Evaluation of Sepofarsen Efficacy, Safety, and Tolerability in Leber Congenital Amaurosis Patients with CEP290 c.2991+1655A>G Mutation: A Randomized, Placebo-Controlled Study

Trial ID: 2024-518378-14-00
Protocol: SB-110-007
Sponsor: Laboratoires Thea

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Diseases & Conditions

Leber's congenital amaurosis

Objectives

The primary objective of this study is to evaluate the **efficacy** of Sepofarsen after 12 months of treatment in subjects with Leber Congenital Amaurosis (LCA) due to the c.2991+1655A>G (p.Cys998X) mutation in the CEP290 gene. This objective is clinically relevant as it aims to determine the potential therapeutic benefits of Sepofarsen in improving or stabilizing visual function in patients affected by this genetic condition, which is characterized by severe visual impairment from birth.

Secondary objectives include:

Evaluating efficacy as assessed by various visual function measures and patient-reported outcome (PRO) measures.
Assessing long-term and sustained efficacy.
Evaluating safety and tolerability.

Participants

The clinical trial involves a total of **16 participants** diagnosed with **Leber congenital amaurosis (LCA)**, specifically LCA10, confirmed through genotyping analysis. The study population includes both male and female subjects, ranging from 6 to adults aged 18 years and older. Participants were selected based on their ability to provide informed consent or assent, and their willingness to comply with study protocols. The trial includes individuals with a confirmed clinical diagnosis of LCA10, characterized by homozygosity or compound heterozygosity for the c.2991+1655A>G mutation. Participants exhibit a **Best Corrected Visual Acuity (BCVA)** equal to or worse than logMAR +0.4, with symmetrical disease between the eyes and a detectable outer nuclear layer in the macular area. The study population is required to have clear ocular media and adequate pupillary dilation for quality retinal imaging. Non-pregnant and non-breastfeeding subjects are included, with women of childbearing potential and fertile males adhering to highly effective contraception methods. The trial encompasses a vulnerable population, ensuring ethical considerations are met throughout the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized**, double-masked, 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. The trial will involve the administration of sepofarsen as a solution for injection via intravitreal use. The study will be conducted over an estimated duration of 12 months, with the primary objective being to assess the change from baseline in best-corrected visual acuity (BCVA) using the Freiburg Acuity and Contrast Test (FrACT) between treatment eyes and placebo control eyes at the 12-month mark.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis, and genetic confirmation of the mutation. Following the screening, participants will be randomized to receive either sepofarsen or placebo. The study will include regular follow-up visits to monitor efficacy and safety, with assessments of visual acuity, retinal sensitivity, and contrast sensitivity, among other parameters. The end-of-study visit will occur at the conclusion of the 12-month treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The expected length of participant involvement is approximately 12 months, with conditions for early termination including non-compliance with study procedures, adverse events, or withdrawal of consent. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable data on the potential therapeutic benefits of sepofarsen for individuals affected by this rare genetic condition.

Treatment

The clinical trial involves the administration of **Sepofarsen**, an experimental medication formulated as a **solution for injection**. Sepofarsen is an **antisense oligonucleotide** designed to target the exonic splicer enhancer sequence at intron 26 of the centrosomal protein 290 pre-mRNA. The active substance, Sepofarsen, is derived from nucleic acid and is administered via **intravitreal use**. The dosing regimen includes a maximum daily dose of 40 µg, with a total maximum dose of 120 µg over a treatment period of 18 months. An alternative dosing schedule involves a maximum daily dose of 160 µg, with a total maximum dose of 160 µg over a 1-month treatment period. The medication is provided by Laboratoires Thea and is identified by the sponsor product code QR-110.

The study also includes a **placebo** as a non-experimental treatment. The placebo is used as a comparator to evaluate the efficacy, safety, and tolerability of Sepofarsen in subjects with **Leber Congenital Amaurosis** due to the c.2991+1655A>G (p.Cys998X) mutation in the CEP290 gene. The placebo does not contain any active substance and is administered in a manner consistent with the experimental treatment to maintain the double-masked nature of the trial.

Efficacy

The efficacy of **Sepofarsen** in the treatment of Leber Congenital Amaurosis (LCA) due to the c.2991+1655A>G (p.Cys998X) mutation in the CEP290 gene will be assessed through a double-masked, randomized, placebo-controlled, paired eye study. The primary endpoint for evaluating efficacy is the 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 include changes from baseline in low luminance visual acuity (LLVA) using FrACT, retinal sensitivity measured by dark-adapted full-field stimulus test (FST), and contrast sensitivity (CS) based on quick contrast sensitivity function (qCSF) at 12 months. Additionally, the Eye-specific Patient Global Impression of Change (PGI-C) and the incidence and severity of ocular and non-ocular adverse events (AEs) will be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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
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.
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.
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.
Symmetrical disease between the two eyes as defined by a BCVA (FrACT) within 0.2 logMAR at baseline.
Detectable outer nuclear layer (ONL) in the macular area as determined by the CRC at Screening
Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as assessed by the Investigator.
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.

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Exclusion Criteria

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.
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.
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.
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).
Presence of any ocular pathology in either eye that may make comparison of the eyes not feasible.
History or presence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus).
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.
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.
History of strabismus causing amblyopia that could cause comparison of visual function between the two eyes unfeasible, as assessed by the Investigator.
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.
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.
Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.
Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
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.
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).
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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	28 Apr 2025	3
France	Recruiting	28 Apr 2025	3
Germany	Recruiting	28 Apr 2025	7
The Netherlands	Recruiting	28 Apr 2025	—
Spain	Recruiting	28 Apr 2025	3
Netherlands	—	—	3