A Study to Evaluate Efficacy, Safety, Tolerability and Exposure After a Repeat-dose of Sepofarsen (QR-110) in LCA10 (ILLUMINATE)

The purpose of this double-masked, randomized, controlled, multiple-dose study is to evaluate the efficacy, safety, tolerability and systemic exposure of sepofarsen (QR-110) administered via intravitreal injection in subjects with Leber's Congenital Amaurosis (LCA) due to the CEP290 p.Cys998X mutation after 24 months of treatment.

At study start subjects will be randomized to one of 3 treatment groups with either active study drug or sham treatment.

Sepofarsen (QR-110) will be administered via intravitreal (IVT) injection into the subject's treatment eye (the subject's worse eye).

Subjects in the sham-procedure group will undergo a procedure that will closely mimic the active injection.

After each dosing subjects will be assessed for safety and tolerability at follow up visits.

After the first eye has been treated for at least 12 months, treatment of the contralateral eye and cross-over of subjects assigned to sham procedure may be initiated in eligible eyes (in a masked manner) based on assessment of benefit/risk (including review of data from all clinical trials), and with concurrence of the Medical Monitor.

Main Inclusion Criteria Relating to Study Initiation:

• Male or female, ≥ 8 years of age at Screening with a 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 from a certified laboratory is acceptable with Sponsor approval.
• BCVA better or equal to Logarithm of the Minimum Angle of Resolution (LogMAR) +3.0 (Hand Motion), and equal to or worse than LogMAR +0.4 in the treatment eye.
• Detectable outer nuclear layer (ONL) in the area of the macula.
• An electroretinogram (ERG) result consistent with LCA. A historic ERG result may be acceptable for eligibility.

Main Exclusion Criteria Relating to Study Initiation:

• Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities).
• Prior receipt of intraocular surgery, periocular surgery, or IVT injection within 1 month prior to study start or planned intraocular surgery or procedure during the course of the study.Subjects who received an intraocular or periocular surgery between 1 to 3 months prior 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 or presence of ocular herpetic diseases.
• Presence of any active ocular infection in the either eye.
• Presence of lens opacities/cataracts in the treatment eye.
• Current treatment or treatment within the past 12 months with therapies known to influence the immune system.
• History of glaucoma, or an IOP greater than 24 mmHg, at is not controlled with medication.
• History of amblyopia
• 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 PQ-110-003 study period.
• Any prior receipt of genetic or stem-cell therapy.
• Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
• Pregnant and breastfeeding subjects.

Main Inclusion Criteria Relating to Treatment Initiation Contralateral Eye:

• BCVA equal to or better than LP (logMAR +4), using the best BCVA reading at Month 12 and based on ETDRS or BRVT.
• Detectable outer nuclear layer (ONL) in the area of the macula.
• Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging.

Main Exclusion Criteria Relating to Treatment Initiation Contralateral Eye:

• Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities).
• History or presence of ocular herpetic diseases.
• Presence of any active ocular infection in either eye.
• Presence of any lens opacities which are clinically significant, would adequately prevent clinical and photographic evaluation of the retina.
• A planned IVT injection or intraocular or periocular surgery/procedure (including refractive surgery) during the course of the study.
• A history of glaucoma or an IOP greater than 24 mmHg that is not controlled with medication.
• History of amblyopia.
• Plans to participate in another study of a drug or device during the study period.
• Pregnant and breastfeeding subjects.