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
T2 - 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 - Eposti, Simona Degli
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
N1 - Funding Information:
The authors have the following interests: This study was sponsored by QLT Inc., the developer of QLT091001. QLT owns and licenses certain intellectual property rights with respect to QLT091001. Drs. Scholl, Moore, Koenekoop, Fishman, Bittner, Dagnelie, Saperstein, Schuchard, Barnes and Birch served as paid consultants for QLT Inc. Dr Saperstein has an equity stake in Retinagenix (licensory to QLT of certain intellectual property rights relating to QLT091001) and is an inventor on patents directly involved with the technology. Dr. Moore is the Chairman of the DSMB of the gene therapy trials of Sanofi and Oxford Biomedica. Dr. Birch is on the DSMC of the gene therapy trial of Sparks. Grants to investigators at Johns Hopkins University are negotiated and administered by the institution (such as the School of Medicine) which receives the grants, typically through the Office of Research and Administration. Individual investigators not named above who participated in the sponsored project were not directly compensated by the sponsor but may have received salary or other support from the institution to support their effort on the project. There are no other patents, further products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
Funding Information:
This study was sponsored by QLT Inc., the developer of QLT091001. Dr. Scholl was supported by the Wynn-Gund Translational Research Acceleration Program Enhanced Research and Clinical Training Award, National Neurovision Research Institute (NNRI) – Foundation Fighting Blindness (FFB; NNCD-CL-0310.0049-JHU-WG); Macular Degeneration Research Award, American Health Assistance Foundation/BrightFocus Foundation (AHAF; M2010042); Unrestricted grant to the Wilmer Eye Institute from Research to Prevent Blindness; and Baylor-Johns Hopkins Center for Mendelian Genetics (National Human Genome Research Institute, NHGRI/NIH; 1U54HG006542-01). Dr. Scholl is the Dr. Frieda Derdeyn Bambas Professor of Ophthalmology. Dr. Koenekoop is supported by the Canadian Foundation Fighting Blindness, Canadian Institutes for Health Research, Fonds de la Recherche en Santee du Quebec, Reseau Vision and NIH. Dr Moore is supported by the National Institute for Health Research UK (Moorfields Biomedical Research Centre). Drs. Scholl, Moore, Koenekoop, Fishman, Bittner, Dagnelie, Saperstein, Schuchard, Barnes and Birch served as paid consultants for QLT Inc. The specific roles of these authors are articulated in the ‘author contributions’ section. QLT Inc. was involved in the study design, data collection and analysis. QLT also provided technical support for manuscript preparation, reviewed the manuscript and participated in the decision to publish. We thank Dr. Robert Wojciechowski (Johns Hopkins Bloomberg School of Public Health) for assistance in mutation reporting of the RPE65 and LRAT genes. We thank Donna Morrison, PhD, and Anne Fisher (QLT Inc.) for data clarification and analysis. Personnel involved in the assessment of best corrected visual acuity (BCVA) and Goldmann Visual Field (GVF) received training and certification from The EMMES Corporation™, Rockville, Maryland. Analysis of pharmacokinetic samples was performed by the QLT Bioanalytical Unit. The study concept and design was provided by QLT Inc. The RET IRD 01 Study Group is represented by the authors listed (Hendrik Scholl, Anthony Moore, Robert Koenekoop, Yuquan Wen, Gerald Fishman, Ingeborgh van den Born, Ava Bittner, Kristen Bowles, Emily Fletcher, Frederick Collison, Gislin Dagnelie, Simona Degli Eposti, Michel Michaelides, David Saperstein, Ronald Schuchard, Claire Barnes, Wadih Zein, Ditta Zobor, David Birch, Janine Mendola, and Eberhart Zrenner) with Hendrik P.N. Scholl, being the lead author (Address: Johns Hopkins University, Wilmer Eye Institute, Maumenee Building, Room 748, 600 N. Wolfe Street, Baltimore, Maryland 21287, United States; Telephone (Office): +1-410-502-2789, Office Fax: +1-443-287- 8343; E-mail: hscholl1@jhmi.edu), the participating sites listed in the Supporting Information (S5 Text) and the people mentioned in these acknowledgments.
Publisher Copyright:
© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0143846
DO - 10.1371/journal.pone.0143846
M3 - Article
C2 - 26656277
AN - SCOPUS:84955599907
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 12
M1 - 0143846
ER -