Clinical trial NCT04517149: 4D-125 in Patients With X-Linked Retinitis Pigmentosa (XLRP)
Official title: 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: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: X-Linked Retinitis Pigmentosa
Keywords: XLRP
Gene therapy
Lead sponsor: 4D Molecular Therapeutics
Sponsor class: INDUSTRY
First posted: 2020-08-18
Enrollment: 21
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence and severity of TEAEs and serious adverse events (SAEs), including clinically significant changes in safety parameters
timeFrame: 24 months to 60 Months
Secondary outcomes:
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Gainesville
country: United States
facility: Vitreo Retinal Associates
state: Florida
city: Ann Arbor
country: United States
facility: University of Michigan Kellogg Eye Center
state: Michigan
city: New York
country: United States
facility: Columbia University Medical Center/Edward Harkness Eye Institute
state: New York
city: Durham
country: United States
facility: Duke University Eye Center/Dept. of Ophthalmology
state: North Carolina
city: Portland
country: United States
facility: Casey Eye Institute, Oregon Health and Science University
state: Oregon
city: Dallas
country: United States
facility: Retina Foundation of the Southwest
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah John A. Moran Eye Center
state: Utah
Study officials:
affiliation: 4D Molecular Therapeutics
name: Schonmei Lee, MD
role: STUDY_DIRECTOR
References: