NAC Attack, A Phase-3, Multicenter, Randomized, Placebo-Controlled Trial in Patents with Retinitis Pigmentosa

PROJECT SUMMARY/ABSTRACT
Retinitis pigmentosa (RP), the most common inherited retinal degeneration, causes severe visual
disability and has no effective treatments. It is caused by mutations in one of a large number of genes
that result in rod photoreceptor degeneration while sparing cones. The loss of rods, which constitute
95% of the cells in the outer retina, results in high levels of oxygen causing oxidative stress which is a
major contributor to gradual degeneration of cone photoreceptors. Cone degeneration causes gradual
constriction of visual fields and eventual blindness. Compelling laboratory data demonstrate that
antioxidants, including N-acetylcysteine (NAC), promote cone survival and function in animal models of
RP. A clinical trial testing oral NAC in 30 RP patients showed good safety with a maximum tolerated
dose of 1800 mg bid, which resulted in good intraocular levels and caused small improvements in cone
function over a 6-month treatment period. This has led to the hypothesis that long-term administration
of NAC can promote cone survival and prevent severe visual disability in patients with RP. This project
is a large multicenter, randomized, double-masked, placebo-controlled clinical trial designed to test that
hypothesis. Ellipsoid zone (EZ) width measured on a spectral domain-optical coherent tomography
scan through the fovea corresponds to remaining cones with intact inner and outer segments and thus
is a biomarker for cone survival. Approximately 438 RP patients with an EZ width between 1500 and
8000 µm will be randomized in a 2:1 ratio to 1800 mg NAC bid or placebo. The primary efficacy
objective is to determine if the cumulative loss of EZ width between baseline and month (M) 45 is
significantly less in eyes of subjects in the treatment group versus those in the placebo group.
Secondary efficacy objectives are to determine if reductions between baseline and M45 in mean
macular sensitivity (measured by microperimetry) or best-corrected visual acuity are decreased by NAC
treatment. A novel exploratory outcome will utilize adaptive optics scanning light ophthalmoscopy,
which allows non-invasive imaging of the cone mosaic with single-cell resolution, to determine if
negative changes in cone density, spacing, regularity, and reflectivity between baseline and M45 are
reduced in the intervention group versus the placebo group. All participants will have whole genome
sequencing which will allow pharmacogenomic analyses. The safety and tolerability of long-term NAC
treatment will be carefully assessed. This clinical trial has the potential to identify a new non-invasive,
oral treatment that prevents severe visual disability in patients with RP regardless of the pathogenic
mutation, thereby addressing a major unmet medical need. In addition, it will provide the most definitive
test yet as to whether oxidative damage plays a major role in cone degeneration in patients with RP
and determine if it is a validated therapeutic target for new treatment development.

Grant Number: 5UG1EY033286-05
NIH Institute/Center: NIH
Principal Investigator: Peter Campochiaro