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

A Two-Year Double-masked, Randomized, Sham-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Estimated): 81
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, B-9000
    • Ghent University Hospital
• Brazil
  • Belo Horizonte, Brazil, 30150270
    • INRET Clínica/ Santa Casa de Misericórdia de Belo Horizonte
  • São Paulo, Brazil, 04021-001
    • Federal University of São Paulo - Hospital São Paulo (UNIFESP-HSP)
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1E8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H4A3J1
      • McGill University Health Centre for Innovative Medicine
• Denmark
  • Glostrup Municipality, Denmark, 2600
    • Rigshospitalet and University of Copenhagen
• France
  • Montpellier, France, 34295
    • Hôpital Gui de Chauliac - CHRU de Montpellier - Maladies Sensorielles Génétique
  • Paris, France, 75012
    • Centre de maladies rares CHNO des Quinze Vingt
• Germany
  • Tübingen, Germany, 72076
    • Universitatsklinikum Tubingen
• Italy
  • Milan, Italy, 20142
    • ASST Santi Paolo e Carlo Hospital, University of Milan
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam University Medical Center - Locatie AMC
  • Nijmegen, Netherlands, 6525 GA
    • Radboud Universitair Medisch Centrum
  • Rotterdam, Netherlands, 3011 BH
    • Het Oogziekenhuis Rotterdam
• United Kingdom
  • Edinburgh, United Kingdom, EH39HA
    • University of Edinburgh / NHS Lothian
  • London, United Kingdom, EC1V 2PD
    • Moorfields Eye Hosptial
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 9DU
      • Oxford Eye Hospital
• United States
  • California
    • San Francisco, California, United States, 94143
      • The University of California, San Francisco
  • Florida
    • Miami, Florida, United States, 33136
      • Bascom Palmer Eye Institute/University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Eye and Ear
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan- Kellogg Eye Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute, Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Scheie Eye Institute
  • Texas
    • Dallas, Texas, United States, 75231
      • Retina Foundation of the Southwest
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin- Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham Procedure; Sham-procedure (no experimental drug administered)	Other: No intervention, will not receive any active study intervention; Sham-procedure (no experimental drug administered)
Experimental: Ultevursen 180/60 μg; 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).	Drug: Intravitreal Injection of Ultevursen; Up to 4 doses over a 24-month period

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 low luminance visual acuity (LLVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart		Month 24
Change from baseline in best-corrected visual acuity (BCVA) using the ETDRS chart		Month 24
Percent change from baseline in EZ area by SD-OCT		Month 24
Percent change from baseline in EZ width by SD-OCT		Month 24
Change from baseline in the Michigan Retinal Degeneration Questionnaire (MRDQ) for subjects ≥13 years of age	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.	Month 24
Change from baseline in the Michigan Vision-Related Anxiety Questionnaire (MVAQ) for subjects ≥13 years of age	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.	Month 24
Frequency and severity of ocular and non-ocular adverse events (AEs)		Up to month 24
Systemic Exposure	Systemic serum concentration of ultevursen	Up to month 24

Collaborators and Investigators

• Sponsor: Laboratoires Thea
• Collaborators: Sepul Bio

Publications and helpful links

General Publications

• Stephenson KAJ, Dhanji SR, Kolawole OU, Gregory-Evans CY, Gregory-Evans K. Ethnic disparities in inherited retinal degenerations. Can J Ophthalmol. 2025 Dec;60(6):e869-e878. doi: 10.1016/j.jcjo.2025.04.007. Epub 2025 Jun 6.

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2024
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: September 25, 2024
• First Submitted That Met QC Criteria: October 2, 2024
• First Posted (Actual): October 4, 2024

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: RP; Retinitis Pigmentosa; USH2A; RNA therapies; antisense oligonucleotide; exon skipping; IVT; NSRP; Deaf Blind; Usher Syndrome Type 2; Exon 13; LUNA
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Eye Diseases; Congenital Abnormalities; Otorhinolaryngologic Diseases; Sensation Disorders; Abnormalities, Multiple; Ear Diseases; Retinal Dystrophies; Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Hearing Loss, Sensorineural; Blindness; Retinal Degeneration; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Retinal Diseases; Usher Syndromes; Retinitis Pigmentosa; Vision Disorders; Eye Diseases, Hereditary; Eye Abnormalities
• Other Study ID Numbers: SB-421a-006; 2024-515199-10-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No