Gene Therapy Clinical Trial for the Treatment of Leber's Hereditary Optic Neuropathy Associated With ND1 Mutations

NCT05820152 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: NFS-02-101
• Study Type: interventional
• Target: 11
• Locations: 2 countries
• Sites: 4

Brief Summary

The objective of this clinical study is to evaluate the safety, tolerability and preliminary efficacy of NFS-02 in the treatment of LHON caused by mitochondrial ND1 gene mutation. This study will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single unilateral intravitreal (IVT) injection of NFS-02 to evaluate its safety, tolerability and preliminary efficacy. The clinical manifestations of all subjects are to be reduced visual acuity caused by LHON associated with ND1 mutation, with laboratory test showing G3460A 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 NFS-02 intravitreal injection at different doses

  52 weeks

• Incidence of serious adverse events (SAEs)

  Incidence of serious adverse events (SAEs)within 52 weeks of NFS-02 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 NFS-02 intravitreal injection at different doses

  52 weeks

Secondary Outcomes (16)

• Proportion (%) of subjects with an improvement of ≥ 0.3 LogMAR from baseline in BCVA in the injected eye and non-injected eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260

• Mean change from baseline in BCVA (LogMAR) in the injected eye and non-injected eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260

• Mean change in BCVA (LogMAR) compared to nadir in the injected eye and non-injected eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260

• Change from baseline in the parameter of microperimetry in the injected eye and non-injected eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260

• Proportion (%) of subjects with a clinically meaningful improvement of injected eye from baseline in microperimetry in the injected eye and non-injected eye

  At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260

Study Arms (1)

NFS-02 Injection

EXPERIMENTAL

Potential doses at the dose-finding stage: 5.0×107 vg, 0.05 mL/eye/dose (low dose) 1.5×108 vg, 0.05 mL/eye/dose (starting dose) 5.0×108 vg, 0.05 mL/eye/dose (intermediate dose) 1.5×109 vg, 0.05 mL/eye/dose (high dose)

Drug: NFS-02 Injection

Interventions

NFS-02 Injection DRUG

The starting dose is 1.5×108 vg, 0.05 mL eye/dose. If drug-related dose-limiting toxicity (DLT) events are observed in \< 2 of the 6 evaluable subjects within 6 weeks after the dosing of NFS-02 at the starting dose, the dose can be escalated to 5.0×108 vg, 0.05 mL eye/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 NFS-02 at the 5.0×108 vg, 0.05 mL eye/dose, the dose can be escalated to 1.5×109 vg, 0.05 mL eye/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 NFS-02 at the starting dose, the dose can be de-escalated to 5.0×107 vg, 0.05 mL eye/dose after the approval by SRC.

NFS-02 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
• Age at the time of signing the informed consent form: the age of the subjects must be ≥ 18 years old and ≤ 75 years old Type of Subject and Disease Characteristics
• The clinical manifested vision loss due to LHON, and any eye BCVA ≥ 0.5 LogMAR
• The genotype testing result shows the presence of G3460A mutation in the ND1 gene, and the absence of the other primary LHON associated mutations in the mitochondrial DNA (mtDNA) (ND4 \[G11778A\] 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 visual acuity (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 Sex
• Male or female
• Male subjects:
• A male subject must agree to take contraceptive measures at least 6 months after the treatment visit, see Appendix 5 for details
• Female subjects:
• A female subject is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least one of the following conditions applies:
• i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 ii) A WOCBP who agrees to follow the contraception guidance in Appendix 5 for at least 6 months after the treatment visit Informed Consent
• Written informed consent form must be obtained from the subject or his/her parent/legal guardian before any study-related procedures is performed (see Section 10.2)

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) (Polman C H et al., 2011), 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 (4)

University of Colorado- Dept of Ophthalmology

Aurora, Colorado, 80045, United States

Location

The First Medical Center of the General Hospital of the Chinese People's Liberation Army

Beijing, Beijing Municipality, China

Location

Zhongshan Ophthalmic Center, Sun Yat-sen University

Guangzhou, Guangdong, China

Location

Optometry Affiliated to Wenzhou Medical University

Wenzhou, Zhejiang, China

Location

MeSH Terms

Conditions

Optic Atrophy, Hereditary, Leber

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

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: 5.0×107 vg, 0.05 mL eye/dose(low dose); 1.5×108 vg, 0.05 mL eye/dose(starting dose); 5.0×108 vg, 0.05 mL eye/dose(intermediate dose); 1.5×109 vg, 0.05 mL eye/dose(high dose)

Study Record Dates

• First Submitted: April 6, 2023
• First Posted: April 19, 2023
• Study Start: August 15, 2023
• Primary Completion: June 24, 2024
• Study Completion: June 24, 2024
• Last Updated: September 20, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

CN (3); US (1)