Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene

Phase 2

Recruiting

• Conditions: Retinitis Pigmentosa (RP); Usher Syndrome Type 2; Deaf Blind; Retinal Disease; Eye Diseases, Hereditary; Eye Disorders Congenital; Vision Disorders
• Interventions: Drug: Intravitreal Injection of Ultevursen; Other: No intervention, will not receive any active study intervention

• Registration Number: NCT06627179
• Lead Sponsor: Laboratoires Thea

Brief Summary

The purpose of this Phase 2b study is to evaluate the 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. This is a multicenter Double-masked, Randomized, Sham-controlled study which will enroll 81 subjects.

Detailed Description

A total of eighty-one (81) RP subjects will be enrolled in this study, randomized in a 2:1 ratio to either ultevursen or sham procedure, respectively. Subjects randomized to the active treatment group will receive therapy with ultevursen administered via intravitreal (IVT) injection to the treatment eye (TE) on Day 1 and at Months 6, 12, and 18. Subjects randomized to sham will undergo a sham procedure in the TE at the corresponding timepoints.

Study Timeline

• Study First Submitted: 2024-09-25
• Study First Submitted QC: 2024-10-02
• Study First Posted: 2024-10-04
• Study Start: 2024-12-11
• Status Verified: 2025-07
• Last Update Submitted: 2025-08-14
• Last Update Posted: 2025-08-20
• Primary Completion: 2027-12
• Study Completion: 2027-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 81

Inclusion Criteria

1. An adult (≥18 years) willing and able to provide informed consent for participation prior to performing any study related procedures

2. OR A minor (8 to <18 years) able to provide age-appropriate assent for study participation with a parent or legal guardian willing and able to provide written permission for the subject's participation prior to performing any study related procedures. 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, in the opinion of the Investigator.

   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, in the opinion of the Investigator.

3. Both eyes exhibit clinical presentation consistent with RP involving Usher syndrome type 2 or NSRP based on ophthalmic, audiologic, or vestibular examinations. At screening, the Investigator will make the clinical diagnosis of "Usher syndrome type 2a," defined as RP with congenital hearing loss, or "non-syndromic RP," defined as RP without congenital hearing loss.

4. A molecular diagnosis of biallelic disease causing variants (pathogenic or likely pathogenic) in the USH2A gene where at least one of the variants is located on exon 13. A historic genotyping report from a certified laboratory is acceptable with Sponsor approval.

5. Clearly visible and measurable SD-OCT horizontal EZ width of ≥2.2 mm in both eyes based on the assessment of the CRC.

6. BCVA ≥55 letters based on ETDRS (equivalent to 20/80 based on Snellen notation, or logarithm of the minimum angle of resolution [logMAR] +0.6) in both eyes.

7. Impairment of VF as assessed by SP with a mean sensitivity greater than 4 decibels (dB) and less than 25 dB measured by a V target size in the TE at screening.

8. Mean sensitivity greater than 2 dB as determined by MP in the TE at screening.

9. Symmetry of baseline disease in both eyes, defined as the mean BCVA (based on ETDRS) of one eye within ≤10 letters of the mean BCVA of the other eye at screening.

