New Leber Hereditary Optic Neuropathy Gene Therapy Trial Doses First Patient


NR082 has been evaluated in 3 previous investigator-initiated trials involving 186 patients.

The first patient has been treated in phase 3 of the GOLD clinical trial (NCT04912843) of Neurophth’s NR082, an investigational gene therapy intended for the treatment of Leber hereditary optic neuropathy (LHON) associated with mtND4 mutations.1

NR082 contains a mitochondria codon-optimized NADH-dehydrogenase subunit 4 gene delivered by a recombinant adeno-associated viral vector, serotype 2 (rAAV2-ND4). It previously received orphan drug designation from the FDA in September 2020, and from the European Medicines Agency (EMA) in January 2022.1,2 Investigational new drug applications for NR082 were cleared by China’s NMPA and the FDA in March 2021 and January 2022, respectively. NR082 was additionally granted breakthrough therapy designation by China’s Center for Drug Evaluation in July 2022.3 It has been evaluated in 3 previous investigator-initiated trials involving 186 patients with LHON and was well-tolerated and demonstrated efficacy in improving visual acuity.1 Clinical durability was shown to last up to 90 months in the first trial.

“There is currently no approved effective treatment for LHON,” Xiaoning Guo, chief medical officer, Neurophth, said in a statement regarding the news.1 “NR082 leverages gene therapy strategy and uses recombinant AAV as the vector to deliver the correct genes to the patients' damaged optic ganglion cells, thus restoring the vitality and visual function of optic ganglion cells. The phase 3 clinical trial is a breakthrough in the ophthalmic gene therapy industry. Neurophth will advance the Phase 3 clinical trial in hope that safe and effective therapy can soon liberate patients from the darkness.”

The multicenter, 2-part GOLD trial will recruit approximately 102 patients with a G11778A mutation in ND4 gene who have no other primary LHON-associated mutations in the mitochondrial DNA (mtDNA). Participants in part 1 and the first 6 evaluable participants in the safety run-in phase of part 2 must be aged between 18 years and 75 years (inclusive). If the safety review committee (SRC) does not determine that there is a safety issue, the randomized double-blind control study in part 2 may enroll patients as young as 12 years old. Participants must maintain the visual acuity determined by the manual visual acuity test (less than or equal to 2.3 LogMAR) and have had vision loss in the eye with worse visual acuity which has lasted more than 6 months but less than 10 years. 

Patients who have a history of virectomy in either eye, have a presence of diseases of the eye or adnexa other than LHON that may interfere with visual assessments, or have presence of mutations other than the LHON-related mutation that cause pathology of the optic nerve, retina, or afferent visual system, will be excluded. Patients must also not have any contraindication to intravitreal (IVT) injection in either eye and must not have any known allergy to NR082’s constituents. Additional exclusion criteria relate to patient health status and treatment history.

Part 2 will begin with a safety run-in phase using the recommended dose determined in part 1 and will monitor safety for at least 6 weeks. If no new safety concerns are observed by the SRC, the sham-injection control study will be initiated.

Patients in the experimental arm will receive the recommended dose and patients in the sham comparator arm will be administered a sham IVT injection. The primary end points of the clinical trial include the incidence rates of adverse events (AEs), serious AEs, and dose-limiting toxicities; and the proportion of participants who show vision improvement of at least 0.3 LogMAR from baseline in best corrected visual acuity (BCVA) at 52 weeks. Secondary end points include the mean change from baseline in BCVA LogMAR of the study eye, changes in visual field index, low contrast sensitivity, assessments of immunogenicity, assessments of vector DNA shedding in tears for both eyes and in whole blood, and changes in quality of life from baseline measured by questionnaires. The study is currently recruiting at Beijing Tongren Hospital, Capital Medical University (CMU), in Beijing, China and has an estimated primary completion date of December 30, 2023.

“As a clinician, I share the same expectation of LHON patients for effective and affordable treatments,” Wenbin Wei, vice president, Beijing Tongren hospital, CMU, added to the statement.1 “NR082 has shown promising safety and efficacy data in all clinical work to date and is officially advanced into a Phase 3 trial. Ophthalmic gene therapy is coming of age. We hope that NR082 will be available soon, making a life-changing difference to patients by technological innovation.”

1. Neurophth announces first patient dosed in Phase III clinical trial for the gene therapy treatment of LHON. News release. Neurophth Therapeutics, Inc. September 27, 2022. 
2. Neurophth Therapeutics' treatment of Leber's hereditary optic neuropathy gene therapy NR082 was granted orphan drug designation by EMA. News release. Neurophth Therapeutics, Inc. January 24, 2022. 
3. China CDE grants breakthrough therapy designation (BTD) to Neurophth’s NR082 in LHON. News release. Neurophth Therapeutics, Inc. July 15, 2022. 
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