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

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.

Fig 1. CONSORT Flow Diagram for the RET IRD 01 Study.

Fig 2. Percent of Treatment Responders for Functional Retinal Area (A, top) and Visual Acuity (B, bottom).

Response in functional retina area was defined as an increase in visual field area from baseline of ≥20% increase in the visual field area in the primary isopter in one or both eyes at two or more visits within 2 months of treatment. Visual acuity response was defined as an increase from baseline in visual acuity of ≥5 ETDRS letter score at two or more visits within 2 months of treatment.

Fig 3. Goldmann Visual Fields and Respective SD-OCT scans of the Central Retina in a Treatment Responder and a Non-Responder.

(A) Normal subject. The horizontal midline scan shows segmentation lines separating Vitreous/Retinal Nerve Fiber Layer (RNFL), RNFL/Retinal Ganglion Cell Layer (RGC), Inner Plexiform Layer (IPL)/Inner Nuclear Layer (INL), INL/Outer Plexiform Layer (OPL), Inner segment (IS)/Outer segment (OS), OS/ Retinal Pigment Epithelium (RPE), Bruch’s Membrane (BM)/Choroid. The OS layer lies between the IS/OS line and the OS/RPE line (see Hood et al. 2009 Ref 19). (B) SD-OCT foveal scan at screening (length of OS layer in the central 20° was 23.1 μm), (C) Goldmann Visual Field (GVF) at screening visit (retinal area of primary isopter = 26 mm²) and at month 1.5 (D) (retinal area of primary isopter = 81 mm²) in a RP patient who showed a treatment response (subject 110 OS, see Table 1). (E) SD-OCT foveal scan at screening (length of OS layer in the central 20° was 6.2 μm), (F) Goldmann Visual Field (GVF) at screening visit (retinal area of primary isopter = 55 mm²) and at month 1 (G) (retinal area of primary isopter was 44 mm²) of a non-responder (subject 402 OS, see Table 1).

Fig 4. Functional MRI for Two Patients (110 and 111) in Response to Patterned Moving Stimuli Varying from High to Low Luminance Contrast.

(A) Depiction of the stimuli at three contrasts, high to low from left to right. (B) For patient 111, before treatment, the visual cortical response was robust for high contrast, modest for medium contrast, and negligible for low contrast. After treatment, the response to medium and low contrast stimuli increased noticeably. The statistical maps for the first (before treatment) and the fourth (after treatment) session are shown (0.01 < p < 0.0001, FDR), each on a flattened representation of the posterior cortex, for both left and right hemisphere. The occipital pole is marked in the lower left panel with a green asterisk for orientation; v-shaped margin of cortex represents the split calcarine sulcus. (C) For patient 111, for medium contrast stimulus, the regions in medial occipital cortex that show significant increased response for all post-treatment scans compared to all pre-treatment scans are shown on medial view inflated brain. (D) Similar results were also obtained for patient 110.