Reviewed by Michel Michaelides, MD
Botaretigene sparoparvovec gene therapy (formerly AAV5-RPGR; MeiraGTx Holdings plc and Janssen Pharmaceuticals, Inc) for the treatment of a common and severe form of retinitis pigmentosa (RP), RPGR– associated X-linked RA, demonstrated improvements in retinal sensitivity and visual function compared to controls and had a manageable adverse event profile, according to Michel Michaelides, MD, of the University of College London Institute of Ophthalmology and Moorfields Eye Hospital in London, United Kingdom.
In a 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, mid and high doses of gene therapy administered to 3, 4 and 3 adults, respectively. An intermediate dose was also administered to 3 children.
The study design also included an expansion phase once dosing was confirmed; the expansion cohort included low- and mid-dose arms with 8 and 11 patients, respectively, and a concurrent control arm in which a low or mid-dose was delayed for 6 months in 13 patients, Michaelides said.
All patients in the study were boys 5 years of age and older and had RA resulting from a pathogenic variant in RPGR. In addition, optical coherence tomography showed relative preservation of central retinal structure.
Safety of gene therapy
Michaelides reported that AAV5-RPGR gene therapy demonstrated an adverse event profile that was anticipated and manageable. Most events were associated with surgery to deliver the vector and resolved without intervention.
During the dose escalation phase, 1 retinal detachment developed and resolved with treatment, as well as 1 case of low dose associated panuveitis. In the dose expansion phase, intraocular pressure increased in 1 patient and resolved with treatment. When a supplemental steroid regimen was used during the expansion phase, inflammation-related adverse events decreased, Michaelides explained.
Efficacy of gene therapy
Pooled data from the low and mid-dose groups showed improvement in mean retinal sensitivity in adults at 6 months compared to untreated controls. The treatment showed an improvement of 2 decibels seen with static perimetry compared to controls and 1 decibel with microperimetry, Michaelides noted. A sensitivity analysis based on the Phase 3 criteria resulted in the exclusion of 2 patients each from the treatment and control groups. Once they have been excluded, greater significance (P < 0.001) the difference was evident.
A point responder analysis of static perimetry of pooled data from adults treated with low and mid doses showed improvement with 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, with the same 5 loci showing improvement at 2 ratings after treatment.
At week 26 post-treatment, 26% of patients in the pooled data group met the definition of responder, and this increased to 48% at week 52. In the control group, 20% were responders at week 26 , with no additional data for week 52 (because patients in the control group receive treatment after the week 26 assessments), Michaelides reported.
Sensitivity analysis using the 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%.
Patients were exposed to a mobility maze 9 months after treatment to determine how visual improvements might contribute to their ability to negotiate in a real environment.
Michaelides highlighted the results obtained in the maze with a light level of 1 lux by a patient treated with the intermediate dose. When the patient walked through the maze initially before treatment, he completed the maze in 61.7 seconds with 2 errors; at 9 months, the patient walked through the maze in 16.4 seconds without error.
“It’s a dramatic portrayal of the impact this gene therapy can have,” Michaelides said.
When examining all treated patients, researchers observed significant reductions in walking time at week 26 compared to baseline and compared to untreated controls. When the Phase 3 criteria were applied, the 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 compared to [with] the control group at 6 months,” concluded Michaelides. “Importantly, all domains of the low luminance questionnaire trended positively, with the extreme illumination domain being nominally significant. Given these strong results, a Phase 3 study is underway.
Michel Michaelides, MD
Michaelides is a consultant and owns shares in MeiraGTx Holdings plc.
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