Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations

Abstract

Importance: X-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss.

Objective: To assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study.

Design, setting, and participants: This was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021.

Main outcomes and measures: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months.

Results: A total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred.

Conclusions and relevance: Results suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials.

Trial registration: ClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.

Figure 1.. Responder Analysis of Dosed Eyes in the Clinical Trial of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) and Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) Studies

Responder analysis (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci) in the XIRIUS trial part 1 therapeutic dose cohorts 3 to 6 using the dosed eyes compared with untreated eyes in the XIRIUS trial (A) and study eyes from participants in the XOLARIS study (B). The shading in panels A and B indicates the difference between the dosed and untreated eye in the XIRIUS trial (A) and the dosed eye in the XIRIUS trial and the study eye in the XOLARIS study (B). Mean retinal sensitivity in 16 central loci vs low-luminance visual acuity (VA) change from baseline for all visits up to month 12 in dosed (C) and untreated (D) fellow eyes among participants in XIRIUS part 1 cohorts 3 to 6 (n = 11; 1 participant had no baseline low-luminance VA). The correlation between change from baseline in mean retinal sensitivity in the 16 central loci assessed by macular integrity assessment microperimetry and low-luminance VA is shown. ETDRS indicates Early Treatment Diabetic Retinopathy Study.

Figure 2.. Retinal Sensitivity in the Clinical Trial of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) Study Part 1 Therapeutic Dose Cohorts 3 to 6

A, Change from baseline in mean central retinal sensitivity for 6 early (month 1) responders. The shading in panel A indicates the difference between the dosed and untreated eye. Error bars represent the SE. B, Mean number of 16 central loci with increased retinal sensitivity from baseline.

Figure 3.. Low-Luminance Visual Acuity (VA) in Dosed and Untreated Eyes in the Clinical Trial of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) Study Part 1

A, Gain in low-luminance VA Early Treatment Diabetic Retinopathy Study (ETDRS) score greater than or equal to 10 letters. B, Gain in low-luminance VA ETDRS score greater than or equal to 15 letters. The shading in panels A and B indicates the difference between the dosed and untreated eye.