Phase 3, Multicenter, Randomized, Double-Masked, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Tinlarebant in the Treatment ofStargardt Disease in Adolescent Subjects

Autosomal recessive Stargardt disease (STGD1) is the most prevalent form of
juvenile macular degeneration. It is a rare, inherited autosomal recessive
disease that causes severe and irreversible blindness by the first or second
decade of life. There is no approved treatment for this condition and remains
an area of unmet need. During STGD1 onset, the retinal pigment epithelium (RPE)
undergoes profound structural changes caused by the excessive accumulation of
toxic vitamin by-products (bisretinoids) and cellular debris (lipofuscin)
within the RPE. These changes are a direct result of the pathogenic mutations
in the ABCA4 gene. The ABCA4 gene encodes a retina-specific AT P-dependent
transporter (known as ABCA4, or Rim Protein) which removes reactive
retinaldehydes from the retina for recycling within the RPE.
In the absence of a functional ABCA4 protein, retinaldehydes accumulate within
photoreceptor outer segments of the retina where they generate
membrane-damaging reactive oxygen species, and also spontaneously react with
cellular lipids. These oxidized membranes and lipid-retinal species are taken
into the RPE through normal diurnal phagocytic processing where they gradually
accumulate. It is theorized that these compounds reach a critical mass within
RPE phagolysosomes and cause dysfunction of the metabolic activities of the RPE
leading to accelerated bisretinoid biosynthesis and accumulation of lipofuscin
which severely compromises the ability of the RPE to provide metabolic and
trophic support to the retina.
An optimal point of intervention in STGD1 is before the accumulation of
cytotoxic bisretinoids and lipofuscin has led to significant structural damage
to the photoreceptors and the RPE. As bisretinoids are products of retinol
derivatives, the rate of bisretinoid formation depends on the availability of
retinol in the retina and the uptake of serum retinol from the bloodstream to
the RPE. Serum retinol is maintained in the bloodstream and is delivered to the
RPE as a ternary complex comprised of retinol binding protein 4 (RBP4) and the
large accessory protein, transthyretin (TTR). The binding of TTR to the
RBP4-retinol complex is required to maintain a high steady-state level of
retinol in the circulation. In the absence of TTR binding to the RBP4-retinol
complex, RBP4-retinol would be released from the liver, but it would be rapidly
eliminated through glomerular filtration in the kidney due to its small size.
Because the eye has a unique preference for uptake of retinol bound to RBP4,
reduction of RBP4-retinol in the circulation will lead to a reduced influx of
retinol to the RPE and the inhibition of bisretinoid formation, which may be
beneficial in the treatment of STGD1.
Tinlarebant (previously known as LBS-008 or BPN-14967) is an RBP4 antagonist
developed as a treatment to slow or halt the progression of STGD1. The ability
of Tinlarebant to bind RBP4 and reduce circulating levels of RBP4-retinol in a
dose-dependent manner has been demonstrated in mice as well as non-human
primates. In STGD1 animal models, Tinlarebant-mediated reduction of
RBP4-retinol was effective to produce a statistically significant reduction in
bisretinoid formation and lipofuscin accumulation, and also prevent
photoreceptor degeneration. The safety and tolerability of Tinlarebant has been
established in Phase 1 clinical studies.
Disease progression in STGD1 is assessed through the measurement of the growth
of atrophic lesions within the retina and RPE as demonstrated in the ProgStar
study. The recommended imaging modalities for evaluating lesion growth rate are
fundus autofluorescence (FAF) photography and spectral domain optical coherence
tomography (SD-OCT) imaging. Other functional tests, such as microperimetry
(optional) and best-corrected visual acuity (BCVA) using the Early Treatment
Diabetic Retinopathy Study (ETDRS) test are also important assessments.

This study has been transitioned to CTIS with ID 2024-513483-26-00 check the CTIS register for the current data.

To assesses the efficacy of Tinlarebant in slowing the rate of growth of
atrophic lesion(s) in adolescent subjects with STGD1.

This is a Phase 3 randomized, double-masked, parallel group, multicenter study
to evaluate the efficacy and safety of Tinlarebant 5 mg in the treatment of
adolescent subjects with STGD1.

Approximately 60 subjects with STGD1 will be enrolled in this study across
multiple sites in Australia, Asia, Europe, and North America. Upon entry into
the study, subjects will be assigned a screening number. Following screening,
eligible subjects will be randomly assigned to begin treatment on Day 1 (Month
1) in 2:1 ratio to receive the study drug (either Tinlarebant 5 mg or matching
placebo). Interactive response technology will be used to administer the
randomization schedule. This study has a screening period of up to 28 days,
treatment period of up to 24 months, and follow-up period of 28 days; thus, the
total duration of study participation is approximately up to 26 months.
Screening assessments will take place within 28 days before the first study
visit (V1) to confirm eligibility for participation in the study and/or for
baseline measurements. After beginning treatment on Day 1, subjects will return
to the study site once every month for the first 4 months, and then every 3
months per the Schedule of Assessments for a total of 13 study visits
(including the Screening visit). Subjects will continue treatment with the
study drug orally once daily for 24 months and will be followed up for safety,
efficacy, and PD assessments.

Subjects will be treated for 24 months with Tinlarebant or placebo. The study
drug is a tablet that should be taken orally every day.

For this study, we will have 2 groups:
• Group 1. The people in this group will get Tinlarebant.
• Group 2. The people in this group will get a placebo.

A draw will decide which treatment is given. The chances of receiving
Tinlarebant is 66% and the probability to receive placebo is 33% (2 is to 1
chance).

The following side effects of Tinlarabant are common:
- Delayed dark adaptation (slowing in the recovery of light sensitivity by
photoreceptors)
- Xanthopsia (colour vision deficiency)
- Night vision impairment

Discomforts patients can experience from the tests during the study:
• Blood collection: Collection of blood may cause bruising at the place where
the needle goes into the skin. Fainting, and in rare cases infection, may occur.
• Blood pressure: The blood pressure cuff used to take blood pressure may cause
discomfort or bruising to the upper arm.
• Heart ultrasound (ECG): The ECG involves sticking patches on the skin. The
skin may become a little red or irritated if a response to the glue used occurs.
• Eye-related assessments and pupil enlargement: There will several kinds of
eye examinations during this study. The subject may feel temporary discomfort
during the eye examinations due to the bright lights. When the investigator is
examining the inside of the eye, sometimes there is a need to put mild pressure
on the eye. This causes mild to moderate discomfort that goes away quickly. The
subject may possibly experience eye swelling from the mild pressure on the eye
from these examinations. For some examinations eye drops may be used to dilate
the pupils of the eyes. The subject may feel side effects and discomforts,
including stinging, sensitivity to lights, and blurring of vision. These
effects of pupil dilation may last for 4 to 6 hours depending on the strength
of the drop used.
• Tonometry: A tonometry test measures the pressure inside the eye, which is
called intraocular pressure (IOP). Eyedrops to numb the surface of the eye may
be used and the eyes will be numb for anywhere from 10 to 30 minutes.