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

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]

Decision date (initial)

2025-03-24

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Laboratoires THEA

External identifiers

EU CT number

2024-515199-10-00

ClinicalTrials.gov

NCT05158296

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

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 (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.
2. 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 EZ width of ≥2.5 mm in both horizontal and vertical scans in both eyes as measured by SD-OCT and 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 >4 decibels (dB) and <25 dB measured by a V4e target size in the TE.
8. Mean sensitivity >2 dB as determined by MP in the TE.
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 eligibility of the subject will be determined in consultation with the Medical Monitor.
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. If this is not present, the Investigator should discuss the case with the Medical Monitor to decide whether it is appropriate for the subject to participate in the study. 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 or vertical width are outside the field of the SD-OCT 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 and with concurrence of the Medical Monitor, 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) topical or systemic carbonic anhydrase inhibitor treatment 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. Receipt of any prior intraocular or periocular surgery or planned intraocular surgery or procedure during the study. Subjects may be considered for inclusion if there are no clinically significant complications of surgery present and following approval by the Medical Monitor.
9. Receipt of any IVT injection prior to study entry. However, subjects who have received a prior IVT injection may be considered for inclusion following approval by the Medical Monitor.
10. History or presence of ocular herpetic disease (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye.
11. 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.
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 90 days or 5 half-lives of Day 1, whichever is longer, or plans to participate in another study of a drug or device during the study.
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 intermittent use of topical steroids may be considered for inclusion following approval by the Medical Monitor.
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, and aminoglycosides).
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 15

1. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Change in retinal sensitivity measured by static perimetry (SP) with topographic analysis (Hill of Vision [HoV])
2. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Change in retinal sensitivity measured by microperimetry (MP) with topographic analysis (HoV)
3. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Change from baseline in retinal sensitivity in a pre-specified area with at least 5 loci
4. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Change from baseline in low luminance visual acuity (LLVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart
5. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Change from baseline in best-corrected visual acuity (BCVA) using the ETDRS chart
6. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Percent change from baseline in EZ area by SD-OCT
7. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Percent change from baseline in EZ width by SD-OCT
8. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Annualized percent change from baseline in EZ area by SD-OCT
9. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Change from baseline in virtual visual maze performance score using Mobility Standardized Test in Virtual Reality (MOSTVR) (applicable for sites with ability to conduct the assessment)
10. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: Change from baseline in dark-adapted full-field stimulus threshold (FST) testing
11. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: 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
12. Efficacy: The following endpoints will be evaluated at Months 12 and 24, unless otherwise specified: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
13. Safety and Tolerability: Frequency and severity of ocular and non-ocular adverse events (AEs)
14. Safety and Tolerability: Incidence of anti-drug antibodies (ADAs) against ultevursen
15. 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

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Results and documents

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

Documents 37 files

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

Application history

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