Gene Therapy Clinical Trial for the Treatment Of Leber's HereDitary Optic Neuropathy Associated With ND4 Mutations

• Status: Recruiting
• Trial end date: 2027-04-30
• Target enrollment: 0
• Participant gender: All

Summary

The objective of this clinical study is to select the optimal dose and evaluate the safety and efficacy of the treatment. Stage 1 is a dose-finding study, which will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single unilateral intravitreal (IVT) injection of NR082 to observe its safety and efficacy. Stage 2 of the clinical trial will be conducted after the dose is determined to further evaluate the safety and efficacy of the study drug. In Stage 2 of the study, the first 6 subjects are aged ≥ 18 years and ≤ 75 years. After monitoring for at least 6 weeks, if there are no new safety signals and the efficacy data is similar to Stage 1, subjects aged 12-17 years can be enrolled upon approval by the Independent Data Monitoring Committee (IDMC). The clinical manifestation of all subjects is reduced visual acuity caused by Leber hereditary optic neuropathy (LHON) associated with ND4 mutation, and laboratory test showed G11778A mutation (a CLIA-certified laboratory), while the reduced visual acuity lasted for >6 months and <10 years.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Wuhan Neurophth Biotechnology Limited Company

Criteria

Inclusion Criteria:

1. Age at signing of informed consent form

1. In Stage 1, the age of the subjects must be ≥ 18 years old and ≤ 75 years old.

2. In Stage 2, the age of the first 6 evaluable subjects must be ≥ 18 years old and ≤ 75 years old, and they must be monitored for at least 6 weeks. If IDMC believes that there is no safety issue, subjects aged 12-17 years old will be enrolled.

2. The clinical manifestation caused by LHON is vision loss, with a visual acuity of ≥ 0.5 LogMAR

3. The genotype test result is that there is G11778A mutation in ND4 gene, and there are no other primary LHON-associated mutations in the mitochondrial DNA (mtDNA) (ND1 or ND6) (confirmed by a CLIA-certified international laboratory)

4. The vision loss in the eye with worse visual acuity lasted > 6 months and < 10 years at screening

5. Pupils can be adequately dilated for a comprehensive eye examination and visual acuity test

6. Each eye of the subject must maintain the VA determined by manual visual acuity test (≤ 2.3 LogMAR) as defined in the standard operating procedure (SOP) for VA tests in this study

7. Negative human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis infection test results

8. Sign the written informed consent form and willing to comply with the clinical study protocol and undergo additional long-term follow-up for about 2 - 4 years

9. Male or female

a)Male subjects:

•A male subject must agree to take contraceptive measures at least 6 months after the treatment visit, see Appendix 6 for details b)Female subjects:

•A female subject is eligible to participate if she is not pregnant (see Appendix 6), not breastfeeding, and at least one of the following conditions applies: i)Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 or ii) A WOCBP who agrees to follow the contraception guidance in Appendix 6 for at least 6 months after the treatment visit

10. Written informed consent form must be obtained from the subject or his/her parent/legal guardian (if the subject is under 18 years of age) (Stage 2) before any study-related procedures are performed (see Section 10.2) If the subject is legally identified as blind (>1.0 LogMAR), an impartial witness must be present throughout the informed consent process and discussion process.

Exclusion Criteria:

1. Any known allergy and/or hypersensitivity to the study drug or its constituents

2. Contraindication to IVT injection in any eye

3. IVT drug delivery to any eye within 30 days prior to the screening visit

4. History of vitrectomy in either eye

5. Narrow angle in any eye contra-indicating pupillary dilation

6. Presence of disorders or diseases of the eye or adnexa, excluding LHON, which may interfere with visual or ocular assessments, including spectral-domain optical coherence tomography (SD-OCT), during the study

7. Presence of known/documented mutations, other than the LHON-causing G11778A ND4 mutation, which are known to cause pathology of the optic nerve, retina or afferent visual system

8. Presence of systemic or ocular/vision diseases, disorders or pathologies, other than LHON, known to cause or be associated with vision loss, or whose associated treatment(s) or therapy(ies) is/are known to cause or be associated with vision loss

9. Presence of optic neuropathy from any cause other than LHON or glaucoma

10. Presence of illness or disease that, in the opinion of the investigator, include symptoms and/or the associated treatments that can alter visual function, for instance cancers or pathology of the CNS, including multiple sclerosis (diagnosis of multiple sclerosis must be based on the 2010 Revisions to the McDonald Criteria) (Polman et al., 2011), and/or diseases or conditions that affect the safety of subjects participating in the study

11. History of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation

12. Participated in another clinical study and receive IMP within 90 days prior to the screening visit

a)Exceptions: Subjects who have completed the clinical study of idebenone as IMP > 90 days prior to the screening visit, and has completely discontinued idebenone at least 7 days prior to dosing are still eligible to participate in the study.

13. Any eye has previously received ocular gene therapy

14. Subjects who refused to stop using idebenone

15. Have undergone ocular surgery of clinical relevance (per investigator's assessment) within 90 days prior to the screening visit

16. Female subjects who are breastfeeding or plan to breastfeed within the first 6 months after the administration of NR082

17. History of drug or alcohol abuse (including heavy smoking, i.e. > 20 cigarettes per day or > 20 pack-years [equivalent to one pack a day for 20 years or 2 packs a day for 10 years])

18. Unable to tolerate (e.g., immunomodulatory regimen) or unable or unwilling to comply with all the protocol requirements

19. Subjects from the study site fail to comply with or do not agree to comply with local and institutional guidelines for suspected 2019 novel coronavirus (COVID-19) infection/testing