Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene

NCT03780257 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: PQ-421a-0012018-002433-38
• Study Type: interventional
• Target: 20
• Locations: 3 countries
• Sites: 7

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of QR-421a administered via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations in exon 13 of the USH2A gene.

Conditions

Retinitis Pigmentosa; Usher Syndrome Type 2; Deaf Blind; Retinal Disease; Eye Diseases; Eye Diseases, Hereditary; Eye Disorders Congenital; Vision Disorders

Keywords

Retinitis Pigmentosa; USH2A; RP; exon 13; RNA therapies; antisense oligonucleotide; exon skipping; STELLAR; IVT; mutations in exon 13 of the USH2A gene; NSRP

Outcome Measures

Primary Outcomes (2)

• Incidence and severity of ocular adverse events (AEs) in the treatment and contralateral eye

  Incidence and severity of ocular AEs

  24 months

• Incidence and severity of non-ocular AEs

  Incidence and severity of non-ocular AEs

  24 months

Secondary Outcomes (15)

• Change in DAC perimetry

  24 months

• Change in static perimetry

  24 months

• Change in EZ area by SD-OCT

  24 months

• Change in BCVA

  24 months

• Change in LLVA

  24 months

Study Arms (2)

QR-421a

EXPERIMENTAL

Single dose administration

Drug: QR-421a

Sham-procedure (dose cohort 1&2 only)

SHAM COMPARATOR

Sham-procedure (no experimental drug administered)

Other: Sham-procedure (dose cohort 1&2 only)

Interventions

QR-421a DRUG

RNA antisense oligonucleotide for intravitreal injection

Also known as: RNA antisense oligonucleotide for intravitreal injection

QR-421a

Sham-procedure (dose cohort 1&2 only) OTHER

Sham-procedure (no experimental drug administered)

Also known as: Sham-procedure

Sham-procedure (dose cohort 1&2 only)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, ≥ 18 years of age.
• Clinical presentation consistent with RP with Usher syndrome type 2 or non-syndromic RP (NSRP), based on ophthalmic, audiologic, and vestibular examinations.
• A molecular diagnosis of homozygosity or compound heterozygosity for 1 or more pathogenic exon 13 mutations in the USH2A gene, based on genetic analysis upon Sponsor approval.
• Impairment of VF in the opinion of the Investigator, as determined by perimetry, with a continuous area of central field greater than or equal to 10 degrees diameter in any axis in the treatment eye, and evidence of functioning rods.
• Willing and able to comply with the protocol, follow study instructions, attend study visits as required and complete all study assessments.
• Willing and able to provide informed consent for participation prior to performing any study related procedures, and suitable verbal, auditory, written and/or tactile sign language communication as to allow informed consent to be obtained, in the opinion of the Investigator.
• No limitations to SD-OCT image collection that would prevent high quality, reliable images from being obtained in both eyes as determined by the investigator.
• Reliable perimetry measurements in both eyes, as described in the Imaging Manual and determined by the Investigator.
• Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as assessed by the Investigator.

You may not qualify if:

• Presence of additional non-exon 13 USH2A pathogenic mutation(s) on the USH2A allele carrying the exon 13 mutation in subjects who are compound heterozygous for mutations in exon 13.
• Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who are homozygous for mutations in exon 13.
• Presence of pathogenic mutations in genes (other than the USH2A gene) associated with Usher syndrome Type 2 or NSRP, or other inherited retinal degenerative diseases or syndromes.
• Presence of any significant ocular or non-ocular disease/disorder (or medication and/or 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. This includes but is not limited to a subject who: 1) is not an appropriate candidate for antisense oligonucleotide treatment, 2) has cystoid macular edema (CME) in the treatment eye. CME is permissible if stable for 3 months (with or without treatment). Past CME is permissible if resolved for more than 1 month.
• History or presence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye.
• Presence of any active ocular infection in either eye.
• Presence of any of the following lens opacities in the treatment eye: cortical opacity ≥ +2, posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 1) clinically significant in the opinion of the Investigator, 2) would adequately prevent clinical and photographic evaluation of the retina.
• History of amblyopia in the treatment eye.
• Worse than 6 diopters myopia in the treatment eye.
• Receipt within 3 months prior to Screening of any intraocular or periocular surgery (including refractive surgery), or an IVT injection or planned intraocular surgery or procedure during the course of the study.
• A history of glaucoma or an IOP greater than 24 mmHg in either eye that is not controlled with medication or surgery at the time of informed consent.
• Use of any investigational drug or device within 90 days or 5 half-lives preceding the first dose of study medication, whichever is longer, or plans to participate in another study of an investigational drug or device during the PQ-421a-001 study period.
• Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease.
• History of malignancy within 5 years prior to Screening, except adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
• Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.

Sponsors & Collaborators

• ProQR Therapeutics: lead

Study Sites (7)

Center for Clinical Research Operations, Massachusetts Eye and Ear

Boston, Massachusetts, 02114, United States

Location

University of Michigan, Kellogg Eye Center

Ann Arbor, Michigan, 48105, United States

Location

Casey Eye Institute, Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Retina Foundation of the Southwest

Dallas, Texas, 75231, United States

Location

Centre for Innovative Medicine, Department of Paediatric Surgery, Montreal Children's Hospital at the McGill University Health Centre

Montreal, H4A 3J1, Canada

Location

Hôpital Gui de Chauliac - CHRU de Montpellier - Maladies Sensorielles Génétique

Montpellier, 34295, France

Location

Centre de maladies rares CHNO des Quinze Vingts

Paris, 75012, France

Location

Related Publications (2)

• Chan CM, Tan TE, Jain K, Bylstra Y, Mathur RS, Tang RWC, Lee BJH, Jamuar SS, Kam S, Vithana EN, Lim WK, Fenner BJ. RETINITIS PIGMENTOSA ASSOCIATED WITH THE EYS C2139Y VARIANT : An Important Cause of Blindness in East Asian Populations. Retina. 2023 Oct 1;43(10):1788-1796. doi: 10.1097/IAE.0000000000003874.

  PMID: 37418643 DERIVED

• Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27.

  PMID: 31215818 DERIVED

MeSH Terms

Conditions

Retinitis Pigmentosa; Usher Syndromes; Retinal Diseases; Eye Diseases; Eye Diseases, Hereditary; Eye Abnormalities; Vision Disorders

Interventions

Intravitreal Injections

Condition Hierarchy (Ancestors)

Retinal Dystrophies; Retinal Degeneration; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Hearing Loss, Sensorineural; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Blindness; Abnormalities, Multiple; Congenital Abnormalities; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Injections, Intraocular; Injections; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• ProQR Medical Monitor

  ProQR Therapeutics

  STUDY DIRECTOR

• ProQR Clinical Trial Manager

  ProQR Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 19, 2018
• Study Start: March 6, 2019
• Primary Completion: October 14, 2021
• Study Completion: October 14, 2021
• Last Updated: April 20, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); CA (1); FR (2)