First patient dosed in phase 3 NPI-001 trial for Usher syndrome RP

The first patient has been dosed in SLO-RP Preserve, a phase 3 trial of NPI-001 (N-acetylcysteine amide; Nacuity Pharmaceuticals) tablets in adults with retinitis pigmentosa (RP) associated with Usher syndrome. The Inherited Retinal Degeneration Clinic at the Retina Foundation of the Southwest in Dallas, Texas, is among the sites enrolling, with additional sites in the United States and Australia.¹

NPI-001 is an oral antioxidant. Its proposed mechanism does not depend on the causative gene, so it is not limited to a single genotype. If the trial is positive, NPI-001 would be a different kind of option for a disease in which the only approved pharmacologic therapy is a gene therapy for 1 rare genotype.

Trial design

SLO-RP Preserve (NCT07710196) is a 24-month, randomized, double-masked, placebo-controlled, parallel-group study. It will enroll up to 80 adults, who will take NPI-001 or placebo orally twice daily and complete 9 in-clinic visits over approximately 2 years.^1,2 The primary outcome is ellipsoid zone (EZ) area at 24 months, an anatomic measure of photoreceptor integrity assessed by spectral-domain optical coherence tomography (SD-OCT). The registry lists an estimated primary completion date of April 2029 and names the Foundation Fighting Blindness as a collaborator.²

Eligible patients are adults aged 18 years and older with RP associated with Usher syndrome. Each eye must have an EZ width of at least 500 µm that includes the fovea, and all EZ edges must be visible. Patients also need at least 20 detectable points on MAIA microperimetry in 1 eye. Exclusion criteria include concurrent vision-limiting retinal disease, glaucoma, uveitis, anticipated cataract surgery within 12 months, chronic liver or kidney disease, severe asthma or chronic obstructive pulmonary disease, and use of N-acetylcysteine (NAC)–containing supplements within 30 days.²

Mark Pennesi, MD, PhD, director of the Inherited Retinal Degeneration Center at the Retina Foundation of the Southwest and the trial's principal investigator, said in the announcement that "patients living with RP associated with Usher syndrome face progressive vision loss with limited treatment options."¹ He added that investigators will evaluate whether NPI-001 can slow progression and preserve vision.

Phase 1/2 basis

The phase 3 design follows SLO-RP (NCT04355689). In that randomized, double-masked, placebo-controlled trial, 49 patients at 4 sites in Australia received NPI-001 250 mg twice daily (500 mg/d) or placebo for 24 months.^3,4 Nacuity reported in September 2025 that NPI-001 slowed EZ area loss by more than 50% compared with placebo over 2 years. The company said the difference was evident by month 6 and persisted through month 24.³ Retinal sensitivity, a functional measure, did not reach statistical significance at 24 months. The company described a numerically slower decline of nearly 30% in the treatment arm.³ Nacuity reported no persistent drug-related adverse events and adherence above 80%.³

Clinical context

Usher syndrome is an autosomal recessive disorder that combines sensorineural hearing loss with RP, with or without vestibular dysfunction. Its estimated prevalence is 4 to 17 per 100,000, and it is the most common cause of combined deaf-blindness worldwide.⁵ The disorder is genetically heterogeneous. MYO7A accounts for more than half of type 1 cases, and USH2A accounts for roughly 80% of type 2 cases.⁵ Because so many genes are involved, gene-specific strategies each reach only a portion of patients.

In RP more broadly, the only FDA-approved disease-specific therapy is voretigene neparvovec-rzyl (Luxturna). It is indicated for confirmed biallelic RPE65 mutation–associated retinal dystrophy, which affects an estimated 1000 to 2000 people in the United States.⁶ For patients with Usher-associated RP, management is supportive.

Drug background

NPI-001 is an amide form of NAC. Its proposed mechanism is to supply cysteine for intracellular glutathione synthesis, which would reduce the oxidative damage thought to drive secondary cone degeneration after rod loss in RP.⁷ Interest in this pathway comes in part from a phase 1 study of oral NAC (the parent compound) in 30 patients with RP. In that study, NAC up to 1800 mg twice daily was generally well tolerated. Gastrointestinal adverse events resolved spontaneously or with dose reduction, and the authors reported possible improvement in suboptimally functioning macular cones. Mean EZ width did not change significantly in any cohort.⁷

NAC itself is being tested in NAC Attack (NCT05537220), a separate NIH-funded, multicenter phase 3 trial of oral NAC 1800 mg twice daily in patients with RP of any genotype.⁸

The FDA granted NPI-001 Fast Track designation for RP in January 2025.⁹ It later received Breakthrough Therapy designation in October 2025.¹⁰ The drug also holds Orphan Drug designation for RP.^1,9

Interpretation and limitations

The phase 1/2 signal rests on a structural end point in a small sample, and the functional end point did not reach significance. Whether slower EZ loss translates into preserved visual function that patients notice is still unproven. SLO-RP Preserve is designed around the same anatomic primary outcome. Its enrollment of up to 80 patients is modest for a confirmatory trial, although it reflects the rarity of the indication.

