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Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial
Peter A Campochiaro1,2, Mustafa Iftikhar1, Gulnar Hafiz1
1Wilmer Eye Institute and.
Abstract:
BACKGROUNDIn retinitis pigmentosa (RP), rod photoreceptors degenerate from 1 of many mutations, after which cones are compromised by oxidative stress. N-acetylcysteine (NAC) reduces oxidative damage and increases cone function/survival in RP models. We tested the safety, tolerability, and visual function effects of oral NAC in RP patients.METHODSSubjects (n = 10 per cohort) received 600 mg (cohort 1), 1200 mg (cohort 2), or 1800 mg (cohort 3) NAC bid for 12 weeks and then tid for 12 weeks. Best-corrected visual acuity (BCVA), macular sensitivity, ellipsoid zone (EZ) width, and aqueous NAC were measured. Linear mixed-effects models were used to estimate the rates of changes during the treatment period.RESULTSThere were 9 drug-related gastrointestinal adverse events that resolved spontaneously or with dose reduction (maximum tolerated dose 1800 mg bid). During the 24-week treatment period, mean BCVA significantly improved at 0.4 (95% CI: 0.2-0.6, P < 0.001), 0.5 (95% CI: 0.3-0.7, P < 0.001), and 0.2 (95% CI: 0.02-0.4, P = 0.03) letters/month in cohorts 1, 2, and 3, respectively. There was no significant improvement in mean sensitivity over time in cohorts 1 and 2, but there was in cohort 3 (0.15 dB/month, 95% CI: 0.04-0.26). There was no significant change in mean EZ width in any cohort.CONCLUSIONOral NAC is safe and well tolerated in patients with moderately advanced RP and may improve suboptimally functioning macular cones. A randomized, placebo-controlled trial is needed to determine if oral NAC can provide long-term stabilization and/or improvement in visual function in patients with RP.TRIAL REGISTRATIONNCT03063021.FUNDINGMr. and Mrs. Robert Wallace, Mr. and Mrs. Jonathan Wallace, Rami and Eitan Armon, Marc Sumerlin, Cassandra Hanley, and Nacuity Pharmaceuticals, Inc.
Insights
Oral N-acetylcysteine (NAC) is safe for retinitis pigmentosa (RP) patients and may improve vision. Further trials are needed to confirm long-term benefits for this degenerative eye disease.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Retinitis pigmentosa (RP) involves progressive degeneration of photoreceptors, leading to compromised cone function due to oxidative stress.
- N-acetylcysteine (NAC) has demonstrated potential in preclinical models to mitigate oxidative damage and enhance cone cell survival and function in RP.
- This study investigates the safety, tolerability, and visual effects of oral NAC in patients diagnosed with RP.
Purpose of the Study:
- To evaluate the safety and tolerability of escalating doses of oral N-acetylcysteine (NAC) in patients with retinitis pigmentosa (RP).
- To assess the impact of oral NAC on key visual function parameters, including best-corrected visual acuity (BCVA) and macular sensitivity.
- To measure changes in ellipsoid zone (EZ) width and aqueous humor NAC levels as indicators of drug penetration and effect.
Main Methods:
- A cohort study involving 30 patients with moderately advanced RP, divided into three groups receiving different daily doses of oral NAC (600 mg, 1200 mg, or 1800 mg bid, then tid).
- Treatment duration was 24 weeks, with assessments including best-corrected visual acuity (BCVA), macular sensitivity, and ellipsoid zone (EZ) width.
- Aqueous humor NAC levels were measured, and linear mixed-effects models were employed to analyze changes in visual function over time.
Main Results:
- Oral NAC was found to be safe and well-tolerated, with a maximum tolerated dose of 1800 mg bid; 9 mild gastrointestinal adverse events were reported and resolved.
- Significant improvements in mean BCVA were observed across all three dosage cohorts during the 24-week treatment period.
- Cohort 3 (1800 mg) showed a statistically significant improvement in macular sensitivity, while EZ width remained unchanged in all groups.
Conclusions:
- Oral N-acetylcysteine (NAC) is a safe and tolerable therapeutic option for patients experiencing moderately advanced retinitis pigmentosa (RP).
- The study suggests that NAC may offer benefits for suboptimally functioning macular cones, potentially improving visual acuity and sensitivity.
- A placebo-controlled, randomized clinical trial is warranted to definitively establish the efficacy of oral NAC for long-term visual stabilization and improvement in RP patients.
