Study to Evaluate Sepofarsen in Subjects with Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)

Phase 3

Not yet recruiting

• Conditions: Leber Congenital Amaurosis 10; Sensation Disorders; Eye Diseases; Blindness; Eye Disorders Congenital; Leber Congenital Amaurosis; Neurological Manifestations; Eye Diseases, Hereditary; Vision Disorder; Retinal Disease
• Interventions: Drug: sepofarsen; Other: Placebo IVT

• Registration Number: NCT06891443
• Lead Sponsor: Laboratoires Thea

Brief Summary

The purpose of this double-masked, randomized, placebo-controlled, paired-eye study is 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.

Detailed Description

This is a double-masked, randomized, placebo-controlled, paired-eye study in which one eye of each subject will serve as a control.

At the start of the study the two eyes of each subject will be randomized such that one eye receives sepofarsen and the other eye receives placebo for the first year. In the second year, for all subjects, the eye that was randomized to receive sepofarsen will continue to receive sepofarsen. For the eye that was randomized to placebo in the first year, treatment in the second year will be allocated, as follows: 50% of the eyes will continue to receive placebo, and 50% of the eyes will receive sepofarsen.

Sepofarsen and placebo will be administered via intravitreal injection every 6 months.

Study Timeline

• Study First Submitted: 2025-02-03
• Status Verified: 2025-03
• Study Start: 2025-03
• Study First Submitted QC: 2025-03-21
• Last Update Submitted: 2025-03-21
• Study First Posted: 2025-03-24
• Last Update Posted: 2025-03-24
• Primary Completion: 2027-11
• Study Completion: 2028-10

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

1. Confirmed clinical diagnosis of LCA10 and a molecular diagnosis of homozygosity or compound heterozygosity for the c.2991+1655A>G mutation in CEP290.
2. Adults: >=18 years / Minors: 6 to <18 years.
3. BCVA (FrACT) equal to or worse than logMAR +0.4 (approximate Snellen equivalent 20/50) to +2.9 logMAR based on quantifiable, reliable FrACT. LP subjects with documented evidence of prior better vision eligible.
4. Symmetrical disease between the two eyes as defined by a BCVA (FrACT) within 0.2 logMAR at baseline.
5. Detectable ONL in the macular area as determined by the CRC at Screening.

Exclusion Criteria

1. Mutations in genes other than the CEP290 gene associated with other IRD diseases or syndromes.
2. Presence of any ocular pathology in either eye that may make comparison of the eyes not feasible.
3. Presence of unstable concurrent 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).
4. Presence of any clinically significant lens opacities/cataracts based on the AREDS lens grading scale.
5. Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sepofarsen - Treatment Eye - up to Month 12	sepofarsen	Subjects to receive Sepofarsen in one eye (160µg first then 40µg) and Placebo in the fellow eye at baseline and at month 6.
Placebo - Fellow Eye - up to Month 12	Placebo IVT	Subjects to receive Sepofarsen in one eye (160µg first then 40µg) and Placebo in the fellow eye at baseline and at month 6.
Continued - Treatment Eye - up to Month 24	sepofarsen	Subjects to receive Sepofarsen (40µg) in one eye and Placebo in the fellow eye at Month 12 and Month 18.
Continued - Fellow Eye - up to Month 24	Placebo IVT	Subjects to receive Sepofarsen (40µg) in one eye and Placebo in the fellow eye at Month 12 and Month 18.
Mixed - Treatment Eye - up to Month 24	sepofarsen	Subjects to receive Sepofarsen (40µg) in one eye and Sepofarsen in the fellow eye (160µg first then 40µg) at Month 12 and at Month 18.
Mixed - Fellow Eye - Month 12 to Month 24	sepofarsen	Subjects to receive Sepofarsen (40µg) in one eye and Sepofarsen in the fellow eye (160µg first then 40µg) at Month 12 and at Month 18.
Mixed - Fellow Eye - up to Month 12	Placebo IVT	Subjects to receive Sepofarsen (40µg) in one eye and Sepofarsen in the fellow eye (160µg first then 40µg) at Month 12 and at Month 18 Note: up to Month 12 these subjects receive placebo in the Fellow Eye, as all subjects do.

Primary Outcome Measures

Name	Time	Method
Change from baseline in Best-Corrected Visual Acuity (BCVA)	12 Months	Change from baseline in BCVA based on the Freiburg Acuity and Contrast Test (FrACT) between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)

Secondary Outcome Measures

Name	Time	Method
Change from baseline in Low Luminance Visual Acuity (LLVA) based on FrACT between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)	Month 12
Change from baseline in Contrast Sensitivity (CS) between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs) based on qCSF	Month 12
Change from baseline in retinal sensitivity as measured by dark-adapted Full-Field Stimulus Test (FST) between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)	Month 12
Eye-specific Patient Global Impression of Change (PGI-C) between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)	Month 12	PGI-C (PATIENT GLOBAL IMPRESSION OF CHANGE ) assesses a patient's perception of overall change in their vision in the respective eye over time. The minimum score (best outcome) is 1 ("Very Much Better") and the maximum score (worst outcome) is 7 ("Very Much Worse"). Higher scores indicate a worse health outcome (greater worsening).
Change from baseline in retinal sensitivity as measured by light-adapted Full-Field Stimulus Test (FST) between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)	Month 12
Response in BCVA (FrACT), defined as an improvement of at least 0.2 logMAR from baseline at 12 months and compared between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs), evaluated by the percentage of eyes that achieve this improvement.	Month 12
Response in BCVA (FrACT), defined as an improvement of at least 0.3 logMAR from baseline at 12 months and compared between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs), evaluated by the percentage of eyes that achieve this improvement.	Month 12
Response in Low Luminance Visual Acuity (LLVA) defined as clinically relevant improvement between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs) at 12 months, evaluated by the percentage of eyes that achieve this improvement.	Month 12
Response in Full-Field Stimulus Test (FST) defined as clinically relevant improvement between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs) at 12 months, evaluated by the percentage of eyes that achieve this improvement.	Month 12
Response in Patient Global Impression of Change (PGI-C) defined as clinically relevant improvement between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs) at 12 months, evaluated by the percentage of eyes that achieve this improvement.	Month 12
Response in Contrast Sensitivity (CS) defined as clinically relevant improvement between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs) at 12 months, evaluated by the percentage of eyes that achieve this improvement.	Month 12
Change from baseline in the Michigan Retinal Degeneration Questionnaire (MRDQ) score for subjects ≥ 13 years of age	Month 12
Change from baseline in the Michigan Vision-Related Anxiety Questionnaire (MVAQ) score for subjects ≥ 13 years of age	Month 12
Change from baseline in the Pediatric Eye Questionnaire (PedEyeQ) score for subjects < 13 years of age	Month 12
Change from baseline in eye-specific Patient Global Impression of Severity (PGI-S) between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)	Month 12	PGI-S (PATIENT GLOBAL IMPRESSION OF SEVERITY ) assesses a patient's perception of severity of their eye condition in the respective eye over the past week. The minimum score (best outcome) is 1 ("None") and the maximum score (worst outcome) is 5 ("Very Severe"). Higher scores indicate a worse health outcome (greater severity).
Change from baseline in Best-Corrected Visual Acuity (BCVA) based on the ETDRS or the BRVT between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)	Month 12
Change from baseline in Low Luminance Visual Acuity (LLVA) based on the ETDRS or the BRVT between Treatment Eyes (TEs) and Placebo Control Eyes (PCEs)	Month 12