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

NCT05293626 | Active Not Recruiting Phase 1 FDA Drug FDA Device

• 1 other identifier: NFS-01-US101
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 3

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.

Conditions

Leber Hereditary Optic Neuropathy (LHON)

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events (AEs)

  Incidence of adverse events (AEs) within 52 weeks of NR082 intravitreal injection at different doses

  52 weeks

• Incidence of serious adverse events (SAEs)

  Incidence of serious adverse events (SAEs)within 52 weeks of NR082 intravitreal injection at different doses

  52 weeks

• Incidence of dose-limiting toxicities (DLT)

  Incidence of dose-limiting toxicities (DLT) (ocular and non-ocular) within 52 weeks of NR082 intravitreal injection at different doses

  52 weeks

Secondary Outcomes (18)

• Proportion (percent) of subjects with an improvement of ≥ 0.3 LogMAR from baseline in Best corrected visual acuity(BCVA) in the study eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 156, 208, and 260

• Mean change from baseline in BCVA (LogMAR) in the study eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 156, 208, and 260

• Mean change in BCVA (LogMAR) compared to nadir*

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 156, 208, and 260

• Change from baseline in thepattern standard deviation (PSD)in the study eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 156, 208, and 260

• Change from baseline in the visual field index (VFI) in the study eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 156, 208, and 260

Study Arms (1)

NR082 injection

EXPERIMENTAL

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)

Drug: NR082 Injection; Device: Injection needle

Interventions

NR082 Injection 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.

NR082 injection

Injection needle 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.

Also known as: Syringe

NR082 injection

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age at the time of signing the informed consent form: the age of the subjects must be ≥ 18 years old and ≤ 75 years old.
• The clinical manifested vision loss due to LHON, and any eye BCVA ≥ 0.5 LogMAR
• 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
• The vision loss in the eye with worse visual acuity lasted \> 6 months and \< 10 years at screening
• Pupils can be adequately dilated for a thorough ocular examination and visual acuity test
• 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
• Willingness to comply with the clinical study protocol and 5 years of long-term follow-up after administration
• Male or female
• A male subject must agree to take contraceptive measures at least 6 months after the treatment visit;
• 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
• 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.

You may not qualify if:

• Any known allergy and/or hypersensitivity to the study drug or its constituents
• Contraindication to IVT injection in any eye
• IVT drug delivery to any eye within 30 days prior to the screening visit
• History of vitrectomy in either eye
• Narrow anterior chamber angle in any eye contra-indicating pupillary dilation
• 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
• 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
• 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
• Presence of optic neuropathy from any cause other than LHON
• 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
• History of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation
• 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.
• Any eye has previously received ocular gene therapy
• Subjects who refused to stop using idebenone

Sponsors & Collaborators

• Neurophth Therapeutics Inc: lead

Study Sites (3)

Stanford Byers Eye Institute

Palo Alto, California, 94303-5353, United States

Location

University of Colorado Health Eye Center

Aurora, Colorado, 80045, United States

Location

Wills Eye Hospital, Neuro Ophthalmology Department

Philadelphia, Pennsylvania, 19107, United States

Location

MeSH Terms

Conditions

Optic Atrophy, Hereditary, Leber

Interventions

Needles; Syringes

Condition Hierarchy (Ancestors)

Optic Atrophies, Hereditary; Optic Atrophy; Optic Nerve Diseases; Cranial Nerve Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Eye Diseases, Hereditary; Eye Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mitochondrial Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Equipment and Supplies

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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)

Study Record Dates

• First Submitted: December 9, 2021
• First Posted: March 24, 2022
• Study Start: May 22, 2023
• Primary Completion: July 1, 2025
• Study Completion (Estimated): December 1, 2029
• Last Updated: September 4, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)