A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene

Study Overview
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Brief Summary
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This study evaluates the safety, tolerability and efficacy of QR-1123 injection in the eye (intravitreal; IVT) injections (one eye/unilateral) in subjects receiving a single dose or repeat doses. Single injections will be assessed in an open label way, and repeat injections will be assessed in a double-masked, randomized, sham-controlled fashion.

Detailed Description
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QR-1123 is an antisense oligonucleotide, designed to specifically target the mutant P23H messenger ribonucleic acid (mRNA) in order to reduce the expression of the P23H protein selectively, while preserving expression of the wild type (WT) rhodopsin (RHO) protein. It is hypothesized that the reduction of mutant P23H mRNA will reduce the deleterious effects of the dominant-negative protein and should result in increased function of WT rhodopsin protein in photoreceptors. Restoration of WT RHO function is expected to improve vision in patients with adRP due to the P23H mutation. The study will comprise up to 8 single dose and repeat dose cohorts. Prior to initiating a higher single dose cohort and/or prior to initiating repeat dose cohort(s), available safety and efficacy data will be reviewed by the DMC. In the single dose cohorts subjects will receive a single, unilateral IVT injection of QR-1123 in an open label fashion. In the repeat dose cohorts subjects will be randomized to receive either a unilateral IVT injection of QR-1123 every 3 months or a unilateral sham procedure every 3 months, in a double masked fashion. Subjects will be followed for safety, tolerability and efficacy for a total period of 12 months.

Official Title
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A Prospective First-In-Human Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa (adRP) Due to the P23H Mutation in the RHO Gene

Conditions
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Autosomal Dominant Retinitis Pigmentosa, Eye Diseases, Eye Diseases, Hereditary, Retinal Dystrophies, Retinal Disease, Retinitis, Vision Tunnel, Vision Disorders

Intervention / Treatment
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* Drug: QR-1123
* Other: Sham procedure


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Male or female, ≥ 18 years of age. Clinical presentation consistent with adRP, based on ophthalmic examinations. Impairment on VF in the opinion of the Investigator, as determined by perimetry. A molecular diagnosis of autosomal dominant form of RP with the P23H mutation in the RHO gene, based on genetic analysis. A clear ocular media and adequate pupillary dilation to permit good quality fundus imaging, as assessed by the Investigator. Main Exclusion Criteria: Presence of additional pathogenic mutations in genes (other than the P23H mutation in the RHO gene) associated with inherited retinal degenerative diseases or syndromes, based on genetic analysis (eg, Usher syndrome, Leber congenital amaurosis, etc). Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities) which, in the opinion of the Investigator and with concurrence of the Medical Monitor, may either put the subject at risk because of participation in the study, may influence the results of the study, or the subject's ability to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QR-1123 Single dose - dose level 1<br>Open label Single dose cohort: dose level 1 | Drug: QR-1123<br>* unilateral IVT injection<br>|
| Experimental: QR-1123 Single dose - dose level 2<br>Open label Single dose cohort: dose level | Drug: QR-1123<br>* unilateral IVT injection<br>|
| Experimental: QR-1123 Single dose - dose level 3<br>Open label Single dose cohort: dose level 3 | Drug: QR-1123<br>* unilateral IVT injection<br>|
| Experimental: QR-1123 Single dose - dose level 4<br>Open label Single dose cohort: dose level 4 | Drug: QR-1123<br>* unilateral IVT injection<br>|
| Experimental: QR-1123 Single dose - dose level 5<br>Open label Single dose cohort: dose level 5 | Drug: QR-1123<br>* unilateral IVT injection<br>|
| Experimental: Repeat dose cohort 1<br>Double-masked, randomized, sham controlled, Repeat dose cohort. Dose levels will be determined following DMC review of obtained safety and efficacy data. | Drug: QR-1123<br>* unilateral IVT injection<br>Other: Sham procedure<br>* Sham procedures (i.e. no penetration of the globe) closely mimic the active injection and serve to mask subjects to treatment assignment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of ocular AEs | Incidence and severity of ocular adverse events scored based on CTCAC in the study and fellow eye | up to 12 months | 
| Incidence and Severity of non-ocular AEs | Incidence and severity of non-ocular adverse events scored based on CTCAC in the study and fellow eye | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in BCVA | Changes in Best corrected visual acuity (BCVA) | up to 12 months | 
| Changes in LLVA | Changes in Low-luminance visual acuity (LLVA) | up to 12 months | 
| Changes in DAC perimetry | Changes in Dark adapted chromatic (DAC) perimetry | up to 12 months | 
| Changes in Static VF | Changes in Static VF (Visual Field) | up to 12 months | 
| Changes in Microperimetry | Changes in Microperimetry | up to 12 months | 
| Changes in SD-OCT | Changes in Spectral Domain-Optical Coherence Tomography | up to 12 months | 
| Changes in FST | Changes in Full-field Stimulus Threshold (FST) | up to 12 months | 
| Changes in Full-field ERG | Changes in Full-field Electroretinogram (ERG) | up to 12 months | 
| Assessment of systemic exposure after treatment with QR-1123 | Serum levels of QR-1123 | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adRP, Retinitis Pigmentosa, P23H mutation, Rhodopsin, antisense oligonucleotide, IVT, autosomal dominant