Gene Therapy for X-linked Retinitis Pigmentosa (XLRP) - Retinitis Pigmentosa GTPase Regulator (RPGR)

This is an open-label phase 1/2 dose-escalation and cohort expansion trial to determine the safety and efficacy of subretinal administration of AAV5-hRKp.RPGR vector in participants with XLRP caused by mutations in RPGR.

• AAV5-RPGR (Genetic): Single, subretinal administration of AAV5-RPGR

Primary outcomes

• Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone. [9 weeks]: The primary outcome is defined as any of the below occurring during the 9 weeks following administration, at least possibly related to the Advanced Therapy Investigational Medicinal Product (ATIMP), not surgery alone: * Reduction in visual acuity by 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more * Severe unresponsive inflammation * Infective endophthalmitis * Ocular malignancy * Grade III or above non-ocular Suspected Unexpected Serious Adverse Reaction (SUSAR)

Secondary outcomes

• Improvements in Visual Function as Assessed by Visual Acuity [Baseline and Month 6]: Change from baseline to Week 26 in best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) chart letter score. The direction of improvement from baseline is an increase in the number of ETDRS letters read over time.
• Improvements in Retinal Function as Assessed by Static Perimetry [Baseline and Month 6]: The number of responders in point-by-point data in Static Perimetry within the full visual field over time. A responder at a single time point is defined as a participant with at least 5 of the same loci with ≥7 dB improvement from baseline at the specific time point and one time point prior.
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Emotional Distress Domain Score [Baseline and Month 6]: Change from baseline to Week 26 in LLQ Emotional Distress Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Extreme Lighting Domain Score [Baseline and Month 6]: Change from baseline to Week 26 in LLQ Extreme Lighting Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) General Dim Lighting Domain Score [Baseline and Month 6]: Change from baseline to Week 26 in LLQ General Dim Lighting Domain score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Mobility Domain Score [Baseline and Month 6]: Change from baseline to Week 26 in LLQ Mobility Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Peripheral Vision Domain Score [Baseline and Month 6]: Change from baseline to Week 26 in LLQ Peripheral Vision Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.

Sex: Male, ages: 5 Years to any

Key inclusion Criteria:

* Males aged 5 years or older
* Have X-linked retinitis pigmentosa confirmed by a retinal specialist (CI or PI)

Key exclusion Criteria:

• Have participated in another research study involving an investigational medicinal therapy for ocular disease within the last 6 months

Participant flow

Outcome results

• Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone. (Primary), Count of participants, Participants: Immediate Low Dose AAV5-hRKp.RPGR 0; Immediate Intermediate Dose AAV5-hRKp.RPGR 0; Immediate High Dose AAV5-hRKp.RPGR 0; Deferred Group 0
• Improvements in Visual Function as Assessed by Visual Acuity (Secondary), Mean, Number of EDTRS letters: Immediate Treatment Group AAV5-hRKp.RPGR 0.6 +/- 4.74; Deferred Group -3.2 +/- 3.87
• Improvements in Retinal Function as Assessed by Static Perimetry (Secondary), Count of participants, Participants: Immediate Treatment Group AAV5-hRKp.RPGR 6; Deferred Group 2
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Emotional Distress Domain Score (Secondary), Mean, Units on a scale: Immediate Treatment Group AAV5-hRKp.RPGR 2.344 +/- 20.1395; Deferred Group -1.389 +/- 8.7152
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Extreme Lighting Domain Score (Secondary), Mean, Units on a scale: Immediate Treatment Group AAV5-hRKp.RPGR 2.956 +/- 9.7080; Deferred Group -8.059 +/- 5.8453
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) General Dim Lighting Domain Score (Secondary), Mean, Units on a scale: Immediate Treatment Group AAV5-hRKp.RPGR 4.115 +/- 14.9706; Deferred Group 1.852 +/- 11.8056
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Mobility Domain Score (Secondary), Mean, Units on a scale: Immediate Treatment Group AAV5-hRKp.RPGR 5.729 +/- 15.8753; Deferred Group 0.926 +/- 6.5145
• Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Peripheral Vision Domain Score (Secondary), Mean, Units on a scale: Immediate Treatment Group AAV5-hRKp.RPGR 1.563 +/- 18.8116; Deferred Group -1.852 +/- 9.1076

Adverse events

Time frame: Data are included from the signing of the ICF until the Month 12 visit.

Serious adverse events by term

Other adverse events by term

• Results publication: Michaelides M, Besirli CG, Yang Y, DE Guimaraes TAC, Wong SC, Huckfeldt RM, Comander JI, Sahel JA, Shah SM, Tee JJL, Kumaran N, Georgiadis A, Minnick P, Zeldin R, Naylor S, Xu J, Clark M, Anglade E, Wong P, Fleck PR, Fung A, Peluso C, Kalitzeos A, Georgiou M, Ripamonti C, Smith AJ, Ali RR, Forbes A, Bainbridge J. Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa. Am J Ophthalmol. 2024 Nov;267:122-134. doi: 10.1016/j.ajo.2024.05.034. Epub 2024 Jun 12. PMID 38871269

• Study Protocol (PDF, 2020-05-01)
• Statistical Analysis Plan (PDF, 2021-11-16)

• James Bainbridge, Prof, Principal investigator, University College, London