Late-Breaking 12-Month Data of Investigational RPGR Gene Therapy Shows Statistically Significant and Continued Vision Improvement in Patients with XLRP

The Janssen Pharmaceutical Companies of Johnson & Johnson announced new 12-month data from the ongoing phase 1/2 trial (NCT03252847) of its investigational gene therapy for inherited retinal disease X-linked retinitis pigmentosa (XLRP). The data showed that low and intermediate doses were well-tolerated and continued to demonstrate statistically significant sustained or increased vision improvement across multiple metrics (mean sensitivity, volumetric and pointwise) and modalities (full-field static perimetry and microperimetry). Data on the novel adeno-associated virus retinitis pigmentosa GTPase regulator (AAV-RPGR), jointly developed with MeiraGTx Holdings, were presented as a late-breaking study at the American Academy of Ophthalmology (AAO) 2020 Virtual Annual Meeting.

In patients with XLRP, the photoreceptors that are responsible for converting light into signals that are sent to the brain, function poorly, leading to degeneration of the retina and legal blindness in adulthood. The companies’ AAV-RPGR gene therapy is being investigated for the most common and severe forms of XLRP caused by mutations in the RPGR gene by preserving and improving vision and slowing retinal degeneration. Currently, there are no available treatments.

“Living with XLRP is extremely devastating for patients and their families, as there is no treatment available and they live each day knowing they will eventually go blind,”Michel Michaelides,[1] B.Sc., MB, BS, MD (Res), FRCOphth, FACS, trial investigator, Consultant Ophthalmologist, Moorfields Eye Hospital, Professor of Ophthalmology, University College London, said in a company news release. “The continuous upward trend in efficacy we’ve observed through 1 year with this gene therapy is extremely promising as a potential way to halt the progression toward blindness in these patients.”

The primary endpoint of the trial is safety, with secondary endpoints assessing changes in visual function at pre-specified timepoints post-treatment. Baseline values were determined in triplicate. In the dose escalation phase, at 12 months, six of seven patients in the low (n=3) and intermediate (n=4) doses demonstrated improvement or stability in retinal sensitivity in the treated eye as measured by full-field static perimetry and mesopic microperimetry.[2]

• Statistically significant differences in mean retinal sensitivity were observed between treated and untreated eyes in the intermediate dose cohort: 1.05 decibel (dB); (90% CI: 0.81, 1.29).
• Statistically significant differences were observed in central visual field progression rate (V30) between treated and untreated eyes in the low: 1.10 dB-sr (steradian)/year; (90% CI: 0.10, 2.10) and intermediate: 1.26 dB-sr/year; (90% CI: 0.65, 1.86) dose cohorts.
• Efficacy signals were observed at first post-treatment assessments at three months with improvements sustained or increased at 12 months.

Safety data to date has demonstrated ocular and systemic safety profiles that are anticipated and manageable. The most common adverse events were related to the surgical procedure, transient and resolved without intervention. In the high dose cohort (n=3), inflammation was evident in two of three adults, and measures of visual function were not improved.

“We have a great sense of urgency to meet the needs of patients living with XLRP. They need transformational treatment as soon as possible to give them the best chance of maintaining their sight,” James List, MD, PhD, Global Therapeutic Area Head, Cardiovascular & Metabolism, Janssen Research & Development, said in the news release. “With our positive 12-month AAV-RPGR data, the stage is now set for advancement into phase 3, bringing us one step closer to our goal of preserving, and potentially improving, vision for these patients.”

Vision-Guided Mobility Data

As part of the study, patients performed a vision-guided mobility maze at baseline and nine-months to assess their ability to navigate across a broad range of controlled light levels (1 lux = deep twilight, 4 lux = residential street lighting, 16 lux = twilight conditions, 64 lux = car park and 256 lux = office work).

In the nine-month analysis, compared to baseline:

• Five of six patients demonstrated improvement in walk time for the treated eye at lux levels 1, 4 or 16.
• Significant improvement was observed between treated and untreated eyes in the low and intermediate dose cohorts (n=6) at 1 lux, -16.1 seconds (90% CI: 9.91, 22.1) and 4 lux, -3.71 seconds (90% CI: 2.83, 4.96); with the greatest improvement at the lowest light level (1 lux).

Vision-guided mobility assessment was not carried out in the high dose cohort at the nine-month timepoint due to an implemented protocol revision to align with the dose-expansion cohort assessment schedule.