Gene Therapy for X-Linked Retinitis Pigmentosa Shows Safety, Efficacy in Phase 1/2 Study


Improvements were reported in retinal function, visual function, and functional vision at 6 months post-treatment.

MeiraGTx’s botaretigene sparoparvovec (AAV-RPGR), a gene therapy in development for the treatment of X-linked retinitis pigmentosa (XLRP) with disease-causing variants in the RPGR gene, has shown to be generally safe and well-tolerated and demonstrated improvements in several vision-related efficacy end points, according to data from the phase 1/2 clinical trial MGT009 (NCT03252847).1

In terms of safety, no dose-limiting events were reported, and most adverse events were transient and related to the surgical delivery procedure. Among the 3 serious adverse events that were reported were 1 case of increased intraocular pressure that resolved upon treatment, 1 retinal tear, and 1 case of panuveitis, the latter 2 of which occurred in the low-dose cohort in the dose-escalation phase of the study.

Notably, 22.7% of treated patients met responder criteria at 26 weeks, increasing to 47.6% at 52 weeks post-treatment. Efficacy data included significant improvements compared with randomized control subjects across several domains. In the overall population of patients treated in the randomized expansion portion, significant improvements in Visual Mobility Assessment (VMA) at lux 1, patient reported outcome extreme lighting, and mean retinal sensitivity in the central 10-degree area were recorded (P <.05), with trends towards significance seen in best corrected visual acuity (P <.10). Among those in the low and intermediate dose cohorts in the dose escalation and expansion phases, significant improvements 6-months post-treatment were observed in low-level VMA, with improvements in treated patients markedly greater than untreated patients as illumination got darker (P-values were .008, .005, and .008 at lux 16, 4, and 1, respectively). Significant improvements were also observed in the extreme lighting domain (P = .020). Additional significant improvements were observed in Early Treatment Diabetic Retinopathy Study visual acuity (P = .031) and mean retinal sensitivity in the central 10-degree area (P <.001).

“XLRP is characterized by early-onset visual field loss with initial difficulty in functioning in dim light conditions followed by progression to blindness and associated loss of independence by young adulthood in most patients,” Michel Michaelides, BSc, MB, BS, MD(Res),FRCOphth, FACS, MGT009 trial investigator and consultant ophthalmologist, and professor of ophthalmology, Moorfields Eye Hospital and University College London, said in a statement.1 “These data demonstrate the potential of treatment with botaretigene sparoparvovec to have a life-changing impact on vision in patients with XLRP, for which there is no currently available therapeutic option.”

The open-label, multicenter study was open to male patients age 5 and older with a diagnosis of XLRP confirmed by a retinal specialist. Patients who had participated in any other research study involving investigational medicinal therapy for ocular diseases within the past 6 months were excluded from the study. Ultimately, 49 patients enrolled in the 3-phase study, which included dose-escalation, pediatric dose confirmation, and an expansion phase. The dose escalation phase evaluated a low (2x1011 vg/mL), intermediate (4x1011 vg/mL), and high (8x1011 vg/mL) dose. In the expansion phase, participants were randomly assigned to either the low or intermediate dose or an untreated control arm, who received either low or intermediate treatment after a 6-month deferral period. The primary end point was the incidence of adverse events related to the sub retinal administration of the therapy. Secondary end points included visual function and retinal function as assessed by ocular examination and retinal assessment respectively, and quality of life as measured by a questionnaire.

“We and our partners at Janssen are extremely encouraged by the consistency of the data from MGT009,” Alexandria Forbes, PhD, the president and CEO of MeiraGTx said on a conference call regarding the study on June 28, 2022.2 “Of particular note is that the data presented compares treatment with botaretigenesparoparvovec to a randomized untreated control, which while it is only at 6 months post-treatment rather than at 12 months as in the phase 3 study, quite closely reflects the design and analysis in the on-going Lumeos study.”

The phase 3 Lumeos (NCT04671433) clinical trial is currently underway and has begun actively dosing patients. It is open to both male and female patients age 3 and older who have XLRP confirmed by a retinal specialist and have a predicted disease-causing sequence variant in RPGR confirmed by an accredited laboratory. A total of 66 patients are expected to enroll in the study. The primary end point is retinal sensitivity as measured by perimetry. Secondary efficacy end points will include changes from baseline in functional vision and visual function. Safety and tolerability will be measured by the number of participants with ocular and non-ocular adverse events and the number of participants with abnormalities in hematologic and clinical chemistry parameters.

1. MeiraGTx announces positive top-line data from the MGT009 phase 1/2 clinical study demonstrating safety and improvement in multiple domains of vision in x-linked retinitis pigmentosa patients treated with botaretigene sparoparvovec (AAV-RPGR) compared to untreated randomized control. News release. MeiraGTx Holdings plc. June 28, 2022. 
2. Top-line data from the MGT009 phase 1/2 clinical study of botaretigene sparoparvovec (AAV-RPGR). Website. June 28, 2022.
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