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

• Published in: Nature medicine Vol. 28; no. 5; pp. 1014 - 1021
• Main Authors: Russell, Stephen R., Drack, Arlene V., Cideciyan, Artur V., Jacobson, Samuel G., Leroy, Bart P., Van Cauwenbergh, Caroline, Ho, Allen C., Dumitrescu, Alina V., Han, Ian C., Martin, Mitchell, Pfeifer, Wanda L., Sohn, Elliott H., Walshire, Jean, Garafalo, Alexandra V., Krishnan, Arun K., Powers, Christian A., Sumaroka, Alexander, Roman, Alejandro J., Vanhonsebrouck, Eva, Jones, Eltanara, Nerinckx, Fanny, De Zaeytijd, Julie, Collin, Rob W. J., Hoyng, Carel, Adamson, Peter, Cheetham, Michael E., Schwartz, Michael R., den Hollander, Wilhelmina, Asmus, Friedrich, Platenburg, Gerard, Rodman, David, Girach, Aniz
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2022; Nature Publishing Group
• Subjects: 692/308; 692/308/2056; 692/308/575; Acuity; Adult; Adverse events; Antigens, Neoplasm - genetics; Antisense oligonucleotides; Antisense RNA; Antisense therapy; Biomedical and Life Sciences; Biomedicine; Blindness; Blindness - genetics; Cancer Research; Cataracts; Cell Cycle Proteins - genetics; Child; Children; Congenital diseases; Cytoskeletal Proteins - metabolism; Drug dosages; Edema; Eye; Hospitals; Humans; Infectious Diseases; Leber congenital amaurosis; Leber Congenital Amaurosis - drug therapy; Leber Congenital Amaurosis - genetics; Medicine; Metabolic Diseases; Molecular Medicine; Neurosciences; Oligonucleotides, Antisense - adverse effects; Ophthalmology; Patients; Pediatrics; Pharmacokinetics; Photoreceptors; Proteins; Retina; Risk assessment; Safety; Safety management; Statistical analysis; Vision, Ocular; Visual acuity; Visual perception
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-022-01755-w

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.
Intravitreal administration of the antisense oligonucleotide sepofarsen in patients with Leber congenital amaurosis type 10 showed a manageable safety profile, ocular adverse events being dose dependent, and achieved meaningful improvements of visual function.