470 and its main metabolites (bimatoprost and bimatoprost acid) was minimal, and there was no accumulation with repeated ocular administration of NCX 470 up to 0.1% twice daily.
Conclusions :
The results of this GLP 28-day ocular toxicity study in Beagle dogs show adequate safety and efficacy to support advancing NCX 470 into phase 2 clinical development.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.