Negative dry AMD results

  Emixustat hydrochloride, a small molecule that showed promise for treating dry age-related macular degeneration (AMD) in an early phase 2 study, failed to reach its primary endpoint of slowing progression of geographic atrophy (GA) associated with AMD in a 24-month phase 2b/3 clinical trial, Frank G Holz MD, University of Bonn, Germany, told the 16th EURETINA Congress in Copenhagen, Denmark. GA lesion growth rates in the three treatment arms of 2.5mg, 5.0mg and 10mg oral emixustat daily did not differ significantly from placebo at any point in the 24-month follow-up period, Dr Holz reported on behalf of the USA-based SEATTLE study group. Changes in best corrected visual acuity were small and similar across the four groups throughout the prospective, randomised, placebo-controlled study involving 508 patients. While no systemic or non-ocular safety issues were identified, more ocular adverse events were observed in the treatment groups. Most common was delayed dark adaptation, observed in 36% to 77% of patients in the treatment groups compared with 10% in the placebo group. Chromatopsia was observed in 22% to 50% in the treatment groups compared with 9% in the placebo group. These were likely related to emixustat’s mechanism of action which inhibits retinal pigment epithelium protein 65 (RPE65), a key rate-limiting enzyme in the visual cycle, Dr Holz said. Unlike most drugs for AMD and other eye diseases, emixustat hydrochloride is taken orally rather than topically or intravitreally, Dr Holz noted. It inhibits RPE65, effectively slowing it down. Early human studies showed emixustat had a measurable pharmacodynamic effect on the retina, Dr Holz said. Among the findings of a phase 2a study were a dose-dependent reduction in rod b-wave amplitude, which inversely relates to visual cycle time. “It showed the oral dose had the desired effect,” he said. The study randomised 508 patients with clinical diagnoses of GA with AMD in one or both eyes, with visual acuity of 35 or more ETDRS letters, or about 20/200 or better. Total GA area ranged from 1.25mm2 to 18mm2, or about 0.5 to 7 disc diameters in the study eye. In eyes with multifocal lesions, one had to be 1.25mm2 and the aggregate no more than 18mm2. Patients with active (or a history of) exudative AMD in the study eye were excluded.

Unlike most drugs for AMD and other eye diseases, emixustat hydrochloride is taken orally rather than topically or intravitreally

The primary efficacy endpoint was the mean rate of change from baseline in total GA area in the study eye as imaged by fundus autofluorescence. Patients were examined at baseline, months 1, 2, 3, 6, 9, 12, 15, 18, and 24, with the study exit visit 30 days after the last dose. No statistically significant differences among the three treatment or placebo groups were observed at 6, 12, 18 or 24 months. Rates of loss of visual acuity were also similar for the four groups, with mean losses by group ranging from about five to eight ETDRS letters at the exit visit. “The data from this study are very important to further elucidate the natural history of GA,” Dr Holz said. Frank G Holz: frank.holz@ukbonn.de

Tags: AMD, Emixustat hydrochloride, geographic atrophy