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

Overview

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).

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2026

Detailed Description

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.

Interventions

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

Arms, Groups and Cohorts

  • Experimental: 4D-125 Dose Exploration
    • 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.
  • Experimental: 4D-125 Dose Expansion
    • 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.
  • Other: Observational
    • Natural History

Clinical Trial Outcome Measures

Primary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: Male

Minimum Age: 12 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • 4D Molecular Therapeutics
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Schonmei Lee, MD, Study Director, 4D Molecular Therapeutics

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