Study to Evaluate the Efficacy Safety and Tolerability of Ultevursen in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (Sirius)

NCT05158296 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: PQ-421a-0032021-002729-74
• Study Type: interventional
• Target: 7
• Locations: 4 countries
• Sites: 15

Brief Summary

The purpose of this study is to evaluate the efficacy safety and tolerability of ultevursen 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; Sirius; IVT; mutations in exon 13 of the USH2A gene; NSRP; Non-Syndromic RP; Inherited Retinal Disorders; Usher Syndrome; Intravitreal Injection; ultevursen

Outcome Measures

Primary Outcomes (1)

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

  Mean change from baseline in best corrected visual acuity(BCVA) based on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart

  18 months of treatment versus sham-procedure

Secondary Outcomes (9)

• Proportion of Patients Who Maintain Vision Defined by BCVA Loss Less Than 15 Letters (ETDRS)

  27 months

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

  27 months

• Change From Baseline in Ellipsoid Zone (EZ) Area and Width as Imaged by Spectral Domain Optical Coherence Tomography (SD-OCT)

  27 months

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

  27 months

• Change From Baseline in Microperimetry

  27 months

Study Arms (3)

Ultevursen 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: Ultevursen

Ultevursen 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: Ultevursen

Sham-procedure

SHAM COMPARATOR

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

Other: Sham-procedure

Interventions

Ultevursen DRUG

RNA antisense oligonucleotide for intravitreal injection

Also known as: RNA antisense oligonucleotide for intravitreal injection

Ultevursen 180/60 µg; Ultevursen 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. The lower age limit for pediatric populations is subject to local regulatory and ethics committee requirements.
• 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 between ≥30 and ≤68 letters (approximate Snellen equivalent 20/250 - 20/50) in the treatment eye using the mean BCVA reading at screening. Subjects with a mean BCVA between \>68 and ≤73 letters will be allowed with documented historic evidence of a BCVA equivalent decline of \>5 letters in both eyes.
• BCVA between ≥30 and ≤73 letters (approximate Snellen equivalent 20/250 - 20/40) in the contralateral eye (CE), using the mean BCVA reading at Screening.
• A difference in mean BCVA readings at Screening between the TE and CE of
• ≤10 letters (based on ETDRS). BCVA differences between eyes that are greater than 10 letters may be allowed however, the Investigator should discuss the case with the Medical Monitor.
• Stable BCVA in the TE and CE, defined as 2 separate BCVA measurements at Screening that fall within ≤ 5 letters for each respective eye.
• A visible EZ layer on SD-OCT in the TE, as determined by 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 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 in both eyes, 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 (in either eye) 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). 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 either 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 or planned intraocular surgery or procedure in either eye during the course of the study. For YAG laser treatment of a posterior capsular opacity, receipt within 1 month prior to Screening or planned procedure in either eye during the course of the study.
• A history of glaucoma or an IOP greater than 21 mmHg in either eye that is not controlled with medication or surgery. IOP measurements between 21 and 24 mmHg may be allowed however, the Investigator should discuss the case with the Medical Monitor.
• 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 (15)

Shiley Eye Institute - UC San Diego

San Diego, California, 92093-0946, United States

Location

University of California, San Francisco

San Francisco, California, 94158, United States

Location

University of Miami, Bascom Palmer Eye Institute

Miami, Florida, 33136, United States

Location

Emory Eye Center

Atlanta, Georgia, 30322, United States

Location

Wilmer Eye Institute, Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

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

Columbia University

New York, New York, 10032, United States

Location

Retina Foundation of the Southwest

Dallas, Texas, 75231, United States

Location

University of Wisconsin - Madison

Madison, Wisconsin, 53705, United States

Location

Universitaetsklinikum Tuebingen Department für Augenheilkunde

Tübingen, 72076, Germany

Location

RadboudUMC

Nijmegen, 6525 GA, Netherlands

Location

Het Oogziekenhuis Rotterdam

Rotterdam, 3011 BH, Netherlands

Location

Oxford Eye Hospital

Headington, Oxford, OX3 9DU, United Kingdom

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 Medical Monitor

  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: Double-masked, randomized, controlled, multiple-dose study. Subjects will be randomized to one of three treatment groups: 1. Group 1: Ultevursen 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: Ultevursen 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: December 15, 2021
• Study Start: December 8, 2021
• Primary Completion: October 12, 2022
• Study Completion: October 12, 2022
• Last Updated: July 12, 2024
• Results First Posted: July 12, 2024

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1); GB (2); US (10); NL (2)