PT  - JOURNAL ARTICLE
AU  - Ryo Kubota
AU  - David G Birch
AU  - Jeff K Gregory
AU  - John M Koester
TI  - Randomised study evaluating the pharmacodynamics of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease
AID  - 10.1136/bjophthalmol-2020-317712
DP  - 2020 Nov 19
TA  - British Journal of Ophthalmology
PG  - bjophthalmol-2020-317712
4099  - http://bjo.bmj.com/content/early/2020/11/18/bjophthalmol-2020-317712.short
4100  - http://bjo.bmj.com/content/early/2020/11/18/bjophthalmol-2020-317712.full
AB  - Background/Aims Stargardt disease is a rare, inherited, degenerative disease of the retina that is the most common type of hereditary macular dystrophy. Currently, no approved treatments for the disease exist. The purpose of this study was to characterise the pharmacodynamics of emixustat, an orally available small molecule that targets the retinal pigment epithelium–specific 65 kDa protein (RPE65), in subjects with macular atrophy secondary to Stargardt disease.Methods In this multicentre study conducted at six study sites in the USA, 23 subjects with macular atrophy secondary to Stargardt disease were randomised to one of three doses of daily emixustat (2.5 mg, 5 mg or 10 mg) and treated for 1 month. The primary outcome was the suppression of the rod b-wave recovery rate on electroretinography after photobleaching, which is an indirect measure of RPE65 inhibition.Results Subjects who received 10 mg emixustat showed near-complete suppression of the rod b-wave amplitude recovery rate postphotobleaching (mean=91.86%, median=96.69%), whereas those who received 5 mg showed moderate suppression (mean=52.2%, median=68.0%). No effect was observed for subjects who received 2.5 mg emixustat (mean=−3.31%, median=−12.23%). The adverse event profile was consistent with prior studies in other patient populations and consisted primarily of ocular adverse events likely related to RPE65 inhibition.Conclusion This study demonstrated dose-dependent suppression of rod b-wave amplitude recovery postphotobleaching, confirming emixustat’s biological activity in patients with Stargardt disease. These findings informed dose selection for a 24-month phase 3 trial (SeaSTAR Study) that is now comparing emixustat to placebo in the treatment of Stargardt disease-associated macular atrophy.