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)

• Published in: PloS one 2015-12, Vol.10 (12), p.e0143846
• Main Authors: Scholl, Hendrik P N, Moore, Anthony T, Koenekoop, Robert K, Wen, Yuquan, Fishman, Gerald A, van den Born, L Ingeborgh, Bittner, Ava, Bowles, Kristen, Fletcher, Emily C, Collison, Frederick T, Dagnelie, Gislin, Degli Eposti, Simona, Michaelides, Michel, Saperstein, David A, Schuchard, Ronald A, Barnes, Claire, Zein, Wadih, Zobor, Ditta, Birch, David G, Mendola, Janine D, Zrenner, Eberhart
• Format: Article
• Language: English
• Subjects: Abnormalities; Acetic acid; Acuity; Acyltransferase; Acyltransferases - genetics; Acyltransferases - metabolism; Administration, Oral; Adult; Anticarcinogenic Agents - adverse effects; Anticarcinogenic Agents - pharmacology; Anticarcinogenic Agents - therapeutic use; Cerebral Cortex - diagnostic imaging; Child; cis-trans-Isomerases - genetics; cis-trans-Isomerases - metabolism; Congenital diseases; Cortex (occipital); Defects; Disease; Diterpenes; Drug Dosage Calculations; Drug therapy; Eye (anatomy); Female; Functional magnetic resonance imaging; Gene therapy; Genetic engineering; Headache; Hemispheres; Hospitals; Humans; Lecithin; Male; Metabolism; Middle Aged; Mutation; Nausea; Occipital lobe; Optical Coherence Tomography; Oral administration; Patients; Photoreceptors; Physiological aspects; Polymorphism, Single Nucleotide; Radiography; Retina; Retinal degeneration; Retinal Ganglion Cells - pathology; Retinal Neurons - pathology; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - drug therapy; Retinoids; Retinyl Esters; Safety; Safety and security measures; Structure-function relationships; Treatment Outcome; Vision; Visual acuity; Visual Acuity - drug effects; Visual cortex; Visual fields; Visual Fields - drug effects; Vitamin A; Vitamin A - adverse effects; Vitamin A - analogs & derivatives; Vitamin A - pharmacology; Vitamin A - therapeutic use; Vomiting; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0143846

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. ClinicalTrials.gov NCT01014052.