Late-Breaking Phase 1/2 Data Demonstrates Safety Profile of Investigational Gene Therapy Botaretigene Sparoparvovec (AAV-RPGR) and Sustained Vision Improvement in Patients with XLRP

MeiraGTx announced the primary results from the phase 1/2 study evaluating the investigational gene therapy botaretigene sparoparvovec (formerly AAV-RPGR) in patients with the inherited retinal disease X-linked retinitis pigmentosa (XLRP) associated with the retinitis pigmentosa GTPase regulator (RPGR) gene.

Treatment with botaretigene sparoparvovec was found to have an acceptable safety profile and efficacy assessments in this proof-of-concept study demonstrated improvements in retinal sensitivity, visual function and functional vision.[1] These findings were presented in a late-breaking oral presentation today at the Retina Subspecialty Day program of the American Academy of Ophthalmology (AAO) 2022 Annual Meeting (Abstract #30071754) by Professor Michel Michaelides.

“We are excited to present these promising phase 1/2 data from our investigational gene therapy, botaretigene sparoparvovec in the late breaking session at this year’s AAO meeting,” Alexandria Forbes, PhD, president, and chief executive officer of MeiraGTx, said in a company news release. “The treatment appears to be safe and well-tolerated, and the improvements observed in each visual domain at six months post-treatment underscores the potential of botaretigene sparoparvovec to address a significant unmet need for those living with XLRP. We look forward to advancing this program which is currently dosing patients in phase 3 LUMEOS trial.”

“Botaretigene sparoparvovec therapy is intended to deliver a healthy copy of the RPGR gene to replace a disease causing one, and potentially restore vision for patients living with XLRP,” said Michel Michaelides, B.Sc., M.B., B.S., M.D. (Res), FRCOphth, FACS, Consultant Ophthalmologist, Moorfields Eye Hospital, Professor of Ophthalmology, University College London and MGT009 study investigator. “The results presented so far show a positive effect of the therapy compared to the randomized untreated control arm, providing us with increased confidence in its potential to treat the underlying cause of XLRP.”

MeiraGTx and Janssen Pharmaceuticals, part 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.

The primary endpoint of the MGT009 study (NCT03252847) was safety, with secondary endpoints measuring changes in assessments of three domains of vision—retinal sensitivity, visual function and functional vision—at specified time points post-treatment.[1] In the study’s dose escalation and expansion phases, sustained or increased functional improvement in each visual domain was observed in participants treated with botaretigene sparoparvovec compared to the randomized untreated control arm of the study at six months post-treatment.[1]

Analyses of the pooled low and intermediate dose cohorts demonstrated improvement in retinal sensitivity in the treated eyes compared to untreated eyes in the randomized concurrent control arm as measured by both full-field static perimetry and microperimetry.[1] An improvement in mean retinal sensitivity as measured by static perimetry in the central 10-degree area of the retina was observed at 6 months in the treated eye compared to untreated eyes in the randomized concurrent control arm [in the full analysis of pooled low and intermediate doses across adults: 1.96 decibel (dB); (±95% CI: 0.59, 3.34); and in the sensitivity analysis when applying the Phase 3 criteria: 2.42 (0.91, 3.93)].[1]

As part of the study, patients performed a functional vision assessment using a visual mobility maze to assess their ability to navigate through simulated real-life obstacles across a broad range of controlled light. At week 26, improvement in walk time was observed between the treated eyes in the low and intermediate dose cohorts and the untreated eyes in the randomized concurrent control arm at low illumination levels (full analysis nominal p-value < 0.05 at lux 1 and lux 16; in the sensitivity analysis when applying the Phase 3 criteria nominal p-value < 0.01 at lux1, lux 4 and lux 16).[1]

The safety profile of botaretigene sparoparvovec observed in MGT009 was consistent with previous reports.[1] Botaretigene sparoparvovec demonstrated an adverse event (AE) profile that was anticipated and manageable.[1] Most AEs were related to the surgical delivery procedure, were transient and resolved without intervention.[1] There were no dose-limiting events.[1] A total of three serious adverse events (SAEs) were observed in the overall phase 1/2 MGT009 clinical study; two SAEs, which were previously reported, were observed in the dose-escalation phase of the study (n=10; one retinal detachment and one panuveitis in the low dose cohort), and a single additional SAE of increased intraocular pressure was observed in the dose escalation phase and resolved with treatment.[1]

Further sensitivity analysis was conducted on study participants by applying the phase 3 LUMEOS (NCT04671433) study eligibility criteria that corroborated the endpoints selected for the phase 3 study.[1] Currently, the LUMEOS study of botaretigene sparoparvovec for the treatment of patients with XLRP with disease-causing variants in the RPGR gene is actively dosing patients.

Session Details:

Saturday, 8:55AM - 9:30AM CT

Section X: Late Breaking Developments, Part II

Presentation details:

Abstract Title: Ph1/2 AAV5-RPGR (Botaretigene Sparoparvovec) Gene Therapy Trial in RPGR-associated X-linked Retinitis Pigmentosa (XLRP)

Presenter: Michel Michaelides, Professor of Ophthalmology, UCL Institute of Ophthalmology in Dept. of Genetics

Date and Time: Saturday, October 1, 2022, at 9:00 a.m. CT (10:00 a.m. ET)

About the Phase 1/2 MGT009 Clinical Trial and Botaretigene Sparoparvovec

The phase 1/2 MGT009 clinical trial (NCT03252847) study was an open-label, multicenter dose escalation study that enrolled patients aged five years and older with XLRP caused by disease causing variants in the retinitis pigmentosa GTPase regulator (RPGR) gene at multiple sites in the United States and the United Kingdom. The primary endpoint was safety and tolerability; secondary endpoints assessed retinal function, visual function, functional vision and quality of life measurements.

The clinical study was composed of three parts: dose-escalation, pediatric dose-confirmation and an expansion phase. In the dose escalation phase, subjects were treated at three escalating doses of botaretigene sparoparvovec; a low (2x1011 vg/mL), an intermediate (4x1011 vg/mL), and a high (8x1011 vg/mL) dose. In the expansion phase, 42 adult male patients were randomized to either immediate treatment with one of two low or intermediate doses or an untreated concurrent control arm with deferred treatment. At six months, the untreated control arm was randomized to receive either the low or intermediate treatment doses. Botaretigene sparoparvovec was administered through subretinal delivery in only one eye. The adult patients received treatment at three doses, and the pediatric cohort (n=3) was treated with an intermediate dose of botaretigene sparoparvovec.

Botaretigene sparoparvovec has been granted Fast Track and Orphan Drug designations by the FDA and PRIority MEdicines (PRIME), Advanced Therapy Medicinal Product (ATMP) and Orphan designations by the European Medicines Agency (EMA).