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

Abstract

ImportanceX-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.ObjectiveTo 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 ParticipantsThis 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 MeasuresIncidence 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.ResultsA 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 RelevanceResults 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 RegistrationClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129

Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials

“…To date, RPGR -associated RP clinical trial design has used a single study eye (usually the worse eye) and used the nontreated eye as an internal control. 11 , 12 Variability arising from fatigue could be reduced if only the study eye is tested and a separate cohort is used as a control; however, this strategy would reduce potential sample sizes, which, in rare diseases, may not be feasible. Furthermore, careful consideration of visual function testing order may minimize variability due to fatigue effects; if microperimetry was selected as the primary outcome measure, perhaps this should be completed prior to any other visual function testing, to minimize fatigue.…”

“… 10 Subsequently, two recent gene therapy trials for RPGR- associated RP have applied a similar criteria as an endpoint for clinical significance, reporting the number of individuals with at least 5 points showing a sensitivity gain of ≥7.0 dB in the treated eye, within the central 16 and 36 loci (when using the 10-2, 68-point testing grid). 11 , 12 Meanwhile, two active RPGR -associated RP clinical trials simply state a change from baseline microperimetry sensitivity as secondary outcome measures without providing more specific endpoint criteria (NCT 03584165 and NCT 03349242). Despite the popularity of microperimetry as an outcome measure in RPGR -associated RP clinical trials, specific endpoint criteria suitability is yet to be explored.…”

Perspectives on Evolving Gene Therapy for X-Linked Retinitis Pigmentosa

“…1 The recently completed phase 1 XIRIUS trial has expanded this gene delivery approach to a potential treatment of X-linked retinitis pigmentosa (XLRP), commonly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. 2 The phase 1 safety XIRIUS trial evaluated gene therapy using a codon-optimized RPGR gene (cotoretigene toliparvovec [BIIB112/AAV8-RPGR]) that had demonstrated stability and increased levels of RPGR expression in a mouse model. 3 This phase 1 clinical trial included 18 eyes of 18 study participants with a genetically confirmed diagnosis of RPGRmutated XLRP and delivered 6 escalating doses of the vector genome (AAV8-RPGR) combination into the subretinal space using standard vitrectomy techniques.…”

“…Management of retinitis pigmentosa and other inherited retinal dystrophies has progressively evolved toward gene therapy, especially after the first successful treatment using an adeno-associated viral vector (AAV8) with gene delivery into retinal photoreceptors . The recently completed phase 1 XIRIUS trial has expanded this gene delivery approach to a potential treatment of X-linked retinitis pigmentosa (XLRP), commonly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene …”

Error in Spelling of Nonauthor Collaborator Name

“…The Original Investigation titled “Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations,” published online February 9, 2023, was corrected to fix the spelling of the first nonauthor collaborator’s name on PubMed. This article was corrected online.…”