Interim Six-Month Data of RPGR Gene Therapy Shows Significant Vision Improvement in Patients Living with X-Linked Retinitis Pigmentosa

July 18, 2020 /BioonBIOON/ -- Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson (JNJ), recently announced six-month data from the ongoing Phase I/II trial MGT009 (NCT03252847) at the 2020 Virtual Annual Meeting of the American Society of Retina Specialists (ASRS). The trial is evaluating the investigational gene therapy AAV-RPGR (adeno-associated virus retinitis pigmentosa GTPase regulator, administered via subretinal injection) for the treatment ofGeneticsX-linked Retinitis Pigmentosa (XLRP). Interim data showed that low and medium doses of AAV-RPGR were well tolerated and indicated significant improvement in vision.

AAV-RPGR is an investigational gene therapy designed to treat patients with X-linked retinitis pigmentosa (XLRP) caused by mutations in the eye-specific RPGR gene (RPGR ORF15). AAV-RPGR aims to deliver a functional copy of the RPGR gene to the subretinal space, thereby improving and maintaining visual function. AAV-RPGR is being co-developed by Janssen and MeiraGTx Holdings for the treatment of patients with XLRP harboring RPGR ORF15 mutations. The data announced herein represent the first data release from this collaborative partnership.

Based on the data from this study, the European Medicines Agency (EMA) granted AAV-RPGR Priority Medicines (PRIME) and Advanced Therapy Medicinal Product (ATMP) designations, which will enhance regulatory interactions and optimize the development plan. The U.S. Food and Drug Administration (FDA) also granted AAV-RPGR Fast Track Designation (FTD). In addition, the EMA andFDAOrphan Drug Designation (ODD) was also granted to AAV-RPGR.

In patients with X-linked retinitis pigmentosa (XLRP), photoreceptors—the cells in the eye responsible for converting light into signals and transmitting them to the brain—are dysfunctional, leading to retinal degeneration and blindness in adulthood. AAV-RPGR is an investigational gene therapy designed to treat the most common and severe form of XLRP caused by mutations in the RPGR gene, aiming to protect and improve vision by slowing retinal degeneration. Currently, there are no approved treatments for this condition.

XLRP (Image source: oxfordbrc.nihr.ac.uk)

This ongoing Phase I/IIClinical TrialThe study is divided into three phases: dose escalation, dose confirmation, and dose expansion. During the dose escalation phase (n=10), adult patients received low, medium, or high doses of AAV-RPGR therapy. AAV-RPGR was administered via subretinal injection, targeting the central retina of the eye with greater baseline impairment, while the fellow eye served as a non-treated control. In the study, multiple retinotomies were permitted to cover the maximum possible area of salvageable retina.

Visual field testing (perimetry) will be conducted using the Octopus 900 full-field static perimetry and the MAIA fundus-tracking microperimetry at baseline, 3 months, 6 months, 9 months, and 12 months to assess baseline retinal function and changes over time. Patients must have evidence of relatively preserved macular retinal structure and be capable of undergoing age-appropriate clinical assessments. Perimetry is a sensitive and standardized method for evaluating retinal function, providing reproducible measurements of retinal sensitivity in both cross-sectional and longitudinal dimensions, thereby accurately determining disease progression over time. The primary endpoint of this trial is safety, and the secondary endpoint is the assessment of changes in visual function at prespecified time points after treatment.

During the dose-escalation phase, at 6 months of treatment, the low-dose group (n=3) and the medium-dose group (n=4) demonstrated significant improvements in retinal sensitivity compared to baseline. Importantly, these improvements were evident when assessed using two perimetric methods (static perimetry and microperimetry) and three analytical measures (mean retinal sensitivity, Hill of Vision volume within the central 30° visual field [V30], and pointwise comparison).

These interim results from participants in the Phase I/II trials indicate that the study findings are of significant importance:(1) In the medium-dose group, there was a significant difference in mean retinal sensitivity between treated and untreated eyes: 1.02 decibels (dB); (90% CI: 0.75, 1.31). (2) In the low-dose group (1.10 dB·sr (steradian)/year; (90% CI: 0.10, 2.10)) and the medium-dose group (1.26 dB·sr/year) (90% CI: 0.65, 1.86), there were significant differences in the rate of central visual field progression (V30) between treated and untreated eyes. (3)Efficacy signals were observed in the first post-treatment assessment at 3 months, with sustained or increased improvement at 6 months.

The safety data obtained to date demonstrate an expected and manageable ocular and systemic safety profile. The most common adverse events were surgery-related, transient, and resolved without intervention. In the high-dose group (n=3), two-thirds of adult patients exhibited significant inflammatory responses, with no improvement in measures of visual function.

Dr. James List, Head of the Global Therapeutic Area for Cardiovascular and Metabolism at Janssen Research & Development, stated, “These findings demonstrate the potential of our investigational AAV-RPGR gene therapy to not only preserve but also improve vision in patients with X-linked retinitis pigmentosa (XLRP). We are encouraged by the data observed to date and look forward to sharing future results and advancing our clinical development program.”

In January 2019, Janssen entered into a global collaboration and license agreement with clinical-stage gene therapy company MeiraGTx Holdings plc to develop, manufacture, and commercialize its clinical-stageHeredityX-linked Retinal Disease Portfolio. AAV-RPGRGene Therapywas developed under this Collaboration and License Agreement. In addition to forming the research collaboration, exploring otherGeneticsIn addition to new targets for retinal diseases, Janssen has also collaborated with MeiraGTx to establish viralVectorCore Competencies in Design, Optimization, and Manufacturing.

In addition to AAV-RGRP, the two parties are also developing two gene therapies for the treatment of achromatopsia: AAV-CNGB3 and AAV-CNGA3. These two gene therapies are delivered via subretinal injection to the retinal region containing the majority of cone cells, aiming to restore cone cell function. AAV-CNGB3 has been granted Orphan Drug Designation (ODD), Rare Pediatric Disease Designation, and Fast Track Designation (FTD) in the United States, and has received Orphan Drug Designation (ODD) and PRIME designation in the European Union.(Bioon.com)

Original Source:Interim Six-Month Data of RPGR Gene Therapy Shows Significant Vision Improvement in Patients Living with X-Linked Retinitis Pigmentosa