Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With <i>RPGR</i> Gene Variations
Lenore von Krusenstiern, Jiajun Liu, Eileen Liao, James A. Gow, Guo Chen, Tuyen Ong, Andrew Lotery, Assad Jalil, Byron L. Lam, Robert E. MacLaren, XIRIUS Part 1 Study GroupXOLARIS Study Group, Imran H. Yusuf, Jasmina Cehajic‐Kapetanovic, Amandeep S. Josan, Cristina Martínez-Fernández de la Cámara, Salwah Rehman, Laura J. Taylor, Jasleen K. Jolly, Kanmin Xue, Anika Nanda, Kirti Jasani, Moreno Menghini, Thomas M. W. Buckley, Anna Paola Salvetti, Suresh Thulasidharan, Miguel Kurc, Samir Khandhadia, Karla Orsine Murtas Dias, Abeir Baltmr, Nakul Mandal, Georgios Tsokolas, Paulo Stanga, Tsveta Ivanova, Muhannd El-Faouri, Sherif Shaarawy, Graeme C. Black, Janet L. Davis, Ninel Z. Gregori, Carlos E. Mendoza‐Santiesteban, Potyra R. Rosa, Kevin G. Evans, Rob Koenekoop, Dominik Fischer, Frank G. Holz, Kamron N. Khan, Jason Horowitz, Mark E. Pennesi, David G. Birch, Michael B. Gorin, Kim Stepien, Jacque Duncan, Tim Stout, Benjamin Bakall, Paul S. Bernstein, E.‐M. Sankila, Carel B. Hoyng, Camiel J.F. Boon, Isabelle Meunier
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.