AAO 2020: Gene therapy for X-linked retinitis pigmentosa achieves significant visual gains at 1 year


Gene therapy for X-linked retinitis pigmentosa is achieving significant visual gains at 1 year mark.

The 1-year data from an ongoing P\phase 1/2 trial (MGT009) (NCT03252847) of an investigational gene therapy for inherited X-linked retinitis pigmentosa (XLRP) showed significant and continued visual improvements in the study patients, all of whom have the most common and severe forms of XLRP resulting from mutations in the RPGR gene, and for which there is no currently available treatment.

The therapy, a novel adeno-associated virus RP GTPase regulator (AAV-RPGR), was developed jointly by Janssen Pharmaceutical Companies of Johnson & Johnson and MeiraGTx Holdings plc.

The major take-aways from the study were the anticipated and manageable safety profile at 1 year that supported moving into a phase 3 study and significant functional vision improvements observed in the time required by patients to walk through a vision-guided mobility maze at the 9-month time point.

The study

MGT009 is an open-label, multicenter, dose-escalation trial of AAV-RPGR. The study patients were 5 years of age and older and were enrolled at sites in the US and UK. The primary endpoints were safety and tolerability, and the secondary endpoints were changes in visual function over time.

The phase 1/2 clinical trial includes dose-escalation, dose-confirmation, and dose-expansion phases. In the dose-escalation phase, 10 adults received low- (3 patients), intermediate- (4 patients), or high-dose (3 patients) AAV-RPGR delivered by subretinal injection that targeted the central retina to their more affected eye. The fellow eye was the untreated control. The patients underwent perimetry and microperimetry at baseline and 3, 6, 9, and 12 months to assess baseline retinal function and changes over time.

The patients also negotiated a vision-guided mobility maze at baseline and 9 months to assess how they navigated through a range of different light levels from 1 to 256 lux (1 lux represented deep twilight, 4 lux residential street lighting, 16 lux twilight, 64 lux a car park, and 256 lux office work).


Regarding the primary endpoint, the results showed ocular and systemic safety profiles that were anticipated and manageable, according to the investigators. The most common adverse events were related to the surgical procedure and these were transient and resolved without treatment. In the high-dose cohort, inflammation was evident in 2 of the 3 adults, and measures of visual function did not improve.

Regarding the secondary endpoints, in the dose escalation phase, at 12 months, six of seven patients in the low- (n = 3) and intermediate- (n = 4) dose groups had improvement or stability in retinal sensitivity in the treated eye measured by full-field static perimetry and mesopic microperimetry.

The assessment of patient performance in the mobility maze at 9 months compared to baseline showed that 5 of 6 patients had an improvement in the time it took to walk through the maze at lux levels 1, 4, or 16.

The investigators saw significant improvement between the treated and untreated eyes in the low- and intermediate-dose groups at 1 lux, -16.1 seconds (90% confidence [CI]: 9.91, 22.1) and 4 lux, -3.71 seconds (90% CI: 2.83, 4.96). The greatest improvement was at the lowest light level (1 lux). The high-dose group did not participate in this assessment.

“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,” said Michel Michaelides, BSc, MB, BS, MD (Res), FRCOphth, FACS, a trial investigator and consultant ophthalmologist, Moorfields Eye Hospital, and professor of ophthalmology, University College London. He also is a scientific founder of, and consultant to, and has a financial relationship with MeiraGTx.

The European Medicines Agency (EMA) granted PRIME (PRIority MEdicines) and Advanced Therapy Medicinal Product (ATMP) designations to AAV-RPGR to increase interactions and optimize development plans based on data from the ongoing phase 1/2 clinical trial. The novel AAV-RPGR therapy also received Fast Track designation from the US Food and Drug Administration (FDA) and Orphan designations from the FDA and EMA.

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