Belite Bio Shares Tinlarebant Phase III Stargardt Data, FDA Rolling Submission at DB Conference

Key Points

• DRAGON Phase III showed a 35.7% treatment effect — tinlarebant slowed annualized DDAF lesion growth to 0.38 mm²/yr versus 0.59 mm²/yr for placebo (P=0.0033; AR(1) analysis P<0.0001) and produced similar ~33% reductions in fellow-eye and total DAF lesion growth.
• Regulatory and development progress: Belite has begun an FDA rolling submission for Stargardt after a pre-NDA meeting and holds multiple designations (breakthrough, fast track, orphan, rare pediatric, Japan Sakigake), while the PHOENIX Phase III GA trial is fully enrolled with 530 subjects.
• Mechanism, pharmacodynamics and safety: Tinlarebant is a once-daily oral RBP4 binder that achieved sustained ~80% RBP4 reduction at 5 mg/day, and demonstrated an excellent two‑year safety/tolerability profile in adolescent Stargardt patients with mainly mild, non‑ocular adverse events.

Belite Bio NASDAQ: BLTE highlighted progress for its lead drug candidate tinlarebant during the 30th Deutsche Bank Depositary Receipts Virtual Investor Conference, outlining late-stage clinical development in Stargardt disease and geographic atrophy (GA) and describing Phase III efficacy and safety results in an adolescent Stargardt population.

Company focus: oral therapy aimed at visual-cycle toxicity

Hendrik Scholl, chief medical officer at Belite Bio, said the company is developing tinlarebant as a “novel once daily oral tablet” designed to bind serum retinol-binding protein 4 (RBP4) to reduce retinol delivery to the eye. The goal, he said, is to slow or halt the formation of toxic retinal byproducts generated in the visual cycle that are implicated in progression of Stargardt disease and GA.

Scholl described the mechanism in detail, stating that tinlarebant has “a hundredfold greater affinity for RBP4 compared to retinol,” competes with retinol for RBP4 binding, and prevents binding to transthyretin (TTR). He said the resulting tinlarebant-RBP4 complex is eliminated through the kidney, reducing retinol delivery to the eye and thereby reducing toxic retinal and A2E formation.

Belite Bio’s approach, Scholl added, is intended to address “the root cause of retinal pathology, namely bisretinoid-mediated toxicity,” rather than complement activation.

Pipeline update and regulatory designations

Scholl said tinlarebant is in development for two indications:

• Stargardt disease: Belite completed a Phase II two-year treatment trial in 13 subjects and a global Phase III trial (DRAGON) in 104 subjects. The company is also running an ongoing Phase II/III two-year treatment trial (DRAGON II) with 73 subjects enrolled.
• Geographic atrophy: Belite is running a Phase III two-year treatment trial (PHOENIX) that is “completely enrolled with 530 subjects,” using atrophic lesion growth assessed by fundus autofluorescence as the primary endpoint.

On the regulatory front, Scholl said the company “started our U.S. FDA rolling submission this month” for Stargardt disease, following discussions with the agency including a pre-NDA meeting. He also cited multiple designations for Stargardt disease, including breakthrough therapy, fast track, rare pediatric disease designation, and orphan drug designation in the U.S., Europe, and Japan, as well as Japan’s Sakigake designation.

DRAGON Phase III: lesion-growth endpoint showed statistically significant slowing

Scholl said DRAGON and DRAGON II are double-blind, placebo-controlled global trials with two-year treatment periods designed for adolescent Stargardt patients. In DRAGON, subjects were ages 12 to 20, had Stargardt disease with at least one ABCA4 mutation identified, and met lesion-size and visual-acuity criteria.

The DRAGON primary endpoint was the annualized rate of lesion growth in definitely decreased autofluorescence (DDAF), a structural endpoint Scholl said was supported by the large international natural history ProgStar study. He noted that DDAF growth has been accepted by the FDA as an approvable endpoint in Stargardt treatment trials.

