ATSN-201 Gene Therapy in RS1-Associated X-linked Retinoschisis

Official title

A Phase 1/2/3, Open-Label, Dose Escalation, Dose Expansion and Randomized, Controlled Study to Evaluate the Safety and Efficacy of ATSN-201 Gene Therapy in Subjects With RS1-Associated X-linked Retinoschisis (LIGHTHOUSE)

Overview

This study will evaluate the safety and efficacy of ATSN-201 in subjects ≥ 6 years of age with RS1-associated X-linked retinoschisis (XLRS).

Detailed description

The study is designed in three parts: a dose escalation phase (Part A), a dose expansion phase (Part B) and a randomized, controlled phase (Part C).

In Part C of the study, eligible patients who enroll in this study will be randomly assigned to be treated with ATSN-201 or to have no treatment; subjects assigned to ATSN-201 will receive the drug as a one-time subretinal injection of ATSN-201 in one eye or both eyes, depending on whether only one or both eyes meet criteria for treatment. Subjects will have regular assessments for 1 year as part of the Main Study Period and additional assessments over the next 4 years as part of the Extension Study Period.

Subjects who do not receive treatment as part of the control group can choose to receive ATSN-201 in one or both eyes after the 1-year Main Study Period if eligible.

Interventions

• Biological ATSN-201
  AAV.SPR-hGRK1-hRS1syn

Primary outcome measures

• Part A (Dose Escalation) and Part B (Dose Expansion): Safety and tolerability as assessed by dose-limiting toxicities and treatment-emergent adverse events [Time frame: From baseline to week 52]
• Part C (Phase 3, Randomized, Controlled) Effect of ATSN-201 on visual function. [Time frame: From baseline to week 52]

Secondary outcome measures (12)

• Part A and Part B: Visual acuity as assessed by best-corrected visual acuity [Time frame: From baseline to week 52]
• Part A and Part B: Visual acuity as assessed by low-luminance visual acuity [Time frame: From baseline to week 52]
• Part A and Part B: Visual function as assessed by contrast sensitivity [Time frame: From baseline to week 52]
• Part A and Part B: Visual function as assessed by microperimetry [Time frame: From baseline to week 52]
• Part A and Part B: Macular structure as assessed by spectral domain optical coherence tomography [Time frame: From baseline to week 52]
• Part A and Part B: Macular structure as assessed by fundus autofluorescence [Time frame: From baseline to week 52]
• Part A and Part B: Subject-reported visual function as assessed by the NEI VFQ-25 in adult subjects [Time frame: From baseline to week 52]
• Part A and Part B: Subject-reported visual function as assessed by the CVAQC in pediatric subjects [Time frame: From baseline to week 52]
• Part A and Part B: Subject-reported visual function as assessed by the MRDQ in subjects 13 years of age or greater. [Time frame: From baseline to week 52]
• Part C: Macular structure as assessed by spectral domain optical coherence tomography [Time frame: From baseline to week 52]
• Part C: Visual acuity as assessed by best-corrected visual acuity or low-luminance visual acuity [Time frame: From baseline to week 52]
• Part C: Visual acuity as assessed by best-corrected visual acuity as measured by Early Treatment Diabetic Retinopathy Study chart [Time frame: From baseline to week 52]

Eligibility criteria

Part A and B:

Inclusion criteria

• Age ≥ 18 for Cohorts 1 through 4, and age ≥ 6 years and < 18 years for Cohort 5.
• Male patients with clinical diagnosis of XLRS caused by mutations in RS1.
• Best corrected visual acuity (BCVA) in study eye of 34 to 73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (corresponding to a Snellen acuity of 20/200 to 20/40).
• Presence of foveal schisis and /or parafoveal/perifoveal schisis in the study eye on SD-OCT per the Principal Investigator.

Exclusion criteria

• Pre-existing eye conditions in the study eye that would contribute significantly to an increased risk of visual loss from a subretinal injection (eg, advanced glaucoma, optic neuropathy, uveitis, corneal transplants).
• Any intraocular surgery (including laser treatment) in the study eye within 6 months prior to Screening or any intraocular surgery anticipated in the study eye during the first 12 months of the study.
• Treatment in a prior ocular gene or cell therapy study.

Part C:

Inclusion criteria

Note: For patients ineligible for bilateral dosing based on the ocular exclusion criteria, the same eye must meet all ocular inclusion criteria, but none of the ocular exclusion criteria, to be eligible for unilateral dosing.

General All of the following criteria must be met for unilateral or bilateral dosing.

• Age ≥ 6 years.
• Genetically male patients with clinical diagnosis of XLRS caused by pathogenic or likely pathogenic mutations in RS1 OR Genetically female patients with clinical diagnosis of XLRS caused by biallelic pathogenic or likely pathogenic mutations in RS1.

Ocular At least 1 eye must meet all of the following criteria for both unilateral and bilateral dosing.

• BCVA of 34 to 73 ETDRS letters (corresponding to a Snellen acuity of 20/200 to 20/40).
• Presence of foveal schisis on SD-OCT.

Exclusion criteria

General None of the following criteria can be met for unilateral or bilateral dosing.

• Treatment with any carbonic anhydrase inhibitor (oral or topical) within 1 month prior to Screening.
• Treatment in a prior ocular gene or cell therapy study.
• Absence of macular schisis.
• BCVA better than 75 ETDRS letters (corresponding to a Snellen acuity of 20/32).
• Pre-existing eye conditions that would contribute significantly to an increased risk of visual loss from a subretinal injection (eg, advanced glaucoma, optic neuropathy, uveitis, corneal transplants).
• Any intraocular surgery (including laser treatment) within 6 months prior to Screening or any intraocular surgery anticipated during the first 12 months of the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 18 centers

• Associated Retina Consultants — Phoenix
• Shiley Eye Institute — La Jolla
• Children's Hospital of Los Angeles — Los Angeles
• Stanford University — Palo Alto
• UC San Francisco — San Francisco
• Bascom Palmer Eye Institute — Miami
• Massachusetts Eye and Ear — Boston
• Boston Children's Hospital — Boston
• … and 10 more centers

United Kingdom · 1 center

• Oxford Eye Hospital — Oxford

Identifiers

NCT: NCT05878860 · ATSN-201-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