TY - JOUR
T1 - 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)
AU - Scholl, Hendrik P N
AU - Moore, Anthony T
AU - Koenekoop, Robert K
AU - Wen, Yuquan
AU - Fishman, Gerald A
AU - van den Born, L Ingeborgh
AU - Bittner, Ava
AU - Bowles, Kristen
AU - Fletcher, Emily C
AU - Collison, Frederick T
AU - Dagnelie, Gislin
AU - Degli Eposti, Simona
AU - Michaelides, Michel
AU - Saperstein, David A
AU - Schuchard, Ronald A
AU - Barnes, Claire
AU - Zein, Wadih
AU - Zobor, Ditta
AU - Birch, David G
AU - Mendola, Janine D
AU - Zrenner, Eberhart
PY - 2015
Y1 - 2015
N2 - UNLABELLED: 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 REGISTRATION: ClinicalTrials.gov NCT01014052.
AB - UNLABELLED: 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 REGISTRATION: ClinicalTrials.gov NCT01014052.
KW - Acyltransferases/genetics
KW - Administration, Oral
KW - Adult
KW - Anticarcinogenic Agents/adverse effects
KW - Cerebral Cortex/diagnostic imaging
KW - Child
KW - Diterpenes
KW - Drug Dosage Calculations
KW - Female
KW - Humans
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - Radiography
KW - Retinal Ganglion Cells/pathology
KW - Retinal Neurons/pathology
KW - Retinitis Pigmentosa/drug therapy
KW - Treatment Outcome
KW - Visual Acuity/drug effects
KW - Visual Fields/drug effects
KW - Vitamin A/adverse effects
KW - Young Adult
KW - cis-trans-Isomerases/genetics
U2 - 10.1371/journal.pone.0143846
DO - 10.1371/journal.pone.0143846
M3 - Article
C2 - 26656277
SN - 1932-6203
VL - 10
SP - e0143846
JO - PLoS ONE
JF - PLoS ONE
IS - 12
ER -