Safety and Efficacy of Emixustat in Stargardt Disease

Stargardt disease is a rare, inherited degenerative disease of the retina affecting approximately 1 in 8000 to 10 000 people and is the most common type of hereditary macular dystrophy. There are no approved treatments for STGD. This disease is characterized by an excessive accumulation of lipofuscin at the level of the retinal pigment epithelium (RPE). Lipofuscin is made of lipids, proteins, and toxic bis retinoids (such as N retinylidene N retinylethanolamine \[A2E\]). Accumulation of the toxic bis retinoids found in lipofuscin is thought to cause RPE cell dysfunction and eventual apoptosis, resulting in photoreceptor death and loss of vision.

Stargardt disease has several sub types, where autosomal recessive STGD (STGD1) accounts for the majority (>95%) of all cases. STGD1 is typically diagnosed in the first 3 decades of life and is caused by mutations of the adenosine triphosphate binding cassette subfamily A member 4 (ABCA4) gene. The ABCA4 gene product transports N retinylidene phosphatidylethanolamine (a precursor of toxic bis retinoids) from the lumen side of photoreceptor disc membranes to the cytoplasmic side where the retinal is hydrolyzed from phosphatidylethanolamine. Mutations of the ABCA4 gene result in accumulation of this precursor in disc membranes that are eventually phagocytized by RPE cells, where the precursors are converted into toxic bis retinoids such as A2E. In addition to being a precursor to A2E, all trans retinal has also been implicated in the pathogenesis of STGD through its role in light-mediated toxicity.

Emixustat hydrochloride (emixustat) has been developed by Acucela Inc. for retinal diseases including Stargardt disease (STGD). Emixustat is a potent inhibitor of RPE65 isomerization activity and reduces visual chromophore (11 cis retinal) production in a dose-dependent and reversible manner. Because 11 cis-retinal and its photoproduct (all trans retinal) are substrates for biosynthesis of retinoid toxins (eg, A2E), chronic treatment with emixustat retards the rate at which these toxins accumulate.

• Emixustat (Drug), also known as emixustat hydrochloride: Once daily oral tablet taken for 24 months
• Placebo (Drug): Once daily oral tablet taken for 24 months

Primary outcomes

• Mean Rate of Change in Total Area of Macular Atrophy, as Measured by Fundus Autofluorescence (FAF) [24 months]: Mean rate of change in total area of macular atrophy, as measured by fundus autofluorescence (FAF)

Sex: All, ages: 16 Years to any

Inclusion Criteria:

* A clinical diagnosis of macular atrophy secondary to Stargardt disease (STGD)
* Macular atrophy measured to fall within a defined size range
* Two mutations of the ABCA4 gene. If only one mutation, a typical STGD appearance of the retina.
* Visual acuity in the study eye of at least 20/320

Exclusion Criteria:

* Macular atrophy secondary to a disease other than STGD
* Mutations of genes, other than ABCA4, that are associated with retinal degeneration
* Surgery in the study eye in the past 3 months
* Prior participation in a gene therapy or stem cell clinical trial for STGD
* Recent participation in a clinical trial for STGD evaluating a complement inhibitor or vitamin A derivative
* Use of certain medications in the past 4 weeks that might interfere with emixustat
* An abnormal electrocardiogram (ECG)
* Certain abnormalities on laboratory blood testing
* Female subjects who are pregnant or nursing

Participant flow

Outcome results

• Mean Rate of Change in Total Area of Macular Atrophy, as Measured by Fundus Autofluorescence (FAF) (Primary), Mean, Rate of change from BL (mm^2/yr): Emixustat 1.280 +/- 0.0783; Placebo 1.309 +/- 0.1002

Adverse events

Time frame: 24 months

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2020-05-21)

• Jeff Gregory, MD, Study director, VP of Clinical Development, Acucela