TOPLINE

A new clinical trial found that a deuterium-modified form of vitamin A — which replaces most of the body's natural vitamin A and stops it from clumping — slowed the growth of retina-damaging lesions by more than 20%, with no serious safety concerns over 2 years.

METHODOLOGY

• In Stargardt disease, a genetic mutation causes vitamin A to clump together into harmful dimers that build up in the retina and damage vision over time. To combat this, researchers conducted a 2-year clinical trial across seven US clinics between 2015 and 2019 to evaluate whether oral gildeuretinol acetate (modified vitamin A) could slow the growth of retina-damaging lesions in these patients.
• The trial enrolled 50 patients aged 12 years or older, all with a genetic form of Stargardt disease. They were randomly split into four groups: one group received 14 mg gildeuretinol acetate once daily for 2 years; another received 24 mg once daily for year 1 before switching to 14 mg for year 2; a third group received a placebo for 2 years; and a crossover group got a placebo for the first year, then switched to the drug for the second year.
• Patients who started on the higher 24-mg dose were switched down to 14 mg after the first year based on tests showing the lower dose was equally effective at replacing natural vitamin A in the eye.
• To boost the size of the comparison group, researchers also added data from 54 other patients with Stargardt disease outside the trial who were tracked over time but not enrolled in any interventional study for the disease.
• The primary efficacy endpoint was the growth rate of retina-damaging lesions over 24 months, tracked using a specialized eye-imaging scan; safety was assessed via treatment-emergent adverse events, serious adverse events, and clinical laboratory testing.

TAKEAWAY

• Retinal lesions grew more slowly in patients taking the drug, at a rate of 0.182 mm/y, compared with 0.232 mm/y in the untreated group (placebo plus the outside comparison group); this represented a 21.6% relative reduction in the growth rate of lesions (P < .001).
• When researchers excluded the outside patient data and compared only the actual trial participants, lesion growth was still slower with the drug (0.206 mm/y) than with placebo (0.242 mm/y), equivalent to a 14.9% relative reduction.
• At 6 months, more than 80% of plasma vitamin A was replaced with gildeuretinol in 39 of 40 participants receiving treatment, and this replacement was sustained throughout the treatment period.
• Most side effects were mild to moderate and occurred at similar rates across all four groups.

IN PRACTICE

"Slowing the progression of a once-inexorable, vision-impairing disease is a worthwhile pursuit with potential to address an unmet medical need," experts wrote in an accompanying editorial.

"In the realm of inherited retinal diseases like Stargardt disease, trials like these validate the premise that slowing of retinal atrophy is, hopefully, more than a tease," they added.

SOURCE

The study was led by Christine N. Kay, MD, of Vitreo Retinal Associates in Gainesville, Florida. It was published online on September 3 in JAMA Ophthalmology.

LIMITATIONS

The trial's small sample size — a challenge common in rare-disease research — led researchers to supplement the comparison group with outside patient data. And because vision loss in Stargardt disease progresses slowly and unevenly, visual acuity couldn't serve as a reliable primary endpoint.

DISCLOSURES

The study was supported by Alkeus Pharmaceuticals and the FDA's Office of Orphan Products Development. Several authors reported receiving grants, personal fees, or research support from Alkeus Pharmaceuticals and other pharmaceutical companies during the conduct of the study. Two authors reported patent interests related to the treatment.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.