Study to Evaluate the Efficacy Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene With Early to Moderate Vision Loss (Celeste)

NCT05176717 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: PQ-421a-0042021-002728-19
• Study Type: interventional
• Target: 5
• Locations: 2 countries
• Sites: 3

Brief Summary

The purpose of this study is to evaluate the efficacy 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 with early to moderate vision loss.

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; Celeste; IVT; mutations in exon 13 of the USH2A gene; NSRP; Intravitreal Injection; Non-Syndromic RP; Inherited Retinal Diseases; Usher Syndrome

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Mean Sensitivity

  Change from baseline in mean sensitivity (based on static perimetry) at 12 months of treatment versus sham-procedure

  12 months

Secondary Outcomes (11)

• Ellipzoid Zone Area (EZ) as Measured by Spectral Domain Optical Coherence Tomography SD-OCT

  27 months

• Change From Baseline in Best Corrected Visual Acuity (BCVA)

  27 months

• Change From Baseline in Spectral Domain Optical Coherence Tomography (SD-OCT) (Other Measures)

  27 months

• Change From Baseline in Low Luminance Visual Acuity (LLVA)

  27 months

• Change From Baseline in Other Measures of Static Perimetry

  27 months

Other Outcomes (1)

• Change From Baseline in Mobility Course Score

  27 months

Study Arms (3)

QR-421a 180/60 µg

EXPERIMENTAL

180 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter

Drug: QR-421a

QR-421a 60/60 µg

EXPERIMENTAL

60 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter

Drug: QR-421a

Sham-procedure

SHAM COMPARATOR

Sham-procedure (no experimental drug administered) on Day 1, Month 3 and every 6 months thereafter

Other: Sham-procedure

Interventions

QR-421a DRUG

RNA antisense oligonucleotide for intravitreal injection

Also known as: RNA antisense oligonucleotide for intravitreal injection

QR-421a 180/60 µg; QR-421a 60/60 µg

Sham-procedure OTHER

Sham-procedure (no experimental drug administered)

Sham-procedure

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, ≥ 18 years of age OR a minor (12 to \< 18 years) with permission from a parent or legal guardian.
• An adult willing to comply with the protocol, follow study instructions, attend study visits as required and willing and able to complete all study assessments. OR A minor able to complete all study assessments and comply with the protocol and has a parent or caregiver willing and able to follow study instructions, and attend study visits with the subject as required.
• Clinical presentation consistent with RP with Usher syndrome type 2 or nonsyndromic form of 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 at screening.
• BCVA better than ≥69 letters (approximate Snellen equivalent 20/40) in the study eye, using the best BCVA reading at Screening.
• Impairment of Visual Field (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 each meridian as measured by a size V4e target, and a mean defect of ≥ 10 dB, in the study eye.
• Clearly visible and measurable ellipsoid zone (EZ) width and/or area on SDOCT, per investigator judgement.
• 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 Best Corrected Visual Acuity (BCVA), perimetry, and other measurements in both eyes, as described in the Study Reference Manual and Imaging Manual and determined by the Investigator.
• No visually significant ocular media opacities 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 have monoallelic exon-13 mutations.
• Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who have biallelic exon 13 mutations.
• 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 has uncontrolled cystoid macular edema (CME) in the study 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 study 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 study eye that resulted in significant vision loss, in the opinion of the Investigator.
• Receipt within 3 months prior to Screening of any intraocular or periocular surgery (including refractive surgery), or an IVT injection other 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.
• 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 course of the study.
• Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease.
• History of malignancy within 2 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.
• Pregnant and breastfeeding subjects. Females of childbearing potential and males must comply with using highly effective methods of contraception as defined in the protocol. Women of non-childbearing potential may be included without the use of adequate birth control.

Sponsors & Collaborators

• Laboratoires Thea: lead
• Sepul Bio: collaborator

Study Sites (3)

Retina Foundation of the Southwest

Dallas, Texas, 75231, United States

Location

University of Wisconsin - Madison

Madison, Wisconsin, 53705, United States

Location

Moorfields Eye Hospital

London, United Kingdom

Location

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

Limitations and Caveats

Study prematurely terminated due to sponsor decision for reasons unrelated to safety

Results Point of Contact

• Title: Zuhal Butuner - Chief Medical Officer
• Organization: Sepul Bio

contact@sepulbio.com

(905) 599-7887

Study Officials

• Sepul Bio Chief Medical Officer

  Sepul Bio

  STUDY DIRECTOR

• Sepul Bio Clinical Operations Director

  Sepul Bio

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Subject, site staff (study coordinator, imaging technician, etc) and Investigator will be completely masked. Physician performing IVT and post-IVT monitoring will know if subject is receiving sham or treatment, but will be masked to the dose level. Pharmacist is the only site staff that will be completely unmasked.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: After primary endpoint is assessed at 12 months, subjects continue the same randomized treatment in the fellow eye. Subjects enrolled to sham treatment will be randomized to receive one of the two ultevursen doses in a parallel design fashion. Double-masked, randomized, controlled, multiple-dose study. Subjects will be randomized to one of three treatment groups: 1. Group 1: QR-421a 180/60 µg (180 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter) 2. Group 2: QR-421a 60/60 µg (60 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter; n = 27) 3. Group 3: Sham-procedure (administered on Day 1, Month 3 and every 6 months thereafter; n = 27)

Study Record Dates

• First Submitted: November 23, 2021
• First Posted: January 4, 2022
• Study Start: December 15, 2021
• Primary Completion: August 2, 2022
• Study Completion: August 2, 2022
• Last Updated: August 7, 2024
• Results First Posted: January 20, 2023

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1); US (2)