title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01014052.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: Hendrik P N
authors.initials: HP
authors.lastname: Scholl
authors.affiliation: Moorfields Eye Hospital and Institute of Ophthalmology, University College London, London, United Kingdom.|Dept. of Ophthalmology, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX, United States of America.|Baylor Visual Function Center, Baylor University Medical Center, Dallas, TX, United States of America.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Chicago Lighthouse, Pangere Center for Inherited Retinal Diseases, Chicago, IL, United States of America.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Fishman
authors.affiliation: Rotterdam Eye Hospital and Ophthalmic Institute, Rotterdam, The Netherlands.
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, United States of America.|Nova Southeastern University, College of Optometry, Fort Lauderdale, FL, United States of America.
authors.forename: Ava
authors.initials: A
authors.lastname: Bittner
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, United States of America.|College of Optometry, University of Houston, Houston, TX, United States of America.
authors.forename: Kristen
authors.initials: K
authors.lastname: Bowles
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, United States of America.|Gloucester Royal NHS Foundation Trust, Gloucester Royal Hospitals, Gloucester, United Kingdom.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Fletcher
authors.affiliation: Chicago Lighthouse, Pangere Center for Inherited Retinal Diseases, Chicago, IL, United States of America.
authors.forename: Frederick T
authors.initials: FT
authors.lastname: Collison
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: Gislin
authors.initials: G
authors.lastname: Dagnelie
authors.affiliation: Moorfields Eye Hospital and Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Simona
authors.initials: S
authors.lastname: Degli Eposti
authors.affiliation: Moorfields Eye Hospital and Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: Vitreoretinal Associates of Washington, Seattle, WA, United States of America.|QLT Inc., Vancouver, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Saperstein
authors.affiliation: QLT Inc., Vancouver, Canada.|Stanford Univ School of Medicine, Palo Alto, CA, United States of America.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Schuchard
authors.affiliation: QLT Inc., Vancouver, Canada.|VA Palo Alto Health Care System, Palo Alto, CA, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Barnes
authors.affiliation: Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Wadih
authors.initials: W
authors.lastname: Zein
authors.affiliation: Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Ditta
authors.initials: D
authors.lastname: Zobor
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX, United States of America.|Ophthalmology, UT Southwestern, Dallas, TX, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.affiliation: McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Janine D
authors.initials: JD
authors.lastname: Mendola
authors.affiliation: Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
mesh_terms: D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging; D002648:Child; D004224:Diterpenes; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D012165:Retinal Ganglion Cells / Q000473:pathology; D055351:Retinal Neurons / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000188:drug therapy*; D000084562:Retinyl Esters; D016896:Treatment Outcome; D014792:Visual Acuity / Q000187:drug effects; D014794:Visual Fields / Q000187:drug effects; D014801:Vitamin A / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult; D019745:cis-trans-Isomerases / Q000235:genetics* / Q000378:metabolism; D000099178:Retinoid Isomerohydrolase
chemical_list: D000217:Acyltransferases; D016588:Anticarcinogenic Agents; D004224:Diterpenes; D000084562:Retinyl Esters; D014801:Vitamin A; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C009166:retinol acetate; C056942:lecithin-retinol acyltransferase