The study is also restricted to patients with relatively preserved central EZ, so any results may not apply to advanced disease or to RP outside Usher syndrome. Clinicians may also want to see how NPI-001 performs compared with NAC, given the ongoing NAC Attack trial and the over-the-counter availability of NAC. The phase 3 exclusion of patients using NAC supplements suggests investigators expect some prospective participants to be taking them.

Results are not expected before 2029.²

References

1. Nacuity Pharmaceuticals announces first patient dosed in global confirmatory phase 3 trial of NPI-001 (N-acetylcysteine amide) tablets for the treatment of retinitis pigmentosa associated with Usher syndrome. News release. Nacuity Pharmaceuticals; October 28, 2026. https://www.globenewswire.com/news-release/2026/10/28/3390215/0/en/nacuity-pharmaceuticals-announces-first-patient-dosed-in-global-confirmatory-phase-3-trial-of-npi-001-n-acetylcysteine-amide-tablets-for-the-treatment-of-retinitis-pigmentosa-assoc.html

2. A 24-month trial of NPI-001 for the preservation of photoreceptors in retinitis pigmentosa associated with Usher syndrome (SLORP Preserve). ClinicalTrials.gov identifier: NCT07710196. Updated October 2026. https://clinicaltrials.gov/study/NCT07710196

3. Nacuity Pharmaceuticals announces positive data from clinical trial evaluating NPI-001 to treat retinitis pigmentosa associated with Usher syndrome. News release. Nacuity Pharmaceuticals; September 11, 2025. https://www.globenewswire.com/news-release/2025/09/11/3148593/0/en/Nacuity-Pharmaceuticals-Announces-Positive-Data-from-Clinical-Trial-Evaluating-NPI-001-to-Treat-Retinitis-Pigmentosa-Associated-with-Usher-Syndrome.html

4. Safety and efficacy of NPI-001 tablets versus placebo for treatment of retinitis pigmentosa associated with Usher syndrome (SLO RP). ClinicalTrials.gov identifier: NCT04355689. Updated June 2026. https://clinicaltrials.gov/study/NCT04355689

5. Toms M, Pagarkar W, Moosajee M. Usher syndrome: clinical features, molecular genetics and advancing therapeutics. Ther Adv Ophthalmol. 2020;12:2515841420952194. doi:10.1177/2515841420952194. https://doi.org/10.1177/2515841420952194

6. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. News release. US Food and Drug Administration; December 19, 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm589467.htm

7. Campochiaro PA, Iftikhar M, Hafiz G, et al. Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial. J Clin Invest. 2020;130(3):1527-1541. doi:10.1172/JCI132990. https://www.jci.org/articles/view/132990

8. Oral N-acetylcysteine for retinitis pigmentosa (NAC Attack). ClinicalTrials.gov identifier: NCT05537220. https://clinicaltrials.gov/study/NCT05537220

9. Nacuity Pharmaceuticals granted U.S. FDA Fast Track designation for NPI-001 (N-acetylcysteine amide) tablets for the treatment of retinitis pigmentosa. News release. Nacuity Pharmaceuticals; January 21, 2025. https://www.globenewswire.com/news-release/2025/01/21/3012724/0/en/Nacuity-Pharmaceuticals-Granted-U-S-FDA-Fast-Track-Designation-for-NPI-001-N-acetylcysteine-amide-Tablets-for-the-Treatment-of-Retinitis-Pigmentosa.html

10. Nacuity Pharmaceuticals granted U.S. FDA Breakthrough Therapy designation for NPI-001 (N-acetylcysteine amide) tablets for the treatment of retinitis pigmentosa. News release. Nacuity Pharmaceuticals; October 2025. https://www.nacuity.com/news/nacuity-pharmaceuticals-granted-u-s-fda-breakthrough-therapy-designation-for-npi-001-n-acetylcysteine-amide-tablets-for-the-treatment-of-retinitis-pigmentosa/