A Double-Masked, Randomized, Placebo-Controlled, Paired Eye Study to Evaluate the Efficacy, Safety and Tolerability of Sepofarsen in Subjects with Leber Congenital Amaurosis (LCA) due to the c.2991+1655A>G (p.Cys998X) Mutation in the CEP290 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

11 Jul 2025 → ongoing

Decision date (initial)

2025-04-07

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Laboratoires Théa

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate efficacy after 12 months of treatment

Secondary objectives 3

1. To evaluate efficacy as assessed by various visual function measures and patient-reported outcome (PRO) measures
2. To evaluate long-term and sustained efficacy
3. To evaluate safety and tolerability

Conditions and MedDRA coding

Leber congenital amaurosis (LCA)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002717-PIP02-20

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. An adult (≥ 18 years) willing and able to provide informed consent for participation prior to performing any study related procedures OR a minor (6 to < 18 years) 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 and pediatric subjects able to provide age-appropriate assent for study participation
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 (6 to < 18 years) 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. Male or female with a confirmed clinical diagnosis of LCA10 and a molecular diagnosis of homozygosity or compound heterozygosity for the c.2991+1655A>G mutation, based on genotyping analysis at Screening. A historic genotyping report is acceptable with Sponsor approval.
4. BCVA (FrACT) equal to or worse than logMAR +0.4 (approximate Snellen equivalent 20/50) to +2.9 logMAR (this includes counting-finger and hand-motion subjects) based on quantifiable, reliable FrACT. Light perception (LP) subjects can be enrolled only with documented evidence of prior better vision.
5. Symmetrical disease between the two eyes as defined by a BCVA (FrACT) within 0.2 logMAR at baseline.
6. Detectable outer nuclear layer (ONL) in the macular area as determined by the CRC at Screening
7. Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as assessed by the Investigator.
8. Non-pregnant and non-breastfeeding subjects. Women of childbearing potential (WOCBP) and fertile males must comply with using highly effective methods of contraception. 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 16

1. Presence of pathogenic or likely pathogenic autosomal-dominant mutations in genes (other than the CEP290 gene) which are known to be associated with other inherited retinal degenerative diseases or syndromes.
2. Any contraindication to IVT injection according to the Investigator’s clinical judgement and the American Academy of Ophthalmology. This includes any active or suspected intraocular inflammation or active or suspected ocular or periocular infection in either eye.
3. 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.
4. 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).
5. Presence of any ocular pathology in either eye that may make comparison of the eyes not feasible.
6. History or presence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus).
7. Presence of any of the following lens opacities/cataracts 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 imaging evaluation of the retina.
8. Receipt within 1 month prior to Screening of any intraocular or periocular surgery (including refractive surgery), or an IVT injection, or planned intraocular surgery or procedure during the study. Subjects who received an intraocular or periocular surgery between 1 to 3 months prior to Screening, may only be considered for inclusion if there are no clinically significant complications of surgery present, and following approval by the Medical Monitor.
9. History of strabismus causing amblyopia that could cause comparison of visual function between the two eyes unfeasible, as assessed by the Investigator.
10. A history of glaucoma or an IOP greater than 24 mmHg that is not controlled with medication or surgery at the time of informed consent.
11. Use any investigational drug within 5 half-lives, use any investigational device within 90 days of Day 1, or plan to participate in another study of a drug and/or device during the study period.
12. Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.
13. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
14. 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.
15. Current use of medications known to be toxic to the lens, retina, or optic nerve (eg, deferoxamine, chloroquine/hydroxychloroquine [Plaquenil®], tamoxifen, phenothiazines, ethambutol, digoxin, and aminoglycosides).
16. 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. Change from baseline in best-corrected visual acuity (BCVA) based on the Freiburg Acuity and Contrast Test (FrACT) between treatment eyes (TEs) and placebo control eyes (PCEs) at 12 months.

Secondary endpoints 5

1. Change from baseline in low luminance visual acuity (LLVA) based on FrACT between TEs and PCEs at 12 months.
2. Change from baseline in retinal sensitivity as measured by dark-adapted full-field stimulus test (FST) between TEs and PCEs at 12 months.
3. Eye-specific Patient Global Impression of Change (PGI-C) between TEs and PCEs at 12 months.
4. Change from baseline in contrast sensitivity (CS) between TEs and PCEs based on quick contrast sensitivity function (qCSF) at 12 months.
5. Incidence and severity of ocular and non-ocular adverse events (AEs).

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

5 EU/EEA countries · 7 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 60 files

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

Application history

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