On this episode of Evidence Based Retina, Rishi Singh, MD, FASRS, and Carlos Quezada-Ruiz, MD, FASRS, chief medical officer of Alkeus Pharmaceuticals, Inc., discuss advances in pharmaceutical treatment for Stargardt disease and other retinal diseases.
The therapeutic shift in retina care
Drs. Singh and Quezada-Ruiz discuss the notable shift in ophthalmology from primarily procedural, localized treatments to systemic, biology-driven therapies that have the potential to modify the course of these diseases.
Alkeus Pharmaceuticals is a biotechnology company based in Cambridge, Massachusetts, founded in 2010. The company aims to preserve the vision of patients affected by retinal diseases, with a primary focus on Stargardt disease.
Understanding Stargardt disease and gildeuretinol
Stargardt disease is caused by mutations in the ABCA4 gene, which results in the formation of toxic vitamin A dimers leading to lipofuscin and cell death and favoring a pro-inflammatory state that results in oxidative stress and complement activation with cellular and functional loss as a result.
Gildeuretinol is a novel molecular entity engineered taking advantage of the kinetic isotope effect, in which three hydrogen atoms within the vitamin A molecule are replaced with deuterium atoms. This targeted modification significantly slows the formation of toxic vitamin A dimers while preserving the normal biological functions of vitamin A, with the potential to maintain retinal structure, physiology, and visual function. 1
Alkeus’ clinical programs and future trials
The company has experienced an evolution towards a late-stage clinical development company with its NORTHSTAR phase 3 study being now the flagship of its comprehensive clinical development program, across Stargardt disease and geographic atrophy.2 To date, Dr. Quezada-Ruiz states that approximately 400 patients (ages 8 to 93) have been dosed with gildeuretinol with follow up durations that range up to 7 years of follow-up.
A series of clinical trials (TEASE-1 through TEASE-4) evaluating gildeuretinol in patients with various stages of Stargardt disease showed promising signals of visual stability and anatomical preservation as follows:3
- TEASE-1: Focused on advanced Stargardt disease with atrophic lesions
- TEASE-2: Focused on intermediate stages, no atrophic lesions
- TEASE-3: Focused on early stages
- TEASE-4: A long-term extension study of patients who were part of any of the other three TEASE studies
“For [a] high-prevalence rare disease, such as Stargardt, having the privilege to design and start a phase three trial with this wealth of data, seeing the benefit-risk profile that we're seeing at this stage, it's actually quite encouraging, and exciting to be quite frank,” explained Dr. Quezada-Ruiz.
Deeper dive into NORTHSTAR
Currently, the NORTHSTAR phase 3 trial targets patients with advanced Stargardt disease and uses the rate of atrophic lesion growth as a primary endpoint.4
Clinical endpoints include anatomical measures, such as rate of growth of retinal atrophic lesions, ellipsoid zone integrity, and importantly, functional endpoints such as low-luminance visual acuity. According to Dr. Quezada-Ruiz, they decided the primary endpoint for NORTHSTAR was going to be similar to TEASE-1 with a focus on patients with advanced Stargardt disease with atrophic lesions at baseline.
The aim was to measure the change over time under the hypothesis that patients treated with gildeuretinol would actually have a slower rate of growth of atrophic lesions versus patients who were receiving placebo.
Dr. Quezada-Ruiz added, “Now this is, of course, one way of doing things. There's other ways, but I think that this also allows us to use an endpoint that has been used before, not only in Stargardt, but also in other diseases, that's reliable, and objectively measured, by an independent reading center.”
To learn more about the NORTHSTAR phase 3 trial, check out the Glance story Alkeus begins dosing in global phase 3 Stargardt trial on oral gildeuretinol!
Improving patient education and early identification
One of the major challenges in the field is identifying patients who may have been misdiagnosed with conditions such as age-related macular degeneration (AMD). Dr. Quezada-Ruiz emphasizes that raising awareness about new treatment options is likely to improve referral patterns from optometrists and general ophthalmologists. This, in turn, will help ensure more accurate diagnoses for individuals with Stargardt disease.
“By having more innovation and bringing the option of a new treatment for these patients, I think the awareness is going to increase, and we're going to see more referrals, both from the optometry community [and] the general ophthalmology community,” he explained. “We will potentially be able to give people living with Stargardt's a treatment option, and hopefully help them preserve their vision for longer.”
