ORAL RETINOID THERAPY

Repeated treatments with oral 9-cis-retinyl acetate (QLT091001 developed by QLT Inc.) in patients with Leber congenital amaurosis (LCA) and/or retinitis pigmentosa (RP) due to RPE65 or LRAT mutations had an acceptable safety profile and led to sustained visual improvements, reported Hendrik P Scholl MD, MA, at the 2015 annual meeting of the Association for Research in Vision and Ophthalmology in Denver, USA.
He presented results from an international, multicentre Phase 1b study that enrolled patients who were treated in an earlier study with a single seven-day course of 9-cis-retinyl acetate at doses of 10 or 40mg/m2. In the second retreatment trial, patients received up to three seven-day courses of the synthetic cis-retinoid at doses of 10, 40 or 60mg/m2. 
The study defined a responder as a patient showing an increase in at least one eye and at least two consecutive visits within six months from the start of any treatment course of ≥20 per cent in the functional retina area of the primary isopter determined from the Goldmann visual field. Some 86 per cent of RP patients and 54 per cent of LCA patients met those criteria. About two-thirds of RP patients and about half of LCA patients were responders using the same criteria, except with a more stringent 40 per cent threshold for improvement. 
Approximately two-thirds of RP patients and three-quarters of LCA patients achieved a visual acuity (VA) response, defined as having a ≥ 5 ETDRS letter increase in at least one eye and at least two consecutive visits within six months from the start of any treatment course. The mean duration of the VA response exceeded five months in the RP patients and was almost 10 months in the LCA subcohort, reported Dr Scholl, the Dr Frieda Derdeyn Bambas Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, US.
“We must be cautious because this is not a placebo-controlled study. However, these are diseases where patients decline over time and never get better. So to see improvement of this magnitude is quite unlikely,” he said.

Adverse events
Most adverse events were mild (78 per cent) or moderate (18 per cent) in intensity, consistent with the retinoid class, and were transient and/or reversible. In addition, their incidence did not increase with successive treatment courses or appear to be dose-related. Headache and fatigue were the most common treatment-related adverse events. There was one serious adverse event – a case of pseudotumor cerebri – that resolved without complications.
Oral 9-cis-retinyl acetate represents a pharmacological retinoid replacement therapy in patients with LRAT and RPE65 mutations, restoring function to their defective visual cycle to allow regeneration of the visual pigment.
Dr Scholl noted that the sustained benefit noted in the study is explained by the systemic route of administration. Preclinical and clinical data suggest that the systemic route of administration may lead to storage of the active compound in tissue depots from where they may be slowly released.
Hendrik P Scholl: hscholl1@jhmi.edu