Study to Evaluate QR-110 in Leber's Congenital Amaurosis (LCA) Due to the c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene

The purpose of this study is to evaluate the safety and tolerability of QR-110 administered via intravitreal injection in subjects with LCA due to the CEP290 p.Cys998X mutation. Subjects will receive QR-110 in one eye every 3 months, for a maximum of 4 doses. Up to 3 dose levels of QR-110 will be evaluated.

• QR-110 (Drug), also known as Sepofarsen: RNA antisense oligonucleotide for intravitreal injection

Primary outcomes

• Frequency and Severity of Ocular Adverse Events in the Treatment and Contralateral Eyes [1 year]

Secondary outcomes

• Frequency and Severity of Non-ocular Adverse Events [1 year]
• Change in Best-corrected Visual Acuity (BCVA) [1 year]
• Change in Full-field Stimulus Test (FST) [1 year]: Average Red Light Score
• Change in Full-field Stimulus Test (FST) [1 year]: Average Blue Light Score

Sex: All, ages: 6 Years to any

Inclusion Criteria:

* Male or female, ≥ 6 years of age at Screening with a clinical diagnosis of LCA and a molecular diagnosis of homozygosity or compound heterozygosity for the CEP290 p.Cys998X mutation.
* Best-corrected visual acuity greater than or equal to light perception in both eyes and equal to or worse than LogMAR +1.0 (Snellen notation 20/200) in the worse eye and equal to or worse than LogMAR +0.7 (Snellen notation 20/100) in the contralateral eye.
* Detectable outer nuclear layer (ONL) in the area of the macula.
* An electroretinogram (ERG) result consistent with LCA.
* Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging.

Exclusion Criteria:

* Syndromic disease.
* Pregnant or breast-feeding female.
* Any clinically significant cardiac disease or defect.
* One or more coagulation parameters outside of the normal range.
* Any ocular disease or condition that could compromise treatment safety, visual acuity or interfere with assessment of efficacy and safety.
* Prior receipt of intraocular surgery or intravitreal injection within 3 months prior to study start or planned intraocular surgery or procedure during the course of the study.
* 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-110-001 study period.
* Any prior receipt of genetic therapy for LCA

Participant flow

Outcome results

• Frequency and Severity of Ocular Adverse Events in the Treatment and Contralateral Eyes (Primary), Count of participants, Participants: QR-110 Low Dose 6; QR-110 Mid Dose 5
• Frequency and Severity of Non-ocular Adverse Events (Secondary), Count of participants, Participants: QR-110 Low Dose 6; QR-110 Mid Dose 5
• Change in Best-corrected Visual Acuity (BCVA) (Secondary), Mean, logMAR: QR-110 Low Dose 2.597 +/- 1.2738; QR-110 Mid Dose 2.990 +/- 1.4153
• Change in Full-field Stimulus Test (FST) (Secondary), Mean, log cd/m2: QR-110 Low Dose -0.7 +/- 0.33; QR-110 Mid Dose -1.2 +/- 0.82
• Change in Full-field Stimulus Test (FST) (Secondary), Mean, log cd/m2: QR-110 Low Dose -0.6 +/- 0.76; QR-110 Mid Dose -0.9 +/- 0.82

Adverse events

Time frame: From the start of the study through to study completion (approx 1 year 11 months)

Serious adverse events by term

Other adverse events by term

• Results publication: Russell SR, Drack AV, Cideciyan AV, Jacobson SG, Leroy BP, Van Cauwenbergh C, Ho AC, Dumitrescu AV, Han IC, Martin M, Pfeifer WL, Sohn EH, Walshire J, Garafalo AV, Krishnan AK, Powers CA, Sumaroka A, Roman AJ, Vanhonsebrouck E, Jones E, Nerinckx F, De Zaeytijd J, Collin RWJ, Hoyng C, Adamson P, Cheetham ME, Schwartz MR, den Hollander W, Asmus F, Platenburg G, Rodman D, Girach A. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial. Nat Med. 2022 May;28(5):1014-1021. doi: 10.1038/s41591-022-01755-w. Epub 2022 Apr 4. PMID 35379979
• Results publication: Cideciyan AV, Jacobson SG, Ho AC, Garafalo AV, Roman AJ, Sumaroka A, Krishnan AK, Swider M, Schwartz MR, Girach A. Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report. Nat Med. 2021 May;27(5):785-789. doi: 10.1038/s41591-021-01297-7. Epub 2021 Apr 1. PMID 33795869
• Results publication: Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27. PMID 31215818
• Results publication: Cideciyan AV, Jacobson SG, Drack AV, Ho AC, Charng J, Garafalo AV, Roman AJ, Sumaroka A, Han IC, Hochstedler MD, Pfeifer WL, Sohn EH, Taiel M, Schwartz MR, Biasutto P, Wit W, Cheetham ME, Adamson P, Rodman DM, Platenburg G, Tome MD, Balikova I, Nerinckx F, Zaeytijd J, Van Cauwenbergh C, Leroy BP, Russell SR. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019 Feb;25(2):225-228. doi: 10.1038/s41591-018-0295-0. Epub 2018 Dec 17. PMID 30559420

• Study Protocol (PDF, 2018-08-08)
• Statistical Analysis Plan (PDF, 2019-08-09)

• Sepul Bio Chief Medical Officer, Study director, Sepul Bio

NIH grants: 2017