Presenting DRAGON results, Scholl said tinlarebant produced a 35.7% treatment effect versus placebo on the primary endpoint using an unstructured covariance matrix (P=0.0033). He added that an analysis using a first-order autoregressive covariance matrix maintained a similar effect size (35.4%) with a smaller standard error and a P value “smaller than 0.0001.” He said DDAF lesion growth was slowed to 0.38 square millimeters per year versus 0.59 square millimeters per year for placebo, comparing those rates to a 0.74 square millimeters per year mean growth rate reported in ProgStar.

Scholl also emphasized fellow-eye findings, noting that despite variability between eyes, tinlarebant reduced DDAF lesion growth in the fellow eye by 33.6% versus placebo, which he characterized as statistically significant.

For the key secondary endpoint—total decreased autofluorescence (DAF), which combines definitely and questionably decreased autofluorescence—Scholl said tinlarebant slowed DAF lesion growth by 33.7% versus placebo. He also reported a 32.7% reduction in fellow-eye DAF growth versus placebo (P=0.017).

Visual acuity and pharmacodynamic marker

Scholl said best-corrected visual acuity did not show significant change over two years in either treatment or placebo arms, which he said was expected and consistent with Stargardt natural history. He reported mean visual acuity in the study eye was 39.9 ETDRS letters at baseline and 39.7 at end of study for tinlarebant, compared with 39.4 at baseline and 40 at end of study for placebo—levels he said correspond to approximately 20/160 Snellen visual acuity.

On pharmacodynamics, Scholl said five milligrams per day of tinlarebant produced a sustained ~80% reduction in circulating RBP4 with “very little variability,” and that RBP4 levels returned near baseline about 28 days after discontinuation.

Safety profile and GA program status

Scholl said tinlarebant maintained an “excellent safety and tolerability profile” over two years in adolescent Stargardt patients. He reported six serious adverse events in total—four in placebo and two in the treatment group—describing them as non-ocular, with four assessed as unrelated and two as unlikely related to treatment. The most reported non-ocular adverse events were nasopharyngitis, headache, and acne, and he said most events were mild and resolved during the study period.

On ocular tolerability, Scholl cited mild xanthopsia and mild delayed dark adaptation/night vision impairment, stating most resolved while on treatment and that there were no serious ocular treatment-emergent events. He also noted four treatment-emergent adverse events led to study drug discontinuation and two led to study discontinuation.

For PHOENIX in geographic atrophy, Scholl said a Phase I study in an elderly population showed the PK/PD profile was the same as in adolescents in DRAGON. He said PHOENIX is enrolled with 530 subjects, uses fundus autofluorescence lesion growth as the FDA-accepted primary endpoint, targets patients with small lesions for early intervention, and tests the same oral dose of five milligrams per day.

In Q&A, Scholl said earlier-stage trials before atrophy develops are possible in principle but could require prohibitive duration to achieve statistical power, while adding that Moorfields Eye Hospital’s Michel Michaelides anticipated potentially greater benefit in patients treated before significant visual acuity loss or lesion development. Scholl also said Belite’s rolling FDA submission is “according to plan,” and that achieving sustained 80% to 90% RBP4 reduction is an improvement versus earlier attempts with the mechanism, adding that Belite believes at least 70% RBP4 reduction is needed to see a treatment effect.

About Belite Bio NASDAQ: BLTE

Belite Bio, Inc NASDAQ: BLTE is a clinical-stage biotechnology company focused on discovering and developing small molecule therapeutics for metabolic and inflammatory diseases. Leveraging a proprietary drug-discovery platform, the company aims to address conditions such as nonalcoholic steatohepatitis (NASH) and obesity by targeting pathways involved in fibrosis, inflammation and metabolic regulation.

Belite Bio’s pipeline includes multiple candidates in preclinical and early clinical development stages.

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