Randomised study evaluating the pharmacodynamics of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease.

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.

Effects of emixustat hydrochloride in patients with proliferative diabetic retinopathy: a randomized, placebo-controlled phase 2 study.

PURPOSE: To evaluate the effects of oral emixustat hydrochloride on pro-angiogenic and inflammatory cytokines in the aqueous humor, as well as other ophthalmic parameters, in subjects with proliferative diabetic retinopathy (PDR). METHODS: Twenty-three patients with PDR, with or without diabetic macular edema (DME), were assigned to emixustat or placebo in daily oral doses ranging from 5 to 40 mg over a step-up titration period, for 84 days. The main outcome measures included levels of IL-1ß, IL-6, IL-8, TGFß-1, and VEGF in the aqueous humor. RESULTS: Seven of 12 subjects (58%) who were randomized to emixustat and 11 of 12 subjects (92%) who were randomized to placebo completed the study. No statistically significant differences between treatment groups were observed for changes in any of the aqueous humor cytokines tested. However, median VEGF levels were slightly reduced in the emixustat but not the placebo group (- 70.0 pg/mL versus + 42.7 pg/mL, or - 11.8% versus + 6.7%). In a post hoc analysis of all subjects (with or without DME), statistically significant differences between treatment arms in mean changes from baseline in central subfield thickness (CST; emixustat - 11.9 µm, placebo + 36.2 µm; P = 0.076) and total macular volume (TMV; emixustat - 0.13 mm3, placebo + 0.23 mm3; P = 0.026) were observed, both favoring emixustat. Emixustat's safety profile was consistent with prior studies (i.e., the adverse events of delayed dark adaptation and visual impairment were more common in subjects treated with emixustat). CONCLUSION: Although this pilot study did not demonstrate statistically significant differences in changes in aqueous humor cytokine levels between the emixustat and placebo groups, VEGF levels were slightly reduced in the emixustat but not in the placebo group. In addition, statistically significant differences favoring the emixustat group were observed in CST and TMV among all subjects. These data warrant further investigation of emixustat's potential therapeutic effects in diabetic retinopathy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02753400 (April 2016).

Emixustat Hydrochloride for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Clinical Trial.

PURPOSE: To determine whether emixustat hydrochloride (emixustat) reduces the rate of enlargement of geographic atrophy (GA) compared with placebo in subjects with age-related macular degeneration (AMD) and to evaluate the safety and tolerability of emixustat over 24 months of treatment. DESIGN: Multicenter, randomized, double-masked, placebo-controlled, phase 2b/3 clinical trial. PARTICIPANTS: Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm2 were enrolled. METHODS: Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, and 25. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence (FAF) images. The change from baseline in normal luminance best-corrected visual acuity (NL-BCVA) was a secondary efficacy end point. RESULTS: Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm2/year; placebo: 1.69 mm2/year; P ≥ 0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low luminance deficit (LLD) at baseline (≥20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55%), chromatopsia (18%), visual impairment (15%), and erythropsia (15%). CONCLUSIONS: Emixustat did not reduce the growth rate of GA in AMD. The most common adverse events were ocular in nature and likely related to the drug's mechanism of action. Data gained from this study over a 2-year period add to the understanding of the natural history of GA and the baseline characteristics affecting the growth rate of GA.

Effect of adjunctive diclofenac with verteporfin therapy to treat choroidal neovascularization due to age-related macular degeneration: phase II study.

BACKGROUND: To determine short-term effects of topical diclofenac administered in conjunction with verteporfin therapy for predominantly classic subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). METHODS: Randomized, multicenter (14), prospective, placebo-controlled, double-masked clinical trial. Patients (n=61) were randomly assigned to treatment with diclofenac sodium ophthalmic solution 0.1% or placebo and followed for 12 weeks. Patients instilled diclofenac or placebo two drops four times daily, 2-4 days before verteporfin treatment until 2 weeks after treatment, then two drops twice daily for 10 weeks. This exploratory study was not powered to detect differences between treatment groups. Statistical analyses were conducted solely to aid interpretation of results. RESULTS: In diclofenac-treated eyes, mean changes in visual acuity letter score from baseline in the diclofenac and placebo groups were +1.8 letters and -1.0 at week 1 (P=0.505 between groups). Mean visual acuity letter scores decreased in both groups at all subsequent visits, with a mean change at 12 weeks of -7.4 with diclofenac and -2.6 with placebo (P=0.213). Percentages of eyes with stable or improved vision (change or=5 letters) were similar in the diclofenac and placebo groups at all study visits. No significant between-group differences in changes from baseline in lesion area, greatest linear dimension (GLD), fluorescein leakage, or retinal thickness were detected. CONCLUSION: In patients with predominantly classic subfoveal CNV due to AMD, administration of topical diclofenac with verteporfin therapy was associated with similar vision outcomes to placebo plus verteporfin therapy.

