Article
作者: Pennesi, Mark ; Gorin, Michael ; Stout, Tim ; Yusuf, Imran H. ; Evans, Kevin G. ; Stanga, Paulo ; Stepien, Kim ; MacLaren, Robert E. ; Jolly, Jasleen K. ; Wood, Laura J. ; Mandal, Nakul ; Hoyng, Carel ; Baltmr, Abeir ; Mendoza-Santiesteban, Carlos E. ; Liao, Eileen ; Rehman, Salwah ; Bakall, Benjamin ; Meunier, Isabelle ; Martinez-Fernandez de la Camera, Cristina ; Boon, Camiel ; Lam, Byron L. ; Khan, Kamron ; Menghini, Moreno ; EL-Faouri, Muhannd ; Rosa, Potyra R. ; Liu, Jiajun ; von Krusenstiern, Lenore ; Duncan, Jacque ; Birch, David ; Gregori, Ninel ; Kurc, Miguel ; Gow, James A. ; Nanda, Anika ; Salvetti, Anna Paola ; Louise Davis, Janet ; Tsokolas, Georgios ; Buckley, Thomas M.W. ; Chen, Guo ; Ong, Tuyen ; Khandhadia, Samir ; Bernstein, Paul S. ; Jasani, Kirti ; Jalil, Assad ; Lotery, Andrew J. ; Horowitz, Jason ; Holz, Frank ; Fischer, Dominik ; Orsine Murta Dias, Karla ; Xue, Kanmin ; Thulasidharan, Suresh ; Josan, Amandeep S. ; Sankila, Eeva-Maria ; Koenekoop, Rob ; Shaarawy, Sherif ; Cehajic-Kapetanovic, Jasmina ; Ivanova, Tsveta ; Black, Graeme
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