Intravitreal Sepofarsen for Leber Congenital Amaurosis Type 10 (LCA10)

Background: Sepofarsen is an RNA antisense oligonucleotide (AON) targeting the common c.2991+1655A>G mutation in the CEP290 gene to treat Leber congenital amaurosis type 10 (LCA10), a condition with severe childhood-onset vision loss or blindness. Methods: In this 12-month, multicenter, open-label, multiple-dose, dose-escalation, phase 1b/2 trial, patients with LCA10 received up to four doses of intravitreal sepofarsen in the worse-seeing eye. Primary end point was safety; secondary end points included vision outcome measures. Findings: Of 11 patients enrolled (8–44 years of age), six received loading/maintenance doses of sepofarsen of 160 µg/80 µg and five received 320 µg/160 µg. Reported cases of cataracts, mild cystoid macular edema, and retinal thinning were 3, 0, and 0, respectively, in the 160-µg/80-µg group and 5, 2, and 2 in the 320-µg/160-µg group. Pooled data (n=11) showed improvements from baseline to Month 12 in treated eyes vs untreated eyes in mean ± standard error of the mean best-corrected visual acuity (BCVA: −0·55 ± 0·26 vs −0·12 ± 0·07 logarithm of the minimum angle of resolution [logMAR], p<0·05), red full-field stimulus test (FST: − 0·91 ± 0·18 vs −0·16 ± 0·16 logarithm of candela per square meter [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-µg/80-µg group (n=6) showed improvement in BCVA (−0·93 ± 0·43 vs −0·22 ± 0·11 logMAR, p=0·13), red FST (−0·66 ± 0·14 vs +0·05 ± 0·17 log cd/m2, p<0·05), and blue FST (−0·63 ± 0·31 vs +0·12 ± 0·16 log cd/m2, p=0·09). Interpretation: Sepofarsen had a manageable safety profile in patients with LCA10. Statistically significant differences were observed for the within-subject improvement in mean visual acuity and FST. These therapeutic benefits add to the accumulating evidence for the clinical utility of targeted AONs in genetic disorders. A phase 2/3 pivotal trial is underway. Trial Registration: NCT03140969. Funding Statement: This trial (NCT03140969) was sponsored and funded by ProQR Therapeutics, Leiden, The Netherlands. Declaration of Interests: SRR, AVC report grant funding from ProQR during the conduct of the study. AVD reports grants and other from ProQr, during the conduct of the study; personal fees from Medscape and Novartis, grants from Spark and NIH, patent Novartis with royalties paid to Spark and a patent University of Iowa issued to Spark, outside the submitted work. BPL reports grants and non-financial support from ProQR Therapeutics, grants from Fund for Research Flanders, during the conduct of the study; grants from GenSight Therapeutics, IVERIC Bio, and Vedere Bio; grants and non-financial support from Novartis Pharma, Spark Therapeutics and RegenXBio, outside the submitted work. CVC reports grants and nonfinancial support from ProQR Therapeutics, during the conduct of the study; grants from GenSight Therapeutics, outside the submitted work. ACH reports grants from ProQR both during the conduct of the study and outside the submitted work. EJ reports grants and non-financial support from ProQR Therapeutics, during the conduct of the study; grants from GenSight Therapeutics, outside the submitted work. JDZ reports grants from ProQR Therapeutics, during the conduct of the study; grants from GenSight Therapeutics, outside the submitted work. RWJC reports other from ProQR Therapeutics, outside the submitted work; a patent (antisense oligonucleotides) for the treatment of Leber congenital amaurosis licensed to ProQR Therapeutics. PA reports share holdings in ProQR. MEC reports grants and personal fees from ProQR, during the conduct of the study; grants and personal fees from Editas Medicine, BridgeBio, and Alia Therapeutics, outside the submitted work. MRS, WDH, FA, GP, and AG are employees of ProQR. DR is a strategic advisor of ProQR. SGJ, AVD, IH, MM, WP, EHS, JW, AVG, AKK, CAP, AS, AJR, EV, FN, and CH have nothing to disclose. Ethics Approval Statement: The protocol and informed consent form were approved by the institutional review board or independent ethics committee at each investigational site before trial initiation. The trial was conducted in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki. Adult participants provided written informed consent. Age-appropriate assent and permission from the parent or legal guardian were obtained for children.