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Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa.
Michaelides, Michel; Besirli, Cagri G; Yang, Yesa; DE Guimaraes, Thales A C; Wong, Sui Chien; Huckfeldt, Rachel M; Comander, Jason I; Sahel, José-Alain; Shah, Syed Mahmood; Tee, James J L; Kumaran, Neruban; Georgiadis, Anastasios; Minnick, Pansy; Zeldin, Robert; Naylor, Stuart; Xu, Jialin; Clark, Michael; Anglade, Eddy; Wong, Peggy; Fleck, Penny R; Fung, Albert; Peluso, Colleen; Kalitzeos, Angelos; Georgiou, Michalis; Ripamonti, Caterina; Smith, Alexander J; Ali, Robin R; Forbes, Alexandria; Bainbridge, James.
Affiliation
  • Michaelides M; 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.
  • Besirli CG; Kellogg Eye Center (C.G.B.), Ann Arbor, Michigan, USA; Janssen Pharmaceuticals (C.G.B.), Raritan, New Jersey, USA.
  • Yang Y; 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.
  • DE Guimaraes TAC; 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.
  • Wong SC; 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 Fou
  • Huckfeldt RM; Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School (R.M.H., J.I.C.), Boston, Massachusetts, USA.
  • Comander JI; Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School (R.M.H., J.I.C.), Boston, Massachusetts, USA.
  • Sahel JA; UPMC Eye Center, University of Pittsburgh School of Medicine (J.-A.S., S.M.S.), Pittsburgh, Pennsylvania, USA.
  • Shah SM; 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.
  • Tee JJL; 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.
  • Kumaran N; 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.
  • Georgiadis A; MeiraGTx (A.G., R.Z., S.N., A.F.), New York, New York, USA.
  • Minnick P; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Zeldin R; MeiraGTx (A.G., R.Z., S.N., A.F.), New York, New York, USA.
  • Naylor S; MeiraGTx (A.G., R.Z., S.N., A.F.), New York, New York, USA.
  • Xu J; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Clark M; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Anglade E; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Wong P; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Fleck PR; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Fung A; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Peluso C; Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
  • Kalitzeos A; 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.
  • Georgiou M; 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 M
  • Ripamonti C; Cambridge Research Systems Ltd. (C.R.), Rochester, UK.
  • Smith AJ; 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.
  • Ali RR; 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.
  • Forbes A; MeiraGTx (A.G., R.Z., S.N., A.F.), New York, New York, USA.
  • Bainbridge J; 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.
Am J Ophthalmol ; 267: 122-134, 2024 Nov.
Article in En | MEDLINE | ID: mdl-38871269
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 111 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Therapy / Visual Acuity / Retinitis Pigmentosa / Dependovirus / Eye Proteins / Genetic Vectors Limits: Adolescent / Adult / Child / Child, preschool / Humans / Male / Middle aged Language: En Journal: Am J Ophthalmol Year: 2024 Type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Therapy / Visual Acuity / Retinitis Pigmentosa / Dependovirus / Eye Proteins / Genetic Vectors Limits: Adolescent / Adult / Child / Child, preschool / Humans / Male / Middle aged Language: En Journal: Am J Ophthalmol Year: 2024 Type: Article