A Multicenter, Prospective, Longitudinal, Observational Study in Children and Adults with Stargardt Disease Secondary to Mutation in the ABCA4 Gene

Population
Stargardt disease type 1 (STGD1) is an autosomal recessive retinopathy caused
by mutations in the retina-specific ATP-binding cassette transporter gene
(ABCA4) located on chromosome 1 (Allikmets et al., 1997; Kaplan et al., 1993).
Stargardt disease is the most common inherited retinal disease (IRD) frequently
quoted in literature as estimated to affect approximately 1 in 8000 to 10,000
individuals originating from Blacharski (Blacharski, 1988; Cremers et al.,
2020; Runhart et al., 2022). A much higher prevalence (1:6,578 to 1:870) has
been estimated in genetic studies based on ABCA4 mutation carrier frequencies
but do not correlate to the observed disease prevalence (Runhart et al., 2022;
Hanany et al., 2020; Riveiro-Alvarez et al., 2009). An accurate prevalence of
ABCA4-related Stargardt disease is difficult to estimate due to its substantial
phenotypic and genotypic heterogeneity (Cremers et al., 2020). The age of onset
and rate of progression varies greatly where central vision loss typically
manifests in early childhood and young adulthood but some individuals may
present later in adulthood (Cremers et al. 2020; Zernant et al., 2017; Zernant
et al, 2018; Runhart et al., 2018). Generally, patients in which the disease
manifests early in life typically have a more severe phenotype and tend to
progress more rapidly, while later age onset is associated with a milder
prognosis (Kohli and Kaur, 2023; Fujinami et al., 2015; Tanaka et al., 2018;
Zernant et al., 2017).

Rationale for a Prospective Observational Study
Although there are numerous ongoing interventional clinical studies in STGD1
including cell transplantation, pharmacotherapy, and gene therapy; one of the
most challenging aspects of conducting clinical studies is the ability to
measure therapeutic benefit.

The Natural History of the Progression of Atrophy Secondary to Stargardt
Disease (ProgStar) Studies were landmark retrospective and prospective
observational studies designed to evaluate disease progression utilizing
structural and functional modalities in a large international cohort of
children and adults with STGD1 (Strauss et al., 2016). The primary objective of
ProgStar was to estimate the yearly progression of STGD1 evaluating the growth
of atrophic lesions measured by FAF imaging. Two distinct types of decreased
autofluorescence were quantified. Areas in which the level of darkness was at
least 90% in reference to the optic nerve head were termed *definitely
decreased autofluorescence* (DDAF), while *questionably decreased
autofluorescence* (QDAF) defined regions with levels of darkness between 50%
and 90% (Ervin et al., 2019). In ProgStar growth rates could be estimated for
both DDAF and QDAF lesions. Mean progression of DDAF was 0.51 mm2/ year, and a
total decreased fundus autofluorescence was 0.35 mm2/ year; the rate of
progression of DDAF and QDAF was dependent on the size of the lesion at
baseline with larger lesions progressing faster than smaller ones (Strauss et
al., 2017 ProgStar, Report 5; Strauss et al., 2017, Report 9). After adjusting
for the initial lesion size, only the comparison of multifocal lesions and
unifocal lesions was significantly different with initial multifocal lesions
progressing more rapidly than unifocal lesions (P <0.0001). A higher rate of
progression was seen for eyes with flecks outside the arcades versus those
without flecks outside the arcades.
There were no differences in the progression of lesion size for eyes with
increased hyperfluorescence at the lesion edge versus those that did not have
increased hyperfluorescence. Compared with age-related macular degeneration
(AMD), STGD1 atrophic lesions progress at a slower rate (Lindner et al., 2017).

