Gene therapy study highlights RPGR-associated X-linked RP

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

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

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

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

safety of gene therapy

Michaelides reported that AAV5 RPGR gene therapy showed a side effect profile that was expected and manageable. Most events were related to 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 low-dose-related panuveitis; During the dose expansion phase, intraocular pressure increased in 1 patient and disappeared with treatment. When an additional steroid regimen was used during the expansion phase, inflammation-related side effects decreased, he explained.

effectiveness of gene therapy

Pooling data from the low and medium dose groups showed an improvement in mean retinal sensitivity in adults at 6 months compared to untreated controls. Treatment showed an improvement of 2 decibels in static perimetry compared to controls and 1 decibel in microperimetry.

A sensitivity analysis based on phase 3 criteria led to the exclusion of 2 patients each from the treatment and control groups. Once they have been excluded, a greater importance (P <0.001) difference was evident.

A point-by-point responder analysis of static perimetry of the pooled data from adults treated with low and medium doses showed improvement at both doses compared to untreated controls. Michaelides defined a responder as a patient with an improvement of at least 7 decibels from baseline at 5 or more loci, and the same 5 loci showed improvement at 2 post-treatment assessments.

At week 26 post-treatment, 26% of patients in the pooled data set met the definition, and this number increased to 48% at week 52; in the control group, 20% were responders at week 26 and no additional data for week 52 (because patients in the control group are being treated after the assessments at week 26), he reported.

Sensitivity analysis using phase 3 criteria applied to the pooled data yielded 24% and 48%, respectively, at the same time point. In the control group, the responder rate was 0%.

Practical Considerations

Patients were subjected to a mobility maze 9 months after treatment to determine how the visual improvements could contribute to their ability to negotiate in a real-world environment.

Michaelides outlined that the results in the maze with a light level of 1 lux were obtained by a patient treated with the medium dose. When walking through the maze at baseline prior to treatment, the patient completed the maze in 61.7 seconds with 2 errors; At 9 months, the patient completed the maze in 16.4 seconds without fail.

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

Considering all treated patients, investigators observed a significant reduction in walking time at week 26 compared to baseline and compared to untreated controls. Using the phase 3 criteria, results were significant at lux levels of 1, 2, and 16.

“We found a good safety profile and saw improvements in retinal sensitivity and functional vision at 6 months compared to the control group,” concluded Michaelides. “Importantly, all areas of the low luminance questionnaire showed a positive trend, with the extreme lighting area being nominally significant. Given these strong results, a phase 3 study is ongoing.”

Michel Michaelides, MD
E: [email protected]

Michaelides is a consultant to MeiraGTx and the owner of MeiraGTx.

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