A 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Laboratoires Thea

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Eye Diseases [C11]

Trial duration

29 Sep 2025 → ongoing

Decision date (initial)

2025-08-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Laboratoires THEA

External identifiers

EU CT number

2024-515199-10-01

ClinicalTrials.gov

NCT06627179

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate efficacy after 24 months of treatment

Secondary objectives 3

1. To evaluate efficacy of other endpoints and/or timepoints
2. To evaluate safety and tolerability
3. To evaluate systemic exposure of ultevursen

Conditions and MedDRA coding

Retinitis Pigmentosa

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. An adult (≥18 years) willing and able to provide informed consent for participation prior to performing any study related procedures OR A minor (12 to <18 years) able to provide age-appropriate assent for study participation with a parent(s) or legal guardian(s) willing and able to provide written permission for the subject’s participation prior to performing any study related procedures
2. Adult willing to comply with the protocol, follow the study instructions, attend study visits as requested, and accept and be able to undergo all study assessments, in the opinion of the investigator.
3. Both eyes present a clinical picture compatible with retinitis pigmentosa (RP) involving a type 2 Usher syndrome or non-syndromic RP according to ophthalmological, audiological, or vestibular examinations. During selection, the investigator will make a clinical diagnosis of 'type 2a Usher syndrome,' 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. MCVA ≥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 >4 decibels (dB) and <25 dB measured by a V target size in the TE at screening (see footnote o in Table 1-1 for more details on subjects who require N-acetylcysteine [NAC] washout).
8. Mean sensitivity >2 dB as determined by MP in the TE at screening (see footnote o in Table 1-1 for more details on subjects who require NAC washout).
9. 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.
10. During the screening period, the difference of BCVA letters (based on ETDRS) from 2 measurements taken separately will need to be within 10 letters. After 3 attempts of the BCVA measurement, if a reliable baseline cannot be obtained, the subject is ineligible.
11. 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. For purposes of determining symmetry, the mean BCVA for each eye will be calculated using all BCVA measures obtained during the screening period.
12. At screening, reliable measurements in MP and SP as described in the Study Reference Manual.
13. No visually significant ocular media opacities and adequate pupillary dilation to permit good quality retinal visibility or imaging in either eye, as assessed by the Investigator.
14. Non-pregnant and non-breastfeeding subjects. Women of childbearing potential (WOCBP) and fertile males must comply with using highly effective methods of contraception (see Section 14.2 for definitions of WOCBP and fertile males and details on highly effective contraception methods). Women of non-childbearing potential may be included without the use of adequate birth control, provided they meet the entry criteria for the study.

Exclusion criteria 20

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. Any contraindication to IVT injection according to the Investigator’s clinical judgment and the American Academy of Ophthalmology (Avery 2014). This includes any active or suspected intraocular inflammation or active or suspected ocular or periocular infection in either eye.
5. At screening, the EZ horizontal width is outside the field of the SDOCT scan based on the assessment of the CRC
6. 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.
7. 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.
8. 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.
9. Receipt of any IVT injection prior to study entry.
10. History or presence of ocular herpetic disease (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye.
11. Presence of any of the following lens opacities in the TE based on the Age-Related Eye Disease Study (AREDS) lens grading scale: 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. Subjects should not be entered into the study if there is likelihood they will require cataract surgery in the TE during the study.
12. History of amblyopia in the TE that has resulted in vision loss, in the opinion of the Investigator.
13. Presence of significant keratopathy or any other media or corneal opacity that would cause scattering of light or alter visual function, especially in low luminance conditions in the TE.
14. A history of glaucoma or an IOP greater than 24 mmHg in the TE that is not controlled with medication or surgery at the time of informed consent.
15. Use of any investigational drug or device within 3 months or 5 halflives of Day 1, whichever is longer, or plans to participate in another study of a drug or device during the study. However, for those subjects in NAC trials or taking over-the-counter supplements containing NAC at screening, SP and MP eligibility must be reverified at baseline following a minimum of 3 months of NAC washout prior to randomization (refer to Table 1-1)
16. Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.
17. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
18. Current chronic treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to steroid implants, chronic systemic steroids, cytostatics, interferons, tumor necrosis factor (TNF)-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). Subjects who have been treated on a short course of systemic steroids within the past 12 months or who require the use of topical steroids may be considered for inclusion
19. Current use of medications known to be toxic to the lens, retina, or optic nerve (e.g., deferoxamine, chloroquine/hydroxychloroquine [Plaquenil®], tamoxifen, phenothiazines, ethambutol, digoxin, pentosan polysulfate sodium, and amiodarone).
20. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Annualized percent change from baseline in EZ width as measured by spectral-domain optical coherence tomography (SD-OCT) up to Month 24.

Secondary endpoints 12

1. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: (Annualized) change from baseline in static perimetry (SP) mean sensitivity
2. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: (Annualized) change from baseline in microperimetry (MP) mean sensitivity
3. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: (Annualized) change from baseline in retinal sensitivity in at least 5 pre-specified loci in SP
4. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: (Annualized) change from baseline in retinal sensitivity in at least 5 pre-specified loci in MP
5. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: (Annualized) change from baseline in low luminance visual acuity (LLVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart
6. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: (Annualized) change from baseline in best-corrected visual acuity (BCVA) using the ETDRS chart
7. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: (Annualized) percent change from baseline in EZ area by SDOCT
8. Efficacy: The following endpoints will be evaluated at Months 12 and 24, and as annualized change with data up to 24 months, unless otherwise specified: Percent change from baseline in EZ width by SD-OCT
9. Efficacy: Evaluated at Months 12 and 24, and as annualized change with data up to 24 months: (Annualized) change from baseline in each domain of the following PROs (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
10. Efficacy: Evaluated at Months 12 and 24, and as annualized change with data up to 24 months: (Annualized) change from baseline in each domain of the following PROs (for subjects ≥13 years of age): Michigan Vision-Related Anxiety Questionnaire (MVAQ) scores in rod-function anxiety and cone-function anxiety
11. Safety and Tolerability: Frequency and severity of ocular and non-ocular adverse events (AEs)
12. Systemic Exposure: Systemic serum concentration of ultevursen.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Laboratoires Thea

Sponsor organisation

Laboratoires Thea

Address

Zone Industrielle Du Brezet, 12 Rue Louis Bleriot 12 Rue Louis Bleriot

City

Clermont Ferrand

Postcode

63100

Country

France

Scientific contact point

Organisation

Laboratoires Thea

Contact name

Zuhal Butuner

Public contact point

Organisation

Laboratoires Thea

Contact name

Zuhal Butuner

Third parties 1

Locations

6 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 55 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications