Author: Michel Michaelides (United Kingdom)
Co-authors: Cagri Besirli, Kamron Khan, Yesa Yang, Chien Wong, Jose Sahel, Mahmood Shah
Purpose
To evaluate how intervention with a gene therapy for X-linked retinitis pigmentosa (XLRP) associated with disease-causing sequence variants in Retinitis Pigmentosa GTPase Regulator (RPGR) affects the natural progression of the disease. RPGR-associated XLRP is among the most severe forms of retinitis pigmentosa, which is the most prevalent inherited retinal dystrophy.
Setting/Venue
MGT011 (NCT03349242) is a prospective longitudinal natural history study of individuals with retinal dystrophy associated with variants in RPGR. A subset of participants from MGT011 were enrolled into MGT009, a multi-centre open-label Phase 1/2 trial of an AAV5-RPGR gene therapy (NCT03252847) conducted at 5 sites across the United States and United Kingdom.
Methods
Participants in MGT011 were assessed at baseline, every 6 months for 2 years, and then annually for up to 5 years. Retinal assessments included Octopus 900 full-field static perimetry and mesopic fundus-guided microperimetry, with analyses including mean retinal sensitivity (MS), visual field modeling and analysis (VFMA), and point-by-point comparisons. Ten adult males aged 18-30 years with RPGR-associated XLRP from MGT011 were identified as suitable for gene therapy intervention and were enrolled in MGT009. In the dose-escalation phase of MGT009, up to 1 mL of 1 of 3 doses (low, intermediate, and high) of AAV5-RPGR was administered to the participant’s poorer-seeing eye. The untreated contralateral eye served as a control. AAV5-RPGR was delivered by subretinal injection. The central retina was targeted, including foveal detachment, with multiple retinotomies permitted to enable coverage of all viable retina. Retinal function was assessed at baseline through 12 months post-treatment. Changes in MS and central 30-degree hill of vision (V30) were examined up to 48 months pre- (MGT011) and 12 months post-intervention (MGT009).
Results
AAV5-RPGR was generally well-tolerated as previously reported. Twelve months following treatment in the low (n=3) and intermediate (n=4) dose cohorts, 6 participants demonstrated improvement or stability in treated-eye retinal sensitivity. For all patients who received the intermediate dose, based on a linear regression model that began in MGT011 ≥36 months prior to enrollment of these patients in MGT009 and continued through 12 months post-intervention, treated eye MS at 12 months post-intervention improved back to levels observed at least 24 months prior to the intervention. Similarly, treated eye VFMA-derived improvement in V30 at 12 months post-intervention reflected levels observed at least 24 months pre-intervention. For the intermediate dose cohort, the natural history MS and V30 data collected ≥36 months pre-intervention were trending downward for both eyes in nearly all participants. For all intermediate dose recipients, the downward trend in MS and V30 results continued for the untreated eye through 12 months post-intervention, indicating continued natural disease progression. Significant differences (P<0.05) were observed between treated and untreated eyes at 12 months for the intermediate dose cohort in MS (1.05 dB [90% CI: 0.81, 1.29]) and V30 (1.26 dB-sr [90% CI: 0.65, 1.86]).
Conlusions
At 12 months post-intervention, treatment with the low and intermediate doses of AAV5-RPGR resulted in clinically meaningful improvements in retinal sensitivity across multiple metrics and modalities. For the intermediate dose cohort, intervention with AAV5-RPGR therapy in the poorer-seeing eye altered the course of natural disease progression. At 12 months post-intervention, MS and V30 in the treated eye were similar to levels observed 24 months pre-intervention, while the untreated eye showed a continued downward trajectory. Given the robust safety and efficacy signals observed at the low and intermediate doses, these two doses are being further explored in a randomized controlled Phase 3 clinical trial (NCT04671433).
Financial Disclosure
Dr. Michaelides is a consultant and holds equity in MeiraGTx, and serves on advisory committees for MeiraGTx and Janssen; he also serves as a consultant for Acucela, 2CTech, Roche, and Stargazer. Dr. Besirli is a consultant for MeiraGTx and Janssen, and receives clinical trial support from the University of Michigan. Dr. Sahel receives grants from LabEx LIFESENSES (ANR-10-LABX-65), IHU FOReSIGHT (ANR-18-IAHU-01), and personal fees from GenSight Biologics, Pixium Vision, Sparing Vision, Prophesee, Tilak, VegaVect, NewSight, and Chronolife.
Comments
Additional Co-authors: 8. James Tee - UCL Institute of Ophthalmology and Moorfields Eye Hospital 9. Neruban Kumaran - UCL Institute of Ophthalmology 10. Anastasios Georgiadis - MeiraGTx (Employee of MeiraGTx and holds equity in MeiraGTx) 11. Stuart Naylor - MeiraGTx (Employee of MeiraGTx and holds equity in MeiraGTx) 12. Robert Zeldin - MeiraGTx (Employee of MeiraGTx and holds equity in MeiraGTx) 13. Jialin Xu - Janssen Pharmaceuticals (Employee of Janssen and holds equity in Johnson and Johnson) 14. Peggy Wong - Janssen Pharmaceuticals (Employee of Janssen and holds equity in Johnson and Johnson) 15. Penny Fleck - Janssen Pharmaceuticals (Employee of Janssen and holds equity in Johnson and Johnson) 16. Pansy Minnick - Janssen Pharmaceuticals (Employee of Janssen and holds equity in Johnson and Johnson) 17. Marvin Sperling - Janssen Pharmaceuticals (Employee of Janssen and holds equity in Johnson and Johnson) 18. Alexander Smith - UCL Institute of Ophthalmology 19. Caterina Ripamonti - Cambridge Research Systems Ltd 20. Robin Ali - UCL Institute of Ophthalmology 21. Alexandria Forbes - MeiraGTx (Employee of MeiraGTx and holds equity in MeiraGTx) 22. James Bainbridge - UCL Institute of Ophthalmology and Moorfields Eye Hospital
