Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT)

Abstract

Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18 patients with RPE65- or LRAT-related retinitis pigmentosa. Eight of 18 patients (44%) showed a ≥20% increase and 4 of 18 (22%) showed a ≥40% increase in functional retinal area determined from Goldmann visual fields; 12 (67%) and 5 (28%) of 18 patients showed a ≥5 and ≥10 ETDRS letter score increase of visual acuity, respectively, in one or both eyes at two or more visits within 2 months of treatment. In two patients who underwent fMRI, a significant positive response was measured to stimuli of medium contrast, moving, pattern targets in both left and right hemispheres of the occipital cortex. There were no serious adverse events. Treatment-related adverse events were transient and the most common included headache, photophobia, nausea, vomiting, and minor biochemical abnormalities. Measuring the outer segment length of the photoreceptor layer with high-definition optical coherence tomography was highly predictive of treatment responses with responders having a significantly larger baseline outer segment thickness (11.7 ± 4.8 μm, mean ± 95% CI) than non-responders (3.5 ± 1.2 μm). This structure-function relationship suggests that treatment with QLT091001 is more likely to be efficacious if there is sufficient photoreceptor integrity.Trial RegistrationClinicalTrials.gov NCT01014052

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

“…[55][56][57] In RPGRIP1 knock-out mice, both improved outer segment morphology and photoreceptor survival, and better preservation of ERG responses have been demonstrated with RPGRIP1 gene replacement using both AAV2 and AAV8 vectors. 71 72 Improved photoreceptor function up to 24 months postsubretinal injection has also been shown in the canine model.…”

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

“…Currently, no approved pharmacological treatment is available, although phase 1b trials of oral 9-cis-retinyl acetate have shown transient increases in Goldmann visual fields area in some participants. 26,27 Here, we report the design, conduct, and safety and efficacy results of a phase 3 study of sequential, bilateral, subretinal administration of voretigene neparvovec in participants with RPE65- mediated inherited retinal dystrophy. To our knowledge, this is the first randomised, controlled, phase 3 study of a gene therapy for a genetic disease.…”

Molecular Basis for Vitamin A Uptake and Storage in Vertebrates

“…Similar results were obtained using chemically inert and more tolerable 9- cis -retinyl acetate or 9- cis -retinyl succinate that serve as pro-drug forms of 9- cis -retinal [137]. In the initial clinical trial (phase 1b) oral administration of 40 mg/m 2 of 9- cis -retinyl acetate (QLT091001) for seven consecutive days resulted in expansion of functional retinal area in 71% of enrolled LCA patients, 43% displayed improved visual acuity [138,139]. Importantly, these functional changes were associated with healthier retinal morphology measured as thinness of photoreceptor cell outer segments.…”