2. Academic Validation
  3. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

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.
Stephen R Russell 1,  Arlene V Drack 2,  Artur V Cideciyan 3,  Samuel G Jacobson 3,  Bart P Leroy 4 5 6,  Caroline Van Cauwenbergh 5,  Allen C Ho 7,  Alina V Dumitrescu 2,  Ian C Han 2,  Mitchell Martin 2,  Wanda L Pfeifer 2,  Elliott H Sohn 2,  Jean Walshire 2,  Alexandra V Garafalo 3,  Arun K Krishnan 3,  Christian A Powers 3,  Alexander Sumaroka 3,  Alejandro J Roman 3,  Eva Vanhonsebrouck 5,  Eltanara Jones 5,  Fanny Nerinckx 5,  Julie De Zaeytijd 5,  Rob W J Collin 8,  Carel Hoyng 9,  Peter Adamson 10,  Michael E Cheetham 10,  Michael R Schwartz 11,  Wilhelmina den Hollander 12,  Friedrich Asmus 13,  Gerard Platenburg 11,  David Rodman 14,  Aniz Girach 11
Affiliations

Affiliations

  • 1 University of Iowa Institute for Vision Research, University of Iowa, Iowa City, IA, USA. [email protected].
  • 2 University of Iowa Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
  • 3 Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
  • 5 Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
  • 6 Division of Ophthalmology and Center for Cellular & Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 7 Wills Eye Hospital/Mid Atlantic Retina, Philadelphia, PA, USA.
  • 8 Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 9 Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 10 UCL Institute of Ophthalmology, London, UK.
  • 11 ProQR Therapeutics, Leiden, The Netherlands.
  • 12 3D-PharmXchange, Tilburg, The Netherlands.
  • 13 Oxular Limited, Magdalen Centre, Oxford, UK.
  • 14 Mineralys Therapeutics, Radnor, PA, USA.
PMID: 35379979 DOI: 10.1038/s41591-022-01755-w
Abstract

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.

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