Abstract
Purpose :
Complement alternative pathway (AP) dysregulation is implicated in the pathogenesis of age-related macular degeneration (AMD). Therapeutic AP inhibition represents a promising strategy for treatment and to delay progression. Challenges remain in delivery of therapeutic agents to posterior tissues including retina and retinal pigmented epithelium (RPE), where cell death constitutes the primary cause of vision loss. This study investigated ocular tissue exposure of danicopan following oral delivery in rabbits. Danicopan is an investigational first-in-class oral inhibitor of the essential AP protein complement factor D (FD). Danicopan has completed clinical Phase 2 studies and is entering Phase 3 for treatment of the blood disorder paroxysmal nocturnal hemoglobinuria (PNH) in patients who have suboptimal responses to a C5 inhibitor alone.
Methods :
Dutch Belted rabbits received oral danicopan or vehicle at doses up to 50 mg/kg BID for up to 14 days. Blood and ocular tissues, including choroid-RPE, retina, optic nerve, iris-ciliary body (ICB) and vitreous humor, were collected before dosing and at 1, 6, 24, 96, 168 and 240 h after the last dose. Danicopan concentrations in plasma and ocular tissues were determined by liquid chromatography/mass spectrometry (LC-MS/MS). Safety was assessed with toxicological and ophthalmic examinations.
Results :
Danicopan distributed substantially to ocular tissues following oral dosing. Danicopan was detected in retina 240 h after the last dose of 14-day study at 50 mg/kg BID, with t½ of 96.1 h, AUClast of 30300 h*ng/g and MRT of 53.2 h. In comparison, danicopan was not detected in plasma 96 h after the last dose, with 16-fold shorter t½, 3-fold lower AUC and 11-fold shorter MRT. Prolonged exposures were also observed in choroid-RPE and ICB although not in the vitreous humor. Danicopan was detected in optic nerve with a similar PK profile to plasma. Danicopan was well tolerated and resulted in no toxicity or ophthalmic abnormalities based on slit lamp biomicroscopy, indirect ophthalmoscopy, rebound tonometry, and ultrasonic corneal pachymetry.
Conclusions :
The investigational complement AP inhibitor danicopan exhibited favorable distribution to key ocular tissues choroid-RPE and retina following oral dosing in rabbits. The results support a clinical study of oral danicopan for the treatment of AMD.
This is a 2020 ARVO Annual Meeting abstract.