Analysis of eligible OCT scans (scans with confounders to analysis such as
subretinal fluid (SRF), epiretinal membrane (ERM) were excluded) revealed that
the mean total retinal thickness was 129.7µm at baseline and decreased 3.1 µm/
year over 24 months. Over the 24-month study duration, there was an increase in
the trajectory of inner retinal (IR) thickness change, while the outer nuclear
layer (ONL), inner segment (IS), outer segment (OS), and total retina thickness
decreased. All these findings were statistically significant (P<0.0001). There
was no change in the intact area for IR (P=0.73), while the ONL, IS, and OS
intact area trajectory showed a decrease per year over 24 months (P<0.0001). In
the prospective study, overall rate of BCVA loss was 0.55 letters/year over 24
months. Eyes with baseline BCVA worse than 20/200 showed an improvement of 0.65
letters/year. At baseline, the mean BCVA for eyes without a foveal lesion was
20/32, and the BCVA change rate over time was 0.1 letters/year (P=0.89). Eyes
with a foveal lesion but having BCVA of 20/70 or better at baseline lost BCVA
at a rate of 3 letters/year (Kong et al., 2017; Kong et al., 2018). Therefore,
authors concluded VA is not a suitable outcome measure except for distinct
subgroups, and alternative functional testing is necessary.

Microperimetry has been shown to be a good tool to enhance the understanding of
functional impairment in STGD. Report 13 of the prospective ProgStar study on
STGD1 showed that the mean change in mean mesopic sensitivity was -0.68 dB/year
(Schönbach et al., 2020). The SMART longitudinal study (a subset of ProgStar
study) in patients with STGD1 demonstrated that all eyes showed a statistically
significant worsening trend. The rates of foveal mMD, extrafoveal mMD and sMD
changes were 0.72, 0.86, and 1.12 dB per year, respectively (Kong et al.,
2022). Rates of change were highest at the edges of the atrophic lesion and
greater rates of decline were noted for both mean and peri-lesional sensitivity
with scotopic than mesopic microperimetry. The scotoma edge mean sensitivity
was 9.36 ± 4.7 dB (SD) at baseline (N = 368 eyes) and 6.52 ± 5.0 dB at 12
months (N = 352). The mean change in sensitivity at 12 months was higher in the
scotoma edge (2.84 dB) than the average of the mean sensitivity of the entire
test field (0.69 dB). (Ervin et al., 2019; Strauss et al., 2019, SMART Study)

ProgStar authors concluded that retrospective data can provide some insight
into the risk factors associated with fast progressors over a longer period of
time, and this was the case for FAF (Strauss et al., 2017, Report 5; Strauss et
al., 2017, Report 9). Inconsistency in acquisition protocols at the
participating clinical centers, for example, for MP, made such an approach not
feasible for certain outcomes in ProgStar. Also, the low resolution of OCT
images (usually taken with the *high-speed mode* rather the *high resolution
mode* as used in ProgStar) was another limitation in grading retrospective
data. Finally, the authors noted that factors associated with deleterious
outcomes 3 or more years after the last follow-up in ProgStar would be helpful
for selecting optimal outcomes, for instance, how EZ changes translate into
functional changes over time (Ervin et al., 2019).

Given the findings from the ProgStar studies, this multicenter, prospective,
longitudinal, observational study in approximately 80 children and adults aims
to evaluate prognostic factors of disease progression and to further describe
the STGD1 patient population, an integral part of planning aspects of future
interventional clinical studies.

Primary Objectives
• To evaluate prognostic factors of disease progression in subjects with
Stargardt disease secondary to mutation in the ABCA4 gene
• To further characterize the STGD1 patient population for future
interventional clinical studies

observational, longitudinal, prospective.

observational study

Risk: minimal. The study measurements are part of the standard repertoire of an
eye clinic with hardly any risks associated with it

Burden: study participation takes time, because additional measurements have to
be taken regularly. For some measurements in the eye clinic it is necessary to
dilate the pupils (using eye drops). This effect is limited in time (the drops
wear off quickly) and effect.

In addition to adults, this study also takes place in teenagers and children
with Stargardt's disease. This is therefore a non-therapeutic study in minors,
so a specific assessment must be made for this group:

- Risk: minimal.

- The study does come with extra burden, but this is limited due to the
circumstances of these subjects: all subjects have Stargardt's disease and are
therefore already under intense supervision by their ophthalmologist. The
subjects are used to - and familiar with - the clinical measurements associated
with this study.

Conclusion: risks are minimal and so is the burden given the circumstances of
the test subjects. The pros outweigh the cons, because there is an advantage at
the group level.