Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa

Michel Michaelides; Cagri G Besirli; Yesa Yang; Thales A C DE Guimaraes; Sui Chien Wong; Rachel M Huckfeldt; Jason I Comander; José-Alain Sahel; Syed Mahmood Shah; James J L Tee; Neruban Kumaran; Anastasios Georgiadis; Pansy Minnick; Robert Zeldin; Stuart Naylor; Jialin Xu; Michael Clark; Eddy Anglade; Peggy Wong; Penny R Fleck; Albert Fung; Colleen Peluso; Angelos Kalitzeos; Michalis Georgiou; Caterina Ripamonti; Alexander J Smith; Robin R Ali; Alexandria Forbes; James Bainbridge

doi:10.1016/j.ajo.2024.05.034

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.

Authors

Michel Michaelides¹, Cagri G Besirli², Yesa Yang³, Thales A C DE Guimaraes³, Sui Chien Wong⁴, Rachel M Huckfeldt⁵, Jason I Comander⁵, José-Alain Sahel⁶, Syed Mahmood Shah⁷, James J L Tee³, Neruban Kumaran⁸, Anastasios Georgiadis⁹, Pansy Minnick¹⁰, Robert Zeldin⁹, Stuart Naylor⁹, Jialin Xu¹⁰, Michael Clark¹⁰, Eddy Anglade¹⁰, Peggy Wong¹⁰, Penny R Fleck¹⁰, Albert Fung¹⁰, Colleen Peluso¹⁰, Angelos Kalitzeos³, Michalis Georgiou¹¹, Caterina Ripamonti¹², Alexander J Smith¹³, Robin R Ali¹⁴, Alexandria Forbes⁹, James Bainbridge³

Affiliations

¹ From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK. Electronic address: michel.michaelides@ucl.ac.uk.
² Kellogg Eye Center (C.G.B.), Ann Arbor, Michigan, USA; Janssen Pharmaceuticals (C.G.B.), Raritan, New Jersey, USA.
³ From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK.
⁴ From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust (S.C.W.), London, UK.
⁵ Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School (R.M.H., J.I.C.), Boston, Massachusetts, USA.
⁶ UPMC Eye Center, University of Pittsburgh School of Medicine (J.-A.S., S.M.S.), Pittsburgh, Pennsylvania, USA.
⁷ UPMC Eye Center, University of Pittsburgh School of Medicine (J.-A.S., S.M.S.), Pittsburgh, Pennsylvania, USA; Gundersen Health System (S.M.S., R.R.A.), La Crosse, Wisconsin, USA.
⁸ Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK; Guy's and St. Thomas' NHS Foundation Trust (N.K.), London, UK.
⁹ MeiraGTx (A.G., R.Z., S.N., A.F.), New York, New York, USA.
¹⁰ Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
¹¹ From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK; Jones Eye Institute, University of Arkansas for Medical Sciences (M.G.), Little Rock, Arkansas, USA.
¹² Cambridge Research Systems Ltd. (C.R.), Rochester, UK.
¹³ From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Centre for Gene Therapy and Regenerative Medicine, King's College London (A.J.S.), London, UK.
¹⁴ From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Gundersen Health System (S.M.S., R.R.A.), La Crosse, Wisconsin, USA.

PMID: 38871269
DOI: 10.1016/j.ajo.2024.05.034

Abstract

Purpose: To assess the safety and efficacy of AAV5-hRKp.RPGR in participants with retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP).

Design: Open-label, phase 1/2 dose escalation/expansion study (ClinicalTrials.gov Identifier: NCT03252847).

Methods: Males (≥5 years old) with XLRP-RPGR were evaluated. In the dose escalation phase, subretinal AAV5-hRKp.RPGR (low: 1.0 × 10¹¹ vg/ml; intermediate: 2.0 × 10¹¹ vg/ml; high: 4.0 × 10¹¹ vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants.

Results: AAV5-hRKp.RPGR was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation-related AEs responded to corticosteroids. Treatment with AAV5-hRKp.RPGR resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52.

Conclusions: AAV5-hRKp.RPGR demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial.

Publication types

Clinical Trial, Phase II
Clinical Trial, Phase I
Randomized Controlled Trial
Multicenter Study

MeSH terms

Adolescent
Adult
Child
Child, Preschool
Dependovirus* / genetics
Electroretinography
Eye Proteins* / genetics
Eye Proteins* / metabolism
Genetic Diseases, X-Linked / genetics
Genetic Diseases, X-Linked / physiopathology
Genetic Diseases, X-Linked / therapy
Genetic Therapy* / methods
Genetic Vectors*
Humans
Male
Middle Aged
Parvovirinae / genetics
Retinitis Pigmentosa* / genetics
Retinitis Pigmentosa* / physiopathology
Treatment Outcome
Visual Acuity* / physiology
Visual Field Tests
Visual Fields / physiology
Young Adult

Substances

Eye Proteins
RPGR protein, human

Supplementary concepts

Adeno-associated virus-5

Associated data

ClinicalTrials.gov/NCT03252847