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

NCT ID: NCT05293626

Last Updated: 2024-09-04

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-22
• Study Completion Date: 2029-12-31

Brief Summary

The objective of this clinical study is to evaluate the safety and efficacy of NR082 in the treatment of LHON caused by mitochondrial ND4 gene mutation. This study will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single unilateral intravitreal (IVT) injection of NR082 to evaluate its safety and efficacy. The clinical manifestations of all subjects are to be reduced visual acuity caused by LHON associated with ND4 mutation, with laboratory test showing G11778A mutation (a CLIA-certified laboratory) and reduced visual acuity lasted for > 6 months and < 10 years.

Detailed Description

At the dose-finding stage, the principle is that the Safety Review Committee (SRC) will decide whether to make dose adjustment based on the safety data of the starting dose. The starting dose is 1.5×109 vg, 0.05 mL eye/dose.The safety of the starting dose will be reviewed by the SRC, and dose escalation or de-escalation is by recommendation of the SRC.The safety of the starting dose will first be performed in 6 evaluable subjects.

Criteria for Dose Modification:

Dose Escalation:

If drug-related dose-limiting toxicity (DLT) events are observed in ≤ 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the starting dose, the dose can be escalated to 4.5×109 vg, 0.05 mL eye/dose (high dose) after the approval by SRC.

Dose De-escalation:

If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the starting dose, the dose can be de-escalated to 0.5×109 vg, 0.05 mL eye/dose (low dose) after the approval by SRC.

If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the high dose, the dose can be de-escalated to 3.0×109vg, 0.05 mL eye/dose (intermediate dose) after the approval by SRC.

Enrollment Sequence:

• The enrollment sequence of any dose group (6 subjects) is that the 2nd subject and the 3rd subject will be enrolled at least 7 days after the enrollment of the 1st subject;
• The 4th, 5th and 6th subjects will be enrolled at least 7 days after the enrollment of the 2nd and the 3rd subjects.

The 7-day interval is to avoid acute safety events to the greatest possible extent

Conditions

Leber Hereditary Optic Neuropathy (LHON)

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

NR082 injection

Potential doses at the dose-finding stage:

• 0.5E9 vg, 0.05 mL/eye/dose (low dose)
• 1.5E9 vg, 0.05 mL/eye/dose (starting dose)
• 3.0E9 vg, 0.05 mL/eye/dose (intermediate dose)
• 4.5E9 vg, 0.05 mL/eye/dose (high dose)

Group Type: EXPERIMENTAL

NR082 Injection

Intervention Type: DRUG

The starting dose is 1.5E9 vg, 0.05 mL eye/dose.

Dose Escalation:

If drug-related dose-limiting toxicity (DLT) events are observed in ≤ 2 of the 6 evaluable subjects using the starting dose within 6 weeks after the dosing of NR082, the dose can be escalated to 4.5E9 vg, 0.05 mL eye/dose (high dose) after approval by SRC.

Dose De-escalation： If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects using the starting dose within 6 weeks after the dosing of NR082, the dose can be de-escalated to 0.5E9 vg, 0.05 mL eye/dose (low dose) after approval by SRC.

If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the high dose, the dose can be de-escalated to 3.0E9 vg, 0.05 mL eye/dose (intermediate dose) after the approval by SRC.

Injection needle

Intervention Type: DEVICE

19G 1 1/2IN TW filter needle with filter element (BD 305200)，used to NR082 Intraocular injection solution dose preparation; 30G 1/2IN injection needle (BD 305106)，used to NR082 Intraocular injection solution administration;

1 ml screw top syringe (BD 309628),used to NR082 Intraocular injection solution dose preparation and administration.

Interventions

NR082 Injection

The starting dose is 1.5E9 vg, 0.05 mL eye/dose.

Dose Escalation:

If drug-related dose-limiting toxicity (DLT) events are observed in ≤ 2 of the 6 evaluable subjects using the starting dose within 6 weeks after the dosing of NR082, the dose can be escalated to 4.5E9 vg, 0.05 mL eye/dose (high dose) after approval by SRC.

Dose De-escalation： If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects using the starting dose within 6 weeks after the dosing of NR082, the dose can be de-escalated to 0.5E9 vg, 0.05 mL eye/dose (low dose) after approval by SRC.

If drug-related dose-limiting toxicity (DLT) events are observed in > 2 of the 6 evaluable subjects within 6 weeks after the dosing of NR082 at the high dose, the dose can be de-escalated to 3.0E9 vg, 0.05 mL eye/dose (intermediate dose) after the approval by SRC.

Intervention Type: DRUG

Injection needle

19G 1 1/2IN TW filter needle with filter element (BD 305200)，used to NR082 Intraocular injection solution dose preparation; 30G 1/2IN injection needle (BD 305106)，used to NR082 Intraocular injection solution administration;

1 ml screw top syringe (BD 309628),used to NR082 Intraocular injection solution dose preparation and administration.

Intervention Type: DEVICE

Other Intervention Names

Syringe

Eligibility Criteria

Inclusion Criteria

1. Age at the time of signing the informed consent form: the age of the subjects must be ≥ 18 years old and ≤ 75 years old.

2. The clinical manifested vision loss due to LHON, and any eye BCVA ≥ 0.5 LogMAR

3. The genotype testing result shows the presence of G11778A mutation in the ND4 gene, and the absence of the other primary LHON associated mutations in the mitochondrial DNA (mtDNA) (ND1 [G3460A] or ND6 [T14484C]) (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 thorough ocular examination and visual acuity test

6. Each eye of the subject must maintain at least Hand Motion VA (≤ 2.3 LogMAR) as defined in the ocular/vision examination manual (operating manual for refraction and VA examinations) in this study

7. Willingness to comply with the clinical study protocol and 5 years of long-term follow-up after administration

8. Male or female

1. A male subject must agree to take contraceptive measures at least 6 months after the treatment visit;

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

9. Written informed consent form must be obtained from the subject or his/her parent/legal guardian before any study-related procedures are performed.If the subject is legally blind (> 1.0 LogMAR or the readings of decimal visual acuity chart <0.1), 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 anterior chamber 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-related 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

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 central nervous system (CNS), including multiple sclerosis (diagnosis of multiple sclerosis must be based on the 2010 Revisions to the McDonald Criteria) , 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 an 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 Injection

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. Human immunodeficiency virus (HIV) antibody, syphilis antibody and HCV antibody positive are excluded; hepatitis B test that shows a clinically significant active infection requiring treatment (defined as the presence of hepatitis B core antibody [HBcAb] positive or hepatitis B surface antigen [HBsAg] positive, and hepatitis B virus deoxyribonucleic acid [HBV-DNA]) > 1000 copies/mL or according to local laboratory method above lower limit of quantitative detection) are excluded

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

20. 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

21. Any other exclusions determined by the investigator

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Neurophth Therapeutics Inc

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Stanford Byers Eye Institute

Palo Alto, California, United States

University of Colorado Health Eye Center

Aurora, Colorado, United States

Wills Eye Hospital, Neuro Ophthalmology Department

Philadelphia, Pennsylvania, United States

Countries

United States

Other Identifiers

NFS-01-US101

Identifier Type: -

Identifier Source: org_study_id