4D-125 in Patients With X-Linked Retinitis Pigmentosa (XLRP)

An Open-label, Phase 1/2 Trial of Gene Therapy 4D-125 in Males With X-linked Retinitis Pigmentosa (XLRP) Caused by Mutations in the RPGR Gene

This is a Phase 1/2 multicenter study with two parallel parts: an observational natural history cohort and an open-label, prospective interventional trial in males with non-syndromic X-linked retinitis pigmentosa (XLRP) due to mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR).

This Phase 1/2 study will gather data in an observational phase Natural History Cohort to further characterize and evaluate natural disease progression in male patients with genetically-confirmed X-linked retinitis pigmentosa (XLRP) caused by mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR). The study will also evaluate the safety and tolerability, as assessed by frequency and severity of ocular and systemic adverse events, as well as preliminary clinical efficacy of a single intravitreal (IVT) injection of 4D-125 at two dose levels in this patient population in one or both eyes (the contralateral eye dose provided the subject is eligible and provides consent). 4D-125 has been developed as a gene replacement therapy for XLRP. After receiving 4D-125, patients will be followed for 24 months with continued safety follow-up and 36 additional months of long-term follow-up. Secondary endpoints will assess preliminary efficacy measures over time after 4D-125 administration.

In Phase 1, up to 2 dose exploration cohorts will be enrolled; each cohort will initially recruit up to 3 patients to receive a single uniocular IVT injection of 4D-125 in a standard 3+3 design. The cohort will be expanded in the event of a dose limiting toxicity (DLT). Any cohort may be expanded by an additional 3 subjects (to a maximum of 12 patients) to provide additional safety information and/or to confirm the selected dose for expansion. Once the dose level has been selected, the Phase 2 Dose Expansion Cohort will be opened to dose an additional 6-12 adult patients, and includes a pediatric sub-population of up to 6 patients. For adult participants only, the contralateral eye may also be dosed with 4D-125 as a single dose, IVT injection provided the subject is eligible and provides consent.

Dose 1 and Dose 2 4D-125 will be administered at the assigned dose level as a single dose, IVT injection on Day 1. The contralateral eye may also be dosed with 4D-125 as a single dose, IVT injection provided the subject is eligible and provides consent.

4D-125 will be administered at the assigned dose level as a single dose, IVT injection on Day 1 in both adults and pediatric participants. For adult participants only, the contralateral eye may also be dosed with 4D-125 as a single dose, IVT injection provided the subject is eligible and provides consent.

4D-125 drug product developed for gene therapy, which comprises an AAV capsid variant (4D-R100) carrying a codon-optimized human Retinitis Pigmentosa GTPase Regulator transgene.

Incidence and severity of TEAEs and serious adverse events (SAEs), including clinically significant changes in safety parameters

Natural History Key Inclusion Criteria: Male, ≥ 6 years of age at the time of informed consent Hemizygous non-syndromic RPGR mutation confirmed by genetic testing Interventional Key Inclusion Criteria: Male, ≥12 years of age Hemizygous non-syndromic RPGR mutation confirmed by genetic testing Phase 1 Dose Exploration: At least one eye amenable to IVT injection and BCVA ≤ 78 ETDRS letters (~20/32) and ≥ 34 ETDRS letters (~20/200) Phase 2 Dose Expansion: At least one eye amenable to IVT injection AND both eyes must have BCVA ≥ 34 ETDRS letters (~20/200) Key Exclusion Criteria (all cohorts) Patient has previously received any AAV treatment Pre-existing eye conditions or surgical complications that would preclude participation in an interventional clinical trial or interfere with the interpretation of study endpoints