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

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.

• Authors: 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 Mendola, Eberhart Zrenner, RET IRD 01 Study Group
• Journal: PloS one (PLoS One) Vol. 10 Issue 12 Pg. e0143846 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26656277 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Diterpenes
• Retinyl Esters
• Vitamin A
• retinol acetate
• Acyltransferases
• lecithin-retinol acyltransferase
• retinoid isomerohydrolase
• cis-trans-Isomerases

Topics

• Acyltransferases (genetics, metabolism)
• Administration, Oral
• Adult
• Anticarcinogenic Agents (adverse effects, pharmacology, therapeutic use)
• 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)
• Retinyl Esters
• Treatment Outcome
• Visual Acuity (drug effects)
• Visual Fields (drug effects)
• Vitamin A (adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Young Adult
• cis-trans-Isomerases (genetics, metabolism)