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How emixustat hydrochloride may help geographic atrophy


Treatment with emixustat hydrochloride may be useful for treating geographic atrophy by modulating visual cycle activity, reducing oxidative stress, and slowing accumulation of vitamin A-based toxins.


Seattle—Emixustat hydrochloride (ACU-4429, Acucela/Otsuka Pharmaceutical) may be a breakthrough in research into geographic atrophy in dry age-related macular degeneration (AMD).

This drug modulates visual cycle activity, reduces oxidative stress, and slows accumulation of vitamin A-based toxins. The drug appears safe and well tolerated with few serious adverse events, noted Pravin U. Dugel, MD, at the annual meeting of the Association for Research in Vision and Ophthalmology.

Dr. Dugel

The non-retinoid small molecule is administered orally and inhibits activity of RPE65 to reduce the rate of vitamin A processing in the visual cycle. The specific activities include reducing vitamin A toxins, reducing the metabolic rate of the photoreceptors, and protecting the retina from light damage.

By inhibiting RPE65 activity, the visual cycle is slowed and production of A2E is reduced.

“Reduction of A2E would then theoretically slow progression of retinal pigment epithelial membrane damage, free radical production, increase inflammation, and the resulting contribution to the progression of dry AMD and geographic atrophy,” said Dr. Dugel, managing partner, Retinal Consultants of Arizona, Phoenix, and clinical associate professor of ophthalmology, Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles.

ENVISION Clarity Trial

A phase II multicenter, randomized, placebo-controlled, double-masked, multidose study (ENVISION Clarity Trial) evaluated emixustat hydrochloride (2, 5, 7, or 10 mg once daily in the morning, or 5 mg once daily at bedtime) versus placebo once daily (3:1 ratio) to assess the safety, tolerability, and pharmacodynamic effects (measured by dark-adapted electroretinography [ERG]) over 3 months.

Inclusion criteria included the presence of geographic atrophy, steady fixation and clear media to allow fundus visualization, and a best-corrected visual acuity of 20/400 or better in the study eye.

Seventy-two subjects were randomly assigned to one oral daily dose of emixustat hydrochloride or placebo for up to 90 days. Adverse events and other safety parameters were collected. ERGs were recorded 30 minutes after dark adaptation. The eyes were photo-bleached and ERGs were recorded immediately and at 10, 20, and 30 minutes. Rod b-wave amplitudes were expressed as a percentage of the pre-bleach, dark-adapted rod amplitude from baseline. The rate of rod recovery (slope) for each emixustat hydrochloride group was compared with the placebo group.

Common ocular adverse effects

In patients treated with emixustat hydrochloride, rod b-wave amplitude suppression (a measurement of rod activity) was dose-dependent, Dr. Dugel noted. In addition, the effects seemed to plateau by day 14. The pharmacologic effect was reversible when the drug was stopped and returned to the baseline level after 1 to 2 weeks off the study drug in all dosage groups.

Chromatopsia and delayed dark adaptation were the most common ocular adverse effects. Visual impairment also occurred in some patients.

  • “Moderate chromatopsia occurred in all treatment groups,” Dr. Dugel said. “It started as early as day 2 and as late as day 52. The effects were intermittent or continuous and varied from 3 hours to 51 days. Two patients in the 5-mg group terminated treatment early because of serious chromatopsia. Fifty percent of patients had mild or moderate chromatopsia that resolved before the end of the study. In the 5-mg group, 10 of the 19 chromatopsia events were 7 days or shorter in duration.”

  • Moderate delayed dark adaptation (intermittent or continuous) began as early as day 3. One patient receiving the 5-mg dose ended treatment early because of serious chromatopsia. Overall, mild and moderate delayed dark adaptation resolved in 25% of patients by the end of the 90-day study. Delayed dark adaptation was expected, Dr. Dugel noted, because of the drug’s mechanism of action. Emixustat hydrochloride slows rod cell function, and because rods are responsible for sight in low-light conditions, delayed dark adaptation may result, he explained.

  • Moderate visual impairment (intermittent or continuous) occurred in the 2-, 7-, and 10-mg treatment groups. They initiated as early as day 2 and as late as day 48. The episodes varied in duration from 3 minutes to 37 days. Overall, 95% of cases of mild and moderate visual impairment that resolved before the end of the study.

“This dose-escalation study of 72 patients with geographic atrophy showed no significant systemic adverse events and the drug was generally safe and well-tolerated,” Dr. Dugel summarized. “Most drug-related adverse events were ocular with mild to moderate severity and started within 2 weeks of dosing and resolved during the 90-day study.  There was potential for a reduced incidence of chromatopsia with evening dosing.”

A long-term phase IIb/III study is under way to evaluate emixustat hydrochloride in subjects with geographic atrophy.


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