Gene therapy trial highlights RPGR-associated X-linked RP


The therapy offers improved retinal sensitivity, visual function, as well as improvements in mobility.

Investigators conducted a dose-escalation trial of AAV5-RPGR that included low, intermediate, and high doses of the gene therapy administered to 3, 4, and 3 adults, respectively.

Investigators conducted a dose-escalation trial of AAV5-RPGR that included low, intermediate, and high doses of the gene therapy administered to 3, 4, and 3 adults, respectively.

Reviewed by Michel Michaelides, MD
A gene therapy for a common and severe form of retinitis pigmentosa (RP), RPGR-associated X-linked RP, botaretigene sparoparvovec (MeiraGTx Holdings plc and Janssen Pharmaceuticals), demonstrated improvements in retinal sensitivity and visual function compared with controls and had a manageable adverse event profile, according to Michel Michaelides, MD, from the UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, UK.

In their multicenter phase 1/2 safety study conducted in the US and UK, Michaelides and colleagues conducted a dose-escalation trial of AAV5-RPGR that included low, intermediate, and high doses of the gene therapy administered to 3, 4, and 3 adults, respectively.

An intermediate dose was administered to 3 children. The study design also included an expansion phase once the dosing was confirmed; the expansion cohort included low- and intermediate-dose arms with 8 and 11 patients, respectively, and a concurrent control arm in which a low- or intermediate dose was deferred for 6 months in 13 patients.

All patients in the study were male 5 years and older and all had RP resulting from a disease-causing variant in RPGR. In addition, optical coherence tomography showed relative preservation of central retinal structure.

Gene therapy safety

Michaelides reported that AAV5-RPGR gene therapy demonstrated an adverse events profile that was anticipated and manageable. Most events were associated with the surgery to deliver the vector and resolved without intervention.

During the dose-escalation phase, 1 retinal detachment developed and resolved with treatment and 1 case of panuveitis associated with the low dose; in the dose-expansion phase, the intraocular pressure increased in 1 patient and resolved with treatment. When an additional steroid regimen was used during the expansion phase, the adverse events related to inflammation decreased, he explained.

Gene therapy efficacy

Pooling of the data from the low- and intermediate-dose groups showed an improvement in the mean retinal sensitivity in adults at 6 months compared with the untreated controls. The treatment showed a 2-decibel improvement seen with static perimetry compared with controls and 1 decibel by microperimetry.

A sensitivity analysis based on phase 3 criteria results in exclusion of 2 patients each from the treatment and control groups. Once they were excluded, a greater significance (P < .001) difference was evident.

A pointwise responder analysis of the static perimetry of the pooled data from the adults treated with low and intermediate doses showed improvement with both doses compared with untreated controls. Michaelides defined a responder as a patient with at least a 7-decibel improvement compared with baseline at 5 or more loci and the same 5 loci showed improvement at 2 evaluations after treatment.

At week 26 after treatment, 26% of patients in the pooled data group satisfied the definition and that increased to 48% at week 52; in the control group, 20% were responders at week 26 and no additional data for week 52 (as patients in the control group receive treatment after the week 26 assessments), he reported.

The sensitivity analysis using phase 3 criteria applied to the pooled data showed 24% and 48%, respectively, at the same time points. In the control group the responder rate was 0%.

Practical considerations

Patients were exposed to a mobility maze 9 months after treatment to determine just what the visual improvements might contribute to their ability to negotiate in a real-world setting.

Michaelides outlined that the results achieved in the maze with a light level of 1 lux by a patient treated with the intermediate dose. When he went through the maze at baseline before treatment, the patient completed the maze in 61.7 seconds with 2 errors; at 9 months, the patient traversed the maze in 16.4 seconds with no errors.

“This is a dramatic representation of the impact this gene therapy can have,” Michaelides explained.

When considering all treated patients, the investigators observed significant reductions in walk time at week 26 compared with baseline and compared to untreated controls. When phase 3 criteria were applied, the results were significant at lux levels of 1, 2, and 16.

“We found a good safety profile and have seen improvements in retinal sensitivity and functional vision compared to the control group at 6 months,” Michaelides concluded. “Importantly, all domains in the low-luminance questionnaire trended positively, with the extreme lighting domain nominally significant. Considering these strong findings, a phase 3 study is underway.”

Michel Michaelides, MD

Michaelides is a consultant to and owns equity in MeiraGTx.

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