Purpose : The cGMP analogue CN03 targets cGMP signalling, a disease driver common to different types of retinal degeneration. For efficient targeting to the neuroretina CN03 was combined with a liposomal (LP) drug delivery system. In rodents, LP-CN03 has shown significant photoreceptor protection and preservation of in vivo retinal function, without major adverse events. The objective of the study was to determine the toxicity of CN03 and LP-CN03, following intravitreal (IVT) or intravenous (IV) administration. IVT administration is the intended human therapeutic route, IV injection was tested to investigate systemic toxicity.

Methods : Cynomolgus monkeys were assigned to five different groups, consisting of one male and one female (n=2). Group 1 served as saline control for IVT and IV dosing, group 2 served as liposome (LP) control. Groups 3 and 4 received IVT injections of either 1X or 10X of the intended therapeutic dose, of either LP-CN03 (left eye) or CN03 (right). Group 5 received 100X IV bolus injections of LP-CN03 (Day 1) and CN03 (Day 25). Toxicity was assessed based on clinical observations, body weights, ophthalmology, intraocular pressure (IOP), electroretinography (ERG), and clinical and anatomic pathology.

Results : IVT administration of LP caused transient white opacity in the vitreous body of all treated eyes, related to the milky consistency of LP. IVT injection of 1X and 10X CN03 was well-tolerated and only showed temporary pupil dilation in one male. IVT injection of 1X and 10X LP-CN03 was additionally associated with particles in the anterior chamber and vitreous body. At 10X, pigmented dots were also noted in the anterior lens capsule. IV injection of 100X LP-CN03 and CN03 was well tolerated and did not cause systemic toxicity. Comparison of pre- and post-dosing ERG did not reveal significant differences (p>0.05) in any of the groups, nor were there any indications of pathological changes in retinal morphology.

Conclusions : IVT injection of CN03 and LP-CN03 at the intended therapeutic dose was not associated with any changes in ophthalmoscopy, electroretinography or histopathology, and only revealed slight pupil dilation in one animal. IV slow bolus injection at 100X the intended therapeutic dose was well tolerated.