New data from Phase 1/2 clinical study of gene therapy for patients with X-linked retinitis pigmentosa announced by MeiraGTx

According to the company, the primary outcome of the MGT009 study is safety, and botaretigene sparoparvovec treatment was found to be generally safe and well-tolerated.

MeiraGTx announced top-line data from the Phase 1/2 clinical study MGT009 (NCT03252847) of botaretigene sparoparvovec (formerly referred to as AAV-RPGR), an investigational gene therapy in development for the treatment of patients with X-linked retinitis pigmentosa (XLRP) with disease-causing variants in the RPGR gene.

Treatment with botaretigene sparoparvovec was found to be generally safe and well-tolerated, and significant improvements were demonstrated in multiple endpoints across each of the three domains of vision—retinal function, visual function, and functional vision—in participants treated with botaretigene sparoparvovec when compared to the randomized untreated control arm of the study at 6 months post-treatment.

MeiraGTx and Janssen Pharmaceuticals, Inc. (Janssen), one of the Janssen Pharmaceutical Companies of Johnson & Johnson, are jointly developing botaretigene sparoparvovec as part of a broader collaboration to develop and commercialize gene therapies for the treatment of inherited retinal diseases.

In the dose escalation and expansion phases of the MGT009 study, improvements in vision were seen in subjects treated with low and intermediate doses of botaretigene sparoparvovec compared to the randomized concurrent control arm at 6 months. Improvements were demonstrated in retinal sensitivity on static perimetry, using both pointwise responder analysis as well as mean retinal sensitivity analysis; functional vision in a vision-guided mobility assessment (VMA); and other measures of visual function and functional vision, including visual acuity using ETDRS and patient-reported outcome measures.

“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,” said Michel Michaelides, BSc MB BS MD(Res) FRCOphth FACS, MGT009 trial investigator, consultant ophthalmologist, Moorfields Eye Hospital and Professor of Ophthalmology, at Moorfields Eye Hospital and University College London. “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.”

Michaelides also is a scientific founder of and consultant to MeiraGTx.

Alexandria Forbes, PhD, president and chief executive officer of MeiraGTx, said the company is

encouraged by these data, which demonstrate improvement following treatment with botaretigene sparoparvovec compared to an untreated randomized control group in a range of endpoints that are relevant to this severe disease.

“These data give us increased confidence in the potential for botaretigene sparoparvovec to meaningfully improve the lives of the thousands of patients with XLP,” Forbes explained.

Forbes also pointed out that as the company continues to enroll the Lumeos Phase 3 study, it is leveraging its wholly-owned, end-to-end GMP manufacturing and quality infrastructure to prepare for potential commercial supply.

The Phase 3 Lumeos study (NCT04671433) of botaretigene sparoparvovec for the treatment of patients with XLRP with disease-causing variants in the RPGR gene is actively dosing patients.

The Phase 1/2 MGT009 clinical study consists of three phases: dose-escalation, pediatric dose-confirmation, and an expansion phase. In the dose escalation phase, subjects were treated at 3 escalating doses of botaretigene sparoparvovec; a low dose of 2x1011vg/mL, an intermediate dose of 4x1011 vg/mL, and a high dose of 8x1011 vg/mL. In the expansion phase, subjects were randomized to either immediate treatment with one of 2 doses, the low or intermediate dose, or an untreated concurrent control arm with deferred treatment.

According to the company, at 6 months, the untreated control subjects were randomized to receive either the low or intermediate treatment doses. Throughout the MGT009 study, a total of 42 adult male subjects were treated with botaretigene sparoparvovec at 3 doses and 3 children were treated at the intermediate dose. Each patient was treated with subretinal delivery of botaretigene sparoparvovec in only one eye.

The primary endpoint of the Phase 1/2 MGT009 clinical study is safety in all patients treated with botaretigene sparoparvovec (n = 45), with exploratory efficacy endpoints measuring changes in assessments of each of the three domains of vision (retinal function, visual function and functional vision) at pre-specified timepoints post-treatment.

Safety findings

Safety findings from MGT009 demonstrate that botaretigene sparoparvovec is generally safe and well-tolerated. Most adverse events (AEs) were related to the surgical delivery procedure, were transient and resolved without intervention. There were no dose-limiting events. A total of 3 serious adverse events (SAEs) were observed in the overall Phase 1/2 MGT009 clinical study. 2 SAEs were observed in the dose-escalation phase of the study (n = 10; 1 retinal tear and 1 panuveitis in the low dose cohort), which have been previously reported. A single additional SAE was observed in the dose expansion phase of the study (n = 32). This SAE was increased IOP and resolved on treatment. No SAEs were observed in the pediatric dose confirmation cohort.

Following the implementation of a modified prophylactic steroid regimen, a reduction in inflammation related AEs was also observed in the expansion phase of the study.

Exploratory efficacy findings

MGT009 demonstrated improvements in each of the three visual domains. Based on nominal p-values (p < 0.05) the following endpoints were significant at 6 months compared to randomized control subjects. In the overall population of immediate treated subjects in just the randomized expansion phase of the study, using the prespecified exploratory analyses, the VMA at lux 1, patient reported outcome (PRO) extreme lighting and mean retinal sensitivity (meanRS) in the central 10 degree area of the retina, demonstrated significant improvement and BCVA approached significance (P < 0.10).

Further analyses reported below were conducted on the population of low and intermediate dose immediate treated subjects from both the dose escalation and the expansion phases of the study applying the Phase 3 Lumeos eligibility criteria. Based on nominal p-values (p < 0.05) the following endpoints were significant at 6 months compared to randomized control subjects:

Functional vision

Performance in the visual mobility assessment (VMA) at low levels of illumination. The relative improvement in treated patients compared to untreated patients increased as illumination levels progressively got darker (nominal p-values were 0.008, 0.005 and 0.008 at lux 16, 4, and 1 respectively).

According to investigators, a significant improvement was observed in the extreme lighting domain of the disease related PRO at 6 months (nominal p-value = 0.020), with trends of improvements in the other patient-reported outcome domains also observed.

Moreover, ETDRS visual acuity (nominal p-value = 0.031), and meanRS in the central 10 degree area of the retina (nominal p-value < 0.001).

The responder criteria showed at least a 7dB improvement from baseline in 5 or more individual loci with the same 5 loci showing improvement at 2 timepoints following treatment. At 26 weeks 5/22 (22.7%) of the treated patients met the responder criteria compared to 0/11 (0%) in the randomized concurrent control arm. The responder rate in the treated arm further improved at 52 weeks to 10/21 (47.6%).

Based on these results, the improvements seen in each of the three visual domains is entirely in keeping with the real-life challenges patients with XLRP experience, having marked functional difficulties especially at low light levels.

According to the company, additional MGT009 data will be submitted for presentation at medical meetings in the second half of this year.