Author: Bart LeRoy (Belgium)
Co-authors: Stephen R Russell, Arlene V Drack, Artur V Cideciyan, Samuel G Jacobson, Allen C Ho, Caroline Van Cauwenbergh
Purpose
Leber congenital amaurosis type 10 (LCA10) is a severe, degenerative inherited retinal disease due to mutations in the CEP290 gene resulting in childhood blindness for which there is no treatment. Sepofarsen is an intravitreal RNA therapy that showed clinically meaningful improvements following unilateral injection in a Phase 1b/2 trial for LCA10 due to the c.2991+1655A>G mutation in the CEP290 gene.
Setting/Venue
An extension trial (Insight; NCT03913130) examined safety and efficacy of treatment with sepofarsen dosed in the second eye of patients who completed the Phase 1b/2 trial, and long-term follow up of treatment in the first eye.
Methods
Patients who completed the Phase 1b/2, multicenter, open-label, multiple dose-escalation sepofarsen trial were given the opportunity to enroll into the extension trial for continued dosing in their first treated eye as well as initiation of treatment in their second eye with either a 160 or 80 µg loading dose followed by 80 µg maintenance doses of intravitreal sepofarsen, using a 6-monthly dosing interval. Nine out of 11 patients from the Phase 1b/2 trial enrolled in the extension trial. As main efficacy parameters, change in best-corrected visual acuity (BCVA) and full-field stimulus test (FST) were assessed.
Results
At data cut-off in July 2020, 4 patients aged 15–45 years had received 1 intravitreal injection of sepofarsen in their second eye and had completed a 3- or 6-month visit. The safety profile of sepofarsen dosed in the second eye of participants was consistent with that observed in the Phase 1b/2 trial. At the 3-month (or equivalent) visit, clinically meaningful (change from baseline) BCVA improvements were reported in 2 of 4 second treated eyes (–2.50, –0.80, –0.06 and 0.00 logMAR compared to baseline), similar to the improvements observed in their first treated eyes (–2.66, –1.28, –0.19 and 0.00 logMAR, respectively). All 4 patients showed red and blue FST improvements (delta reported were –1.10 and –1.60; –0.74 and –0.77; –0.87 and –0.96; –0.81 and –2.35 log cd/m2, respectively compared to baseline), generally similar to the red and blue FST improvements observed in their first treated eye at comparable follow-up visits (–0.51 and –1.15; –0.18 and –0.46; –0.92 and –0.72; –1.81 and –1.85 log cd/m2, respectively).
Conlusions
This data analysis strongly corroborates the clinically meaningful vision improvements and safety profile previously observed in the Phase 1b/2 trial. Second-eye responses to sepofarsen parallel the first-eye treated responses both in visual acuity and retinal sensitivity (FST) improvements. Further analyses on this ongoing extension trial, the Phase 2/3 trial (Illuminate; NCT03913143) and a pediatric trial (Brighten, EudraCT 2020-000535-45) are expected.
Financial Disclosure
BPL is or has recently been a consultant to Alia Therapeutics, Bayer, Biogen, GenSight Therapeutics, IVERIC Bio, Novartis, ProQR Therapeutics, SparingVision, Spark Therapeutics, Soffina, REGENXBIO, Vedere Bio and ViGeneron. He has received, receives or will soon receive trial support from Biogen, GenSight Therapeutics, MeiraGTx, Novartis, and ProQR Therapeutics. Travel support has come from GenSight Therapeutics, IVERIC Bio, Novartis, ProQR Therapeutics and Spark Therapeutics. Neither BPL nor any of his close family members have any financial interests in any of aforementioned companies. Specific to the study presented: BPL, SRR, AVD, AVC, ACH, and SGJ report grant funding from ProQR Therapeutics during the conduct of the study. BPL, SRR, and AVD and are a member of the ProQr Advisory Board. CVC and AKK have nothing to disclose. WDH, AHH, MRS, and AG are employees of ProQR.
Comments
Additional Co-authors: 7. Julie De Zaeytijd - Department of Ophthalmology & Center for Medical Genetics 8. Arun K. Krishnan - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 9. Wilhelmina den Hollander - ProQR Therapeutics, Leiden, Netherlands 10. Adriana Hollestein-Havelaar - ProQR Therapeutics, Leiden, Netherlands 11. Michael R. Schwartz - ProQR Therapeutics, Leiden, Netherlands 12. Aniz Girach - ProQR Therapeutics, Leiden, Netherlands