Occult with no classic subfoveal choroidal neovascular lesions in age-related macular degeneration: clinically relevant natural history information in larger lesions with good vision from the Verteporfin in Photodynamic Therapy (VIP) Trial: VIP Report No. 4.

OBJECTIVE: To determine whether data from patients with age-related macular degeneration (AMD) assigned to the placebo group in the Verteporfin in Photodynamic Therapy (VIP) Trial provide a rationale for continuation or cessation of follow-up of individuals with subfoveal occult choroidal neovascularization (CNV) with no classic lesions, presumed recent disease progression, larger lesion size (>4 disc areas), and a higher level of visual acuity (approximate Snellen equivalent, > or =20/50 in the affected eye) in whom no treatment is given at initial examination. METHODS: In a prospective, noncomparative case series, angiograms of participants assigned to a placebo group who had occult with no classic lesion composition at baseline were reviewed to identify conversion to minimally classic (area of classic CNV >0% but <50% of the entire lesion area) or predominantly classic (area of classic CNV > or =50% of the entire lesion area) composition. RESULTS: Of the 114 patients with AMD assigned to the placebo group, 89 were judged to have occult with no classic lesion composition at baseline in the study eye when fluorescein angiograms were reviewed in late 2001 for this report. By 24 months, 7 (8%) of the 89 patients had lesions that converted to predominantly classic composition, and 41 (46%) had minimally classic composition. Among the 24 patients with a baseline visual acuity better than 20/50(-1) and lesion size greater than 4 disc areas whose lesions did not convert to predominantly classic composition, the visual acuity of 18 (75%) dropped below 20/50. Six of these 18 continued to have occult with no classic CNV with a visual acuity of 20/100 or better and had a lesion size no greater than 9 disc areas at the time that visual acuity dropped below 20/50. CONCLUSIONS: Continued monitoring, rather than cessation of follow-up, is recommended for patients with occult with no classic lesions, similar to those patients enrolled in the VIP Trial who did not initially receive treatment when they had relatively large lesions with good visual acuity. In these cases, if visual acuity decreases or predominantly classic features develop, photodynamic therapy with verteporfin or pegaptanib sodium injections may be considered.

Natural history of minimally classic subfoveal choroidal neovascular lesions in the treatment of age-related macular degeneration with photodynamic therapy (TAP) investigation: outcomes potentially relevant to management--TAP report No. 6.

OBJECTIVE: To determine if there is a rationale for monitoring patients with age-related macular degeneration who have a minimally classic subfoveal choroidal neovascular lesion and do not receive treatment at initial examination. METHODS: Participants assigned to placebo who had a minimally classic lesion composition at baseline were identified from the TAP Investigation. Fluorescein angiograms at baseline and follow-up examinations from these participants were reviewed by photograph reading center graders to determine if any follow-up angiograms had converted from a minimally classic lesion composition to a predominantly classic lesion composition. MAIN OUTCOME MEASURES: Proportion of minimally classic lesions at baseline that converted to a predominantly classic lesion composition, time of this conversion, and visual acuity and lesion size at the time of conversion. RESULTS: Of the 207 patients assigned to placebo in the TAP Investigation, 98 were judged to have a minimally classic lesion at baseline in the study eye when the fluorescein angiograms were reviewed in 2001. Of these 98 patients, 39 (40%) had lesions that converted to a predominantly classic lesion composition, including 21 by the month 3 examination. At the time of conversion, 32 (82%) lesions were no greater than 9 disc areas, including 20 (51%) with visual acuity of 20/200 or better. CONCLUSIONS: These data would suggest that patients with minimally classic lesions, in whom no therapy is recommended initially, should be monitored so that potential conversion to a predominantly classic lesion can be identified promptly and verteporfin therapy considered.