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)

Hendrik P N Scholl, Anthony T. Moore, Robert K. Koenekoop, Yuquan Wen, Gerald A. Fishman, L. Ingeborgh Van Den Born, Ava Bittner, Kristen Bowles, Emily C. Fletcher, Frederick T. Collison, Gislin Dagnelie, Simona Degli Eposti, Michel Michaelides, David A. Saperstein, Ronald A. Schuchard, Claire Barnes, Wadih Zein, Ditta Zobor, David G. Birch, Janine D. MendolaEberhart Zrenner

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number0143846
JournalPLoS One
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

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acyltransferases
Retinitis Pigmentosa
Retinal Pigments
phosphatidylcholines
vitamin A
mouth
pigments
Safety
photoreceptors
Proteins
proteins
retinyl acetate
Occipital Lobe
Photophobia
nausea
Retinal Degeneration
headache
Optical tomography
tomography
Optical Coherence Tomography

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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). / 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; Eposti, Simona Degli; Michaelides, Michel; Saperstein, David A.; Schuchard, Ronald A.; Barnes, Claire; Zein, Wadih; Zobor, Ditta; Birch, David G.; Mendola, Janine D.; Zrenner, Eberhart.

In: PLoS One, Vol. 10, No. 12, 0143846, 01.12.2015.

Research output: Contribution to journalArticle

Scholl, HPN, Moore, AT, Koenekoop, RK, Wen, Y, Fishman, GA, Van Den Born, LI, Bittner, A, Bowles, K, Fletcher, EC, Collison, FT, Dagnelie, G, Eposti, SD, Michaelides, M, Saperstein, DA, Schuchard, RA, Barnes, C, Zein, W, Zobor, D, Birch, DG, Mendola, JD & Zrenner, E 2015, '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)', PLoS One, vol. 10, no. 12, 0143846. https://doi.org/10.1371/journal.pone.0143846
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 ; Eposti, Simona Degli ; Michaelides, Michel ; Saperstein, David A. ; Schuchard, Ronald A. ; Barnes, Claire ; Zein, Wadih ; Zobor, Ditta ; Birch, David G. ; Mendola, Janine D. ; Zrenner, Eberhart. / 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). In: PLoS One. 2015 ; Vol. 10, No. 12.
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