This is a dose-finding study followed by 2-year extension study to evaluate safety and tolerability of Tinlarebant in adolescent subjects with Stargardt disease

Tinlarebant, in the Phase 1b study, 5mg orally in cycle 1 once a day for 14 days, 2mg, 5mg or 10mg orally in cycle 2 once a day for 14 days. Tinlarebant, in the Phase 2 study Subjects continuing from Phase 1b into Phase 2 will receive their individualised optimal dose of tinlarebant, as determined in Phase 1b, orally once daily for 24 months (corresponding to 96 weeks). New subjects enrolling in Phase 2 will undergo dose optimisation as per the Optimal Dose Selection Criteria and receive their individualised optimal dose orally once daily for 24 months (corresponding to 96 weeks). The optimal dose of tinlarebant is defined as the dose that reduces a subject’s plasma RBP4 levels to a concentration of less than or equal to 1 µM without producing an adverse event (AE), which in the opinion of the Investigator would result in discontinuation of the subject from the study. Optimal dose selection criteria: Tinlarebant will be self-administered orally once daily for 2 cycles, 14 days per cycle. Each subject enrolled in the study will receive 5 mg tinlarebant (starting dose) in Cycle 1. Pharmacodynamic and safety data (based on general safety assessments and vision questionnaire) will be collected on Day 1 and Day 8 of each cycle. Subjects will receive 10 mg tinlarebant in Cycle 2 if the plasma RBP4 concentration is above 1 µM and there are no safety concerns; 5 mg tinlarebant if the plasma RBP4 concentration is equal to or below 1µM and there are no safety concerns; 2 mg tinlarebant if there are safety concerns. General safety assessments include vital signs, physical examination, 12-lead ECG, Clinical Laboratory Testing, visual acuity, dark adaptation and adverse events. The SRC will oversee dose escalation, de-escalation, and discontinuation per subject, throughout the Phase 1b portion and for any new subjects joining the study in Phase 2 (i.e., those who have not previously completed Phase 1b). A Data Safety Monitoring Board (DSMB) will meet periodically throughout both Phase 1b and Phase 2 to provide full study oversight (e.g., after 3-5 subjects have completed Phase 1b) and to determine progression from Phase 1b to Phase 2. The optimal dose selection criteria were specifically designed for this study. Phase 2 (new subjects only) The starting dose for any subjects enrolled in Phase 2 who have not been through Phase 1b will be as per the Phase 1b dosing plan or may be guided by the DSMB based on available data. The individualised optimal dose for new subjects joining the study in Phase 2 will be determined based on their RBP4 and safety data [based on the optimal dose definition and selection criteria described for Phase 1b]. For dose optimisation, only new subjects who are enrolled in Phase 2 of the study will be required to undergo blood sampling for PK (plasma tinlarebant), and PD (plasma RBP4, and serum retinol [Vitamin A]) analyses at Visits 1-6. The SRC will provide oversight of dose escalation during the Phase 2 portion for new subjects. Adherence monitoring For phase 1b a 1-week supply of the study drug will be dispensed on Day 1 and 8 of each cycle. Subjects should bring the study drug medication bottle(s), including any unused capsules and drug administration diary, back to the clinic for drug accountability on Day 8 of each cycle and Cycle 2 Day 14. For all subjects in phase 2 the study drug will be dispensed at Visit 1, for subjects continuing from Phase 1b this will be a 6-week supply, and for new subjects joining the study in Phase 2 this will be a 1-week supply and the study drug will be dispensed weekly until Visit 5. Subjects should bring the study drug medication bottle(s), including any unused capsules and drug administration diary, back to the clinic for drug accountability on each visit following the initial visit. Throughout phase 1b and 2 accurate records will be kept regarding when and how much study drug is dispensed and used by each subject in the study. Reasons for departure from the expected dispensing regimen must also be recorded. At the completion of the study, all study drugs will be reconciled