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

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.

• 4D-125 IVT Injection (Biological): 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.
• Observational (Other): Natural History

Primary outcomes

• Incidence and severity of TEAEs and serious adverse events (SAEs), including clinically significant changes in safety parameters [24 months to 60 Months]

Sex: Male, ages: 12 Years to any

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

• Schonmei Lee, MD, Study director, 4D Molecular Therapeutics