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)
Open accessAbstract
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.
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High doses of vitamin A in QLT091001 treatment caused side effects including headaches, photophobia, nausea, reduction in serum HDL, and increases in serum triglycerides, ALT, and AST.
“However, some patients noted headaches, photophobia, nausea, reduction in serum high density lipoprotein concentrations, and increases in serum triglycerides, alanine aminotransferase and aspartate aminotransferase concentrations due to high doses of vitamin A [120,121].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [120]
The Safety and other clinical measures section reports treatment-related headache, photophobia, nausea, reduced HDL, and increased ALT and AST; it also reports increased triglycerides after QLT091001 treatment. The Discussion links headaches and nausea to the highest doses in separate healthy-volunteer studies, but the paper does not establish that high doses of vitamin A caused all these effects in the patients studied. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPatients affected by these inactivating deletions suffer from early-onset and more severe retinal dystrophy.
“In fact, patients affected by these inactivating deletions suffer from early-onset and more severe retinal dystrophy [132,139,140,141].”
From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [139]
The Discussion (page unavailable) says RPE65 and LRAT deficiencies can cause early-onset severe rod-cone dystrophy. The Patients and Methods section lists some patients with deletions, but the paper does not establish that those deletions cause earlier onset or more severe disease than other mutations. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOral QLT091001 in patients with defective RPE65 and LRAT genes demonstrated improvement in vision in an open-label phase 1b trial.
“An open-label, prospective, multi-center, phase 1b clinical trial of oral administration of QLT091001 in patients with defective RPE65 and LRAT genes also demonstrated improvement in vision.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [120]
Treatment with oral synthetic cis-retinoid QLT091001 showed promising results in patients with LRAT pathogenic variants.
“Treatment with oral synthetic cis-retinoid QLT091001 showed promising results in patients.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [120]
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- Authors
- Scholl, H. P. N., Moore, A. T., Koenekoop, R. K., Wen, Y., Fishman, G. A., van den Born, L. I., Bittner, A., Bowles, K., Fletcher, E. C., Collison, F. T., Dagnelie, G., Degli Eposti, S., Michaelides, M., Saperstein, D. A., Schuchard, R. A., Barnes, C., Zein, W., Zobor, D., Birch, D. G., Mendola, J. D., Zrenner, E., & RET IRD 01 Study Group
- Affiliations
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- McGill University Health Centre (CA)
- Baylor University Medical Center (US)
- Moorfields Eye Hospital (GB)
- QLT (Canada) (CA)
- VA Palo Alto Health Care System (US)
- National Institutes of Health (US)
- University of Tübingen (DE)
- Retina Foundation of the Southwest (US)
- Corresponding author
- Scholl, Hendrik P. N.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-12-10
- Volume
- 10
- Issue
- 12
- Pages
- e0143846
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4687523
- OpenAlex
- W2194139052
- Cited by
- 71
- References
- 44
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 10 · 2020: 9 · 2019: 6 · 2018: 11 · 2017: 8 · 2016: 4 · 2013: 1
- FWCI
- 3.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship@McGill (McGill) (submittedVersion, public-domain)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Johns Hopkins University
- National Institute for Health and Care Research (NF-SI-0507-10204)
- Johns Hopkins Bloomberg School of Public Health
- Canadian Institutes of Health Research
- National Human Genome Research Institute (U54HG006542)
- National Eye Institute (R01EY009339)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- retinitis pigmentosa, oral retinoid therapy, visual cycle, photoreceptor outer segment length, structure-function relationship, visual acuity, visual field, treatment response prediction, retinal degeneration
- MeSH terms
- Retinyl Esters, Retinoid Isomerohydrolase, Acyltransferases, Administration, Oral, Adult, Cerebral Cortex, Child, Diterpenes, Female, Humans, Male, Middle Aged, Radiography, Retinal Ganglion Cells, Retinitis Pigmentosa, Visual Acuity, Visual Fields, Vitamin A, Anticarcinogenic Agents, Treatment Outcome, cis-trans-Isomerases, Polymorphism, Single Nucleotide, Drug Dosage Calculations, Retinal Neurons, Young Adult
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