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 journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)e0143846
JournalPLoS ONE
Volume10
Issue number12
DOIs
Publication statusPublished - 2015

Keywords

  • Acyltransferases/genetics
  • Administration, Oral
  • Adult
  • Anticarcinogenic Agents/adverse effects
  • Cerebral Cortex/diagnostic imaging
  • Child
  • Diterpenes
  • Drug Dosage Calculations
  • Female
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Radiography
  • Retinal Ganglion Cells/pathology
  • Retinal Neurons/pathology
  • Retinitis Pigmentosa/drug therapy
  • Treatment Outcome
  • Visual Acuity/drug effects
  • Visual Fields/drug effects
  • Vitamin A/adverse effects
  • Young Adult
  • cis-trans-Isomerases/genetics

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