Gene Therapy Restores Vision in Children with
AIPL1-Related Retinal Dystrophy

• As disclosed in the paper, 4 out of 4 young children with the AIPL1-related retinal dystrophy, LCA4, benefited substantially from unilateral subretinal administration of rAAV8.hRKp.AIPL1 with improved visual acuity, functional vision, and protection against progressive retinal degeneration
• Following the strong safety and substantial efficacy demonstrated in this first cohort of 4 children treated unilaterally, a further 7 children have now been treated bilaterally and all showed substantial benefit from treatment with rAAV8.hRKp.AIPL1
• Meaningful responses have been observed in 11 out of 11 LCA4 children treated to date with rAAV8.hRKp.AIPL1
• All 11 children treated with rAAV8.hRKp.AIPL1 between 1 and 4 years old were legally blind at birth, and all gained visual acuity after 4 or more weeks following a single one time delivery of rAAV8.hRKp.AIPL1

MeiraGTx Holdings, a vertically integrated, clinical stage genetic medicines company, today announced the publication of results from the first-in-human interventional study to treat children with AIPL1-associated severe retinal dystrophy. The data were published in The Lancet in a paper titled, “Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study“. This paper presents data from the first 4 children treated unilaterally with rAAV8.hRKp.AIPL1. A further 7 children with LCA4 were treated bilaterally with rAAV8.hRKp.AIPL1 demonstrating similarly remarkable effects on vision, with all 11 of the 11 children treated who were blind at birth now having visual acuity in the treated eyes.

Retinal dystrophy due to genetic deficiency of AIPL1 causes severe impairment of sight from birth. The study published today in The Lancet sought to evaluate whether early intervention by gene supplementation therapy was safe and could improve outcomes in young children with this condition. The findings indicate that children under the age of 4 years old with AIPL1-related retinal dystrophy benefited substantially from subretinal administration of rAAV8.hRKp.AIPL1, with improved visual acuity and functional vision and evidence of protection against progressive retinal degeneration, without serious adverse effects.

The non-randomized, single-arm, clinical study conducted in the UK involved four children aged one year to three years with severe retinal dystrophy associated with biallelic disease-causing sequence variants in AIPL1. The genetic medicine was a recombinant adeno-associated viral vector, comprising the human AIPL1 coding sequence driven by a human rhodopsin kinase promoter region (rAAV8.hRKp.AIPL1). The product was manufactured under a Specials License from the UK Medicines and Healthcare products Regulatory Authority (MHRA) and made available to affected children with local ethics approval. The product was administered to one eye of each child by subretinal injection. Outcome measures included visual acuity (as assessed with standard-of-care testing as well as a novel touchscreen test), functional vision (assessed by observing and recording the children’s visual behavior and their ability to perform simple vision-guided tasks), visual evoked potentials (assessed by recording cortical electrophysiological responses to full-screen black-and-white flickering stimuli), and retinal structure (assessed with handheld OCT and widefield fundus imaging).

Prior to intervention, the children’s binocular visual acuities (VA) were limited to perception of light. At a mean of 3.5 years (range 3.0 to 4.1 years), after intervention the VAs of their treated eyes improved to a mean of 0.9 logarithm of the minimal angle of the minimum angle of resolution (LogMAR) (range 0.8 to 1.0); VAs before intervention were equivalent to 2.7 LogMAR. In contrast, the VAs of their untreated eyes became unmeasurable at the final follow-up. In the 2 children able to comply with testing, an objective test of VA confirmed improvements in visual function, and measurement of visual evoked potentials showed enhanced activity of the visual cortex, specific to the treated eyes. In 3 of the children, structural lamination of the outer retina was better preserved in the treated eye than in the untreated eye, and, for all 4 children, retinal thickness appeared better preserved in the treated eye than in the untreated eye.

To date, two cohorts of children have been treated with rAAV8.hRKp.AIPL1. The first cohort of 4 children (data published in The Lancet) received treatment in one eye. A second cohort has now been treated, with 7 children (ages 1 to 3 years old) receiving sequential bilateral treatment. Meaningful responses have been observed in all 11 out of 11 LCA4 children treated with rAAV8.hRKp.AIPL1 to date.

“We are incredibly excited to see the transformative effect of treatment with rAAV8.hRKp.AIPL1 in every one of the young children who received this genetic medicine,” said Alexandria Forbes, Ph.D., president and chief executive officer of MeiraGTx. “LCA4 is one of the most severe forms of inherited blindness and the results from these 11 young children are truly remarkable. The improvements demonstrated are unrivalled in treatment benefit compared to any ocular gene therapy in any IRD. These improvements extended outside the meaningful effects on vision and result in life-changing benefits in all areas of development including communication, behavior, schooling, mood, psychological benefits and social integration.” Dr. Forbes continued, “With these truly exceptional results in hand, we are working with global regulators on expedited approval of rAAV8.hRKp.AIPL1 to provide access to babies born with AIPL1-related LCA4.”

Following recent meetings with the MHRA, the Company intends to submit a Marketing Authorization Application (MAA) under exceptional circumstances for rAAV8.hRKp.AIPL1 based on the results from the 11 treated children with no further clinical data required, and the Company has aligned on an expedited CMC package to support approval. The Company is also currently engaging with the Food and Drug Administration (FDA) to discuss a path forward for expedited approval in the United States.

rAAV8.hRKp.AIPL1 has been granted orphan drug as well as rare pediatric disease designation (RPDD) by the FDA and orphan designation by the European Commission.

A replay of the webcast will be available on the Investors & Media page of the Company’s website.

Source – MeiraGTx