The following transcript has been edited for clarity.

Diana V. Do, MD: Welcome to Retinal Physician. I’m Diana V. Do, MD. Today I’m joined by 2 leaders in retina, Kenneth C. Fan, MD, MBA, and Baruch D. “Barry” Kuppermann, MD, PhD. We’re talking about treatments in development for Stargardt disease. And I want to discuss gildeuretinol (ALK-001; Alkeus/Tarsus Pharmaceuticals). Tell us about the exciting mechanism of action and how it might help people with Stargardt.

Kenneth C. Fan, MD, MBA: Gildeuretinol is a very interesting drug. It’s taken once a day orally. We know in Stargardt that defective ABCA4 causes buildup of retinol, vitamin A, which dimerizes together. The dimerization causes lipofuscin buildup and then cell death. And so in order to prevent that dimerization, they place a deuterium molecule at a certain carbon position. It prevents the cleavage and dimerization of retinol and vitamin A and reduces oxidative stress, reducing those toxic byproducts.

Dr. Do: Wonderful. And now we have some clinical evidence in clinical trials, the TEASE program. Tell us, Barry, about these results.

Baruch D. Kuppermann, MD: Well, it’s exciting because this vitamin A substitution with deuterium also doesn’t affect the visual cycle. We’ll talk about that a bit later, but the TEASE program is 4 studies—2 that have been completed, 2 that are ongoing—but 400+ patients and over 800 patient-years worth of study. In TEASE-1, patients with more advanced disease and atrophic lesions showed a decrease in the rate of growth of the atrophic lesions. TEASE-2, which were earlier-stage patients, showed decrease in their rate of deterioration of the ellipsoid zone. So there were excellent anatomic results there, with decreasing rates [observed] from 6 months through 24 months. They wait until the 6-month period because it takes about 6 months for the native vitamin A to be depleted and replaced by the deuterated vitamin A. In that period of time, there was roughly a 30% reduction in rate of growth in the 2 studies.

Separately, they also saw some functional benefit in low-luminance visual acuity, a benefit of about 2 letters or so in the TEASE-2 program.

They also have some patients in the SAGA program, which is geographic atrophy. Again, although there are different initiating events in these 2 diseases, the vitamin A could have an impact because of the RPE changes. So again, in the SAGA study, there was a 4-letter benefit in low-luminance vision.

Dr. Do: This is very exciting. It’s an oral agent, as you mentioned, Kenneth. What about safety? Are there any concerns about that?

Dr. Fan: Great question. I think safety is always top of mind. It’s the most important thing and luckily there is not much to say. All of the safety signals are very positive. It was a super well-tolerated medication. No serious adverse events (SAEs) related to the study drug, no evidence of retinal toxicity at the 14-mg dose. So we’re super excited. A lot of sites are launching for their phase 3 NORTHSTAR study, so we’re really excited to see what the data show.

Dr. Kuppermann: Corollary to that, again, the important thing is because it doesn’t influence a visual cycle, why don’t you talk about some of the things that we’re not seeing that we could see potentially?

Dr. Fan: That’s a great question. So concerns with vitamin A, obviously hypervitaminosis A, chromatopsia, dark adaptation, night blindness—none of those things were seen in the study. So overall a super consistent and well-tolerated safety profile.

Dr. Kuppermann: So again, there’s a pivotal phase 3 trial that has been initiated, still in its early days, with 115 patients per arm. So 230 patients overall randomized in a 1:1 allocation to the 14-mg dose of gildeuretinol vs placebo for a 24-month period of time.

Dr. Do: This is very exciting for our patients with Stargardt, potentially another option in the pipeline for them. And thank you so much for leading this innovation. RP