Exclusion Criteria

1. Presence of additional non-exon 13 USH2A pathogenic or likely pathogenic variant on the USH2A allele carrying the exon 13 mutation in subjects who have one exon 13 disease causing variant and one non-exon 13 disease causing variant.
2. Presence of additional non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who have biallelic exon 13 mutations.
3. Presence of pathogenic or likely pathogenic variants in genes (other than the USH2A gene) which are known to be associated with other inherited retinal degenerative diseases or syndromes. Specifically, the presence of homozygous or compound heterozygous known disease-causing mutations in other genes involved in recessive retinal dystrophies, or the confirmed presence of a known single disease-causing variant in genes involved in dominant, X-linked, or mitochondrial retinal dystrophy genes is exclusionary.
4. At screening, the EZ horizontal or vertical width are outside the field of the SD-OCT scan based on the assessment of the CRC.
5. Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities) which, in the opinion of the Investigator may either put the subject at risk because of participation in the study, may impact the subject's ability to participate in the study, or may interfere with assessment of efficacy and safety in the study.
6. Presence of unstable concurrent cystoid macular edema (CME), or subject started on (or changed dose of) any medication for CME in the 3 months prior to enrollment. CME is allowed if stable for 3 months (with or without treatment). However, stable CME that disrupts the EZ width measurement, as determined by CRC, is an exclusion.
7. Any intraocular surgery within 3 months of study entry or any planned intraocular or peri-ocular surgery during the study. Subjects may be eligible after 3 months post-surgery as long as they have fully recovered, in the opinion of the Investigator.
8. Receipt of any IVT injection prior to study entry.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ultevursen 180/60 μg	Intravitreal Injection of Ultevursen	Subjects will receive an intravitreal injection (IVT) of ultevursen with concentrations of 3.6 mg/mL for initial dose and 1.2 mg/mL for maintenance doses every 6 months thereafter through Month 18 (up to 4 doses).
Sham Procedure	No intervention, will not receive any active study intervention	Sham-procedure (no experimental drug administered)
Ultevursen 180/60 μg	Intravitreal Injection of Ultevursen	Subjects will receive an intravitreal injection (IVT) of Ultevursen with concentrations of 3.6 mg/mL for initial dose and 1.2 mg/mL for maintenance doses every 6 months thereafter through Month 18 (up to 4 doses).
Sham Procedure	No intervention, will not receive any active study intervention	Sham-procedure (no experimental drug administered)

Primary Outcome Measures

Name	Time	Method
To evaluate efficacy after 24 months of treatment	24 Months	Annualized percent change from baseline in ellipsoid zone (EZ) width as measured by spectral-domain optical coherence tomography (SD-OCT) up to Month 24.

Secondary Outcome Measures

Name	Time	Method
Annualized change from baseline in static perimetry (SP) mean sensitivity	Month 24
Annualized change from baseline in microperimetry (MP) mean sensitivity	Month 24
Change from baseline in best-corrected visual acuity (BCVA) using the ETDRS chart	Month 24
Change from baseline in low luminance visual acuity (LLVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart	Month 24
Percent change from baseline in EZ width by SD-OCT	Month 24
Percent change from baseline in EZ area by SD-OCT	Month 24
Change from baseline in the Michigan Retinal Degeneration Questionnaire (MRDQ) for subjects ≥13 years of age	Month 24	Michigan Retinal Degeneration Questionnaire (MRDQ) scores in central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity Unabbreviated scale title: Michigan Retinal Degeneration Questionnaire Minimum and Maximum values: -3 and +3 Higher scores indicate a worse outcome.
Change from baseline in the Michigan Vision-Related Anxiety Questionnaire (MVAQ) for subjects ≥13 years of age	Month 24	Michigan Vision-Related Anxiety Questionnaire (MVAQ) scores in rod-function anxiety and cone-function anxiety.; Unabbreviated scale title: Michigan Vision-Related Anxiety Questionnaire Minimum and Maximum values: -3 and +3 Higher scores indicate a worse outcome.
Frequency and severity of ocular and non-ocular adverse events (AEs)	Up to month 24
Systemic Exposure	Up to month 24	Systemic serum concentration of ultevursen

Trial Locations

Locations (14)

Oxford Eye Hospital; 🇬🇧 Headington, Oxford, United Kingdom

Massachusetts Eye and Ear; 🇺🇸 Boston, Massachusetts, United States

University of Michigan- Kellogg Eye Center; 🇺🇸 Ann Arbor, Michigan, United States

Casey Eye Institute, Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

Retina Foundation of the Southwest; 🇺🇸 Dallas, Texas, United States

University of Wisconsin- Madison; 🇺🇸 Madison, Wisconsin, United States

Moorfields Eye Hosptial; 🇬🇧 London, United Kingdom

Massachusetts Eye and Ear; 🇺🇸 Boston, Massachusetts, United States

University of Michigan- Kellogg Eye Center; 🇺🇸 Ann Arbor, Michigan, United States

Casey Eye Institute, Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

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