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

• ClinicalTrials.gov Identifier: NCT04517149
• Recruitment Status: Active, not recruiting
• First Posted: August 18, 2020
• Last Update Posted: January 31, 2023
• Sponsor: 4D Molecular Therapeutics
• Information provided by (Responsible Party): 4D Molecular Therapeutics

Tracking Information

• First Submitted Date: August 14, 2020
• First Posted Date: August 18, 2020
• Last Update Posted Date: January 31, 2023
• Actual Study Start Date: June 9, 2020
• Estimated Primary Completion Date: June 2026 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: December 20, 2022): Incidence and severity of TEAEs and serious adverse events (SAEs), including clinically significant changes in safety parameters [ Time Frame: 24 months to 60 Months ]

Original Primary Outcome Measures (submitted: August 14, 2020)

Incidence and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) [ Time Frame: 24 months ]

Incidence and severity of TEAEs and SAEs, including clinically significant changes in safety parameters.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: X-Linked Retinitis Pigmentosa

Intervention

• 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

Study Arms

• 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.

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 30, 2023): 21
• Original Estimated Enrollment (submitted: August 14, 2020): 37
• Estimated Study Completion Date: May 2029
• Estimated Primary Completion Date: June 2026 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04517149
• Other Study ID Numbers: 4D-125-C001
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: 4D Molecular Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: 4D Molecular Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Schonmei Lee, MD; 4D Molecular Therapeutics

• PRS Account: 4D Molecular Therapeutics
• Verification Date: January 2023