June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Results of a phase 1b/2 trial of intravitreal (IVT) sepofarsen (QR-110) antisense oligonucleotide in Leber congenital amaurosis 10 (LCA10) due to p.Cys998X mutation in the CEP290 gene
Author Affiliations & Notes
  • Stephen R Russell
    Ophthalmology, Univ of Iowa Hospitals & Clinics, Iowa City, Iowa, United States
  • Arlene V Drack
    Ophthalmology, Univ of Iowa Hospitals & Clinics, Iowa City, Iowa, United States
  • Artur V Cideciyan
    Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Samuel G Jacobson
    Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Bart Peter Leroy
    Ophthalmology, Center for Medical Genetics, Ghent University Hospital & Ghent University, Ghent, Belgium
    Ophthalmology, Ophthalmic Genetics & Visual Electrophysiology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Wanda L. Pfeifer
    Ophthalmology, Univ of Iowa Hospitals & Clinics, Iowa City, Iowa, United States
  • Alina V. Dumitrescu
    Ophthalmology, Univ of Iowa Hospitals & Clinics, Iowa City, Iowa, United States
  • Alexandra V. Garafolo
    Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Allen C. Ho
    Ophthalmology, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
  • Caroline Van Cauwenbergh
    Ophthalmology, Center for Medical Genetics, Ghent University Hospital & Ghent University, Ghent, Belgium
  • Julie De Zaeytijd
    Ophthalmology, Center for Medical Genetics, Ghent University Hospital & Ghent University, Ghent, Belgium
  • Aniz Girach
    ProQR Therapeutics, Leiden, Netherlands
  • Wil den Hollander
    ProQR Therapeutics, Leiden, Netherlands
  • Mike Schwartz
    ProQR Therapeutics, Leiden, Netherlands
  • David M. Rodman
    ProQR Therapeutics, Leiden, Netherlands
  • Footnotes
    Commercial Relationships   Stephen Russell, ProQR Therapeutics, Inc (F); Arlene Drack, ProQR Therapeutics, Inc (F); Artur Cideciyan, ProQR Therapeutics, Inc (F); Samuel Jacobson, ProQR Therapeutics, Inc (F); Bart Leroy, ProQR Therapeutics, Inc (F); Wanda Pfeifer, None; Alina Dumitrescu, None; Alexandra Garafolo, ProQR Therapeutics, Inc (F); Allen Ho, ProQR Therapeutics, Inc (F); Caroline Van Cauwenbergh, ProQR Therapeutics, Inc (F); Julie De Zaeytijd, ProQR Therapeutics, Inc (F); Aniz Girach, ProQR Therapeutics, Inc (E); Wil den Hollander, ProQR Therapeutics, Inc (E); Mike Schwartz, ProQR Therapeutics, Inc (E); David Rodman, ProQR Therapeutics, Inc (E)
  • Footnotes
    Support  ProQR grants to University of Iowa, University of Pennsylvania and University of Ghent
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 866. doi:
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      Stephen R Russell, Arlene V Drack, Artur V Cideciyan, Samuel G Jacobson, Bart Peter Leroy, Wanda L. Pfeifer, Alina V. Dumitrescu, Alexandra V. Garafolo, Allen C. Ho, Caroline Van Cauwenbergh, Julie De Zaeytijd, Aniz Girach, Wil den Hollander, Mike Schwartz, David M. Rodman; Results of a phase 1b/2 trial of intravitreal (IVT) sepofarsen (QR-110) antisense oligonucleotide in Leber congenital amaurosis 10 (LCA10) due to p.Cys998X mutation in the CEP290 gene. Invest. Ophthalmol. Vis. Sci. 2020;61(7):866.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : LCA10 is a severe, degenerative inherited retinal disease resulting in childhood blindness, which has no treatment. The most common causative mutation is p.Cys998X in the CEP290 gene. Safety, pharmacokinetics (PK), and efficacy of sepofarsen, an RNA antisense oligonucleotide, in subjects with LCA10 were evaluated.

Methods : In a 12-month, multicenter, open-label, multiple-dose escalation, phase 1b/2 study (NCT03140969), subjects (N=11) aged 8–44 years received sepofarsen at loading/maintenance dose of 160/80 µg (n=6) or 320/160 µg (n=5) via 1–4 IVT injections in the eye with worse best-corrected visual acuity (BCVA). Primary endpoint: frequency and severity of ocular adverse events (AEs) in the treated (TE) and untreated contralateral (CE) eyes. Secondary endpoints included serum PK, non-ocular AEs, and change in functional and anatomic ophthalmic findings.

Results : There were 8 cases of cataract; 6 needed surgery. In the 320/160 µg group, 2 cases of mild cystoid macular edema (successfully treated) and 2 cases of subclinical retinal thinning occurred. No events led to subject withdrawal. Serum levels of sepofarsen were below the level of quantification for all subjects. Pooled dose group data showed significant improvement in TE from baseline (BL) to M12 vs CE in mean BCVA (-0.55 [standard error of the mean 0.26] vs -0.12 [0.07] logMAR; p<0.05), red full-field stimulus threshold (FST; -0.91 [0.18] vs -0.16 [0.16] log cd/m2; p<0.01), and blue FST (-0.79 [0.23] vs 0.02 [0.11] log cd/m2; p<0.02). The 160/80 µg dose group showed significant improvement in TE at M12 vs BL in mean BCVA (-0.93 [0.43] logMAR vs BL; p<0.01), red FST (-0.66 [0.14] log cd/m2 vs BL; p<0.01), and blue FST (-0.63 [0.31] log cd/m2 vs BL; p<0.01; Table, Figure). For CE, changes in mean BCVA, red FST, and blue FST were not significant vs BL. A significant improvement in composite mobility course score was seen in TE (+4.0 [1.27] levels vs BL; p<0.01) and CE (+2.7 [1.11] levels vs BL; p<0.05). P-values are based on a mixed model repeated measurement analysis over all visits.

Conclusions : Although sepofarsen treatment is associated with cataract development, it is well tolerated and shows improvement in BCVA, FST, and mobility course. The 160/80 µg dose has a more favorable benefit:risk profile than 320/160 µg. The phase 2/3 trial is ongoing.

This is a 2020 ARVO Annual Meeting abstract.

 

 

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