HOPE FOR CURING BLINDNESS

For Stargardt Disease and Geographic Atrophy

Tinlarebant, or LBS-008, if approved, would provide a novel treatment option for people living with autosomal recessive Stargardt disease, type 1 (STGD1), and geographic atrophy (GA), two retinal degenerative diseases that eventually lead to blindness. Tinlarebant is a once-a-day oral therapy that is intended to reduce the accumulation of toxins in the eye that cause STGD1 and contribute to GA. These toxins are byproducts of the visual cycle, which is dependent on the supply of vitamin A (retinol) to the eye. Tinlarebant works by reducing and maintaining levels of serum retinol binding protein 4 (RBP4), protein that transports retinol from the liver to the eye. By modulating the amount of retinol entering the eye, Tinlarebant reduces the formation of toxins. In clinical trials, Tinlarebant has demonstrated its target specificity, potency, and safety in STGD1 patients. Given that a common cause of disease progression in both STGD1 and GA is characterized by the aberrant accumulation of cytotoxic byproducts of vitamin A, we are optimistic for a positive outcome of our clinical trial for Tinlarebant in GA patients as well.

Tinlarebant was selected by the National Institute of Health (NIH) Blueprint Neurotherapeutics Network (BPN) in 2011 as a promising drug candidate for treating dry AMD. GA is the advanced form of dry AMD. The BPN was launched in 2004 to foster small-molecule neurotherapeutic development, bringing together a unique blend of grant dollars, industry-standard scientific expertise, and contract resources under a milestone-driven cooperative agreement program.

Additionally, the mechanism of action utilized by Tinlarebant was recognized and recommended as a priority for clinical development in both STGD1 and GA in a systematic review published by the U.K. National Institute for Health Research (NIHR) in 2018. The NIHR screened close to 8,000 articles in 2018 for its systematic review on treatments for dry AMD and STGD1. Its principal findings included that research focus should be at earlier stages in both diseases (before vision is impaired) and that the most promising treatments for both diseases appear to be prevention of lipofuscin and bisretinoid accumulation. Therefore, the NIHR recommended the mechanism of RBP4 inhibition, which is utilized by Tinlarebant, as a promising treatment in STGD1 and GA.

Clinical Trials

We have completed a two-year Phase 2 study of Tinlarebant in adolescent STGD1 subjects. Data from the trial showed a sustained lower atrophic lesion growth in Tinlarebant-treated subjects compared to ProgStar participants possessing similar baseline characteristics (aged ≤18 years) (p<0.001). In the Phase 2 trial, 42% of Tinlarebant-treated subjects (5 out of 12) did not develop atrophic retinal lesions during the 24-month treatment period.

We have also completed enrollment of a pivotal global Phase 3 trial of Tinlarebant in adolescent STGD1 subjects (“DRAGON”) with 104 subjects across 11 countries. The DRAGON study is a multi-center, randomized, double masked, placebo-controlled study to evaluate the safety and efficacy of Tinlarebant.

Our DRAGON II studies continue to progress. We have completed a Phase 1b trial evaluating pharmacokinetics and pharmacodynamics of Tinlarebant in Japanese subjects. Separately, we have begun dosing in the Phase 2/3 portion of our DRAGON II trial evaluating the efficacy, safety, and tolerability of Tinlarebant in approximately 60 adolescent STGD1 subjects across the U.S., U.K., and Japan.

In GA, we have begun dosing in a pivotal, global Phase 3 trial of Tinalrebant (“PHOENIX”) and, to date, have received approval to initiate the PHOENIX trial in eight countries. The PHOENIX study is a multi-center, randomized, double‑masked, placebo-controlled study to evaluate the safety and efficacy of Tinlarebant.

Tinlarebant has been granted Orphan Drug Designation in the U.S., Europe and Japan, as well as Rare Pediatric Disease (RPD) designation and Fast Track Designation (FTD) in the U.S. and Sakigake (Pioneer Drug) Designation in Japan.

DISEASE PROFILE

Stargardt Disease

STGD1 is the most common inherited retinal dystrophy (causing blurring or loss of central vision) in both adults and children. The disease is caused by mutations in a retina-specific gene (ABCA4), which results in progressive accumulation of toxins (bisretinoids) leading to retinal cell death and progressive loss of central vision. Researchers have identified more than 500 mutations in the ABCA4 gene in STGD1 patients, and some STGD1 patients suffer severe visual impairment by the age of 20. The prevalence rate of STGD1 is estimated to be 10 to 12.5 in 100,000 people in the U.S.¹

The fluorescent properties of bisretinoids and the development of retinal imaging systems have helped ophthalmologists identify and monitor disease progression. However, currently there are no FDA-approved treatments for STGD1.

¹ Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2017 Jan;101(1):25-30.

MECHANISM OF ACTION

Visual Cycle

The processing of vitamin A (aka, retinol, or all-trans retinol) in the visual cycle begins with the delivery of circulating retinol to the RPE. The ternary complex of RBP4-retinol-TTR is presented to RBP4 receptors, which are located on the basal surface of RPE. The RBP4-TTR vehicle serves to solubilize retinol and produce a large molecular size complex that resists elimination in the kidney. Upon entry into the RPE, retinol undergoes a series of enzymatic reactions resulting in generation of the visual chromophore, 11-cis retinal. The visual chromophore is delivered to the retina where it combines with opsin to form the light-sensitive visual pigment, rhodopsin. Photoactivation of rhodopsin liberates all-trans retinal, which is transported out of the retina by the ABCA4 protein.