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

• ClinicalTrials.gov Identifier: NCT05820152
• Recruitment Status: Recruiting
• First Posted: April 19, 2023
• Last Update Posted: December 12, 2023
• Sponsor: Neurophth Therapeutics Inc
• Information provided by (Responsible Party): Neurophth Therapeutics Inc

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Leber Hereditary Optic Neuropathy (LHON)	Drug: NFS-02 Injection	Phase 1; Phase 2

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 1.5×108 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 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.

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 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.

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: 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)
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Multi-regional, Single-Arm, Open-Label, Dose-Finding Clinical Trial to Evaluate the Safety, Tolerability and Efficacy of Gene Therapy for Leber's Hereditary Optic Neuropathy (LHON) Associated With ND1 Mutation
• Actual Study Start Date: August 15, 2023
• Estimated Primary Completion Date: December 30, 2024
• Estimated Study Completion Date: December 30, 2029

Arms and Interventions

Arm

Intervention/treatment

Experimental: NFS-02 Injection; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events (AEs) [ Time Frame: 52 weeks ]
   Incidence of adverse events (AEs) within 52 weeks of NFS-02 intravitreal injection at different doses
2. Incidence of serious adverse events (SAEs) [ Time Frame: 52 weeks ]
   Incidence of serious adverse events (SAEs)within 52 weeks of NFS-02 intravitreal injection at different doses
3. Incidence of dose-limiting toxicities (DLT) [ Time Frame: 52 weeks ]
   Incidence of dose-limiting toxicities (DLT) (ocular and non-ocular) within 52 weeks of NFS-02 intravitreal injection at different doses

Secondary Outcome Measures :

1. Proportion (%) of subjects with an improvement of ≥ 0.3 LogMAR from baseline in BCVA in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260 ]
   ETDRS visual acuity charts will used to assess proportion (percent) of subjects with an improvement of ≥ 0.3 LogMAR from baseline in Best corrected visual acuity(BCVA)
2. Mean change from baseline in BCVA (LogMAR) in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260 ]
   ETDRS visual acuity charts will used to assess mean change from baseline in BCVA (LogMAR)
3. Mean change in BCVA (LogMAR) compared to nadir in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260 ]
   ETDRS visual acuity charts will used to assess mean change in BCVA (LogMAR) compared to nadir
4. Change from baseline in the parameter of microperimetry in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260 ]
   Microperimetry parameters will evaluate alterations in function of different region the retina. The major parameter to be documented is mean sensitivity
5. Proportion (%) of subjects with a clinically meaningful improvement of injected eye from baseline in microperimetry in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260 ]
   Microperimetry parameters will evaluate alterations in function of different region the retina. The major parameter to be documented is mean sensitivity. A clinically meaningful improvement is defined as an improvement of 7 decibels (dB) or more post-treatment from a baseline in a pre-defined area consisting of 5 or more points in central 20° vision on microperimetry (a pre-defined area is set as central 36 loci among 68 loci of the whole grid)
6. Change from baseline in contrast sensitivity in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260 ]
   The contrast sensitivity examination measures the subject's ability to discern targets presented at varying spatial frequencies or sizes under different contrast levels. The contrast sensitivity examination measures the full range of visual sensitivity, including brightness and contrast, and it may be used as a comprehensive assessment of visual function
7. Change from baseline in visual evoked potential (VEP) parameters in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 40, 52, 78, 104, 130, 156, 182, 208, 234, and 260 ]
   VEP is a visual electrophysiological examination used to identify possible ischemic optic neuropathy, including the P100 Latency,P100 Amplitude,P2 Latency,P2 Amplitude
8. To evaluate immunogenicity [ Time Frame: At Weeks 1, 2, 6, 12, 26, 40, and 52 ]
   A central laboratory will be used to evaluate anti-AAV2 neutralizing antibodies in the serum samples of all subjects. These samples will be tested by the sponsor or its designee to detect anti-AAV2 neutralizing antibodies in the samples and report the titer of confirmed positive samples. Samples confirmed positive for anti-AAV2 neutralizing antibodies will also be evaluated for the presence of neutralizing antibodies
9. To evaluate immunogenicity [ Time Frame: At Weeks 1, 2, 6, 12, 26, 40, and 52 ]
   The interferon gamma enzyme-linked immunospot (ELISpot) assay will be performed to measure the proliferative response of lymphocytes to AAV2 antigen and ND1 peptide. The number of activated cells in the sample was calculated
10. To evaluate vector shedding [ Time Frame: At Weeks 1, 2, 6, 12, 26, 40, and 52 ]
    Assessment of vector DNA shedding in tears (both eyes).Samples were analyzed to determine the presence of viral DNA in tears
11. To evaluate biodistribution [ Time Frame: At Weeks 1, 2, 6, 12, 26, 40, and 52 ]
    Assessment of biodistribution in whole blood. Samples were analyzed to determine the presence of viral DNA in whole blood
12. To evaluate the improvement in BCVA in the injected eye and non-injected eye (< 0.3 LogMAR) [ Time Frame: At Weeks 52, 78, 104, 130, 156, 182, 208, 234 and 260 ]
    ETDRS visual acuity charts will used to assess proportion (percent) of subjects with an improvement of ≥ 0.2 LogMAR and ≥ 0.1 LogMAR from baseline in BCVA Proportion (percent) of subjects with visual acuity of > 1.0 LogMAR before and after treatment
13. Change from baseline in retinal nerve fiber layer (RNFL) thickness in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 52, 78, 104, 130, 156, 182, 208, 234 and 260 ]
    OCT is an imaging technology to investigate the ocular fundus by using of the basic principle of low-coherence light interferometry. It detects the reflection or diffusion signals of biological tissue layers of different depths by inputting low coherence light and obtains the images and quantitative results of the microscopic structure of the retina
14. Change from baseline in retinal ganglion cell complex thickness in the injected eye and non-injected eye [ Time Frame: At Weeks 2, 6,12, 26, 52, 78, 104, 130, 156, 182, 208, 234 and 260 ]
    OCT is an imaging technology to investigate the ocular fundus by using of the basic principle of low-coherence light interferometry. It detects the reflection or diffusion signals of biological tissue layers of different depths by inputting low coherence light and obtains the images and quantitative results of the microscopic structure of the retina
15. To evaluate the change from baseline in VFQ-25 [ Time Frame: At Weeks 12, 26，52, 78, 104, 130, 156, 182, 208, 234 and 260 ]
    VFQ-25 is a 25-item short form version of the 51-item National Eye Institute Visual Function Questionnaire (NEI VFQ), which can effectively measure patient-reported outcomes (including quality of life, QoL). All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively.
16. To evaluate the change from baseline in quality of SF-36 [ Time Frame: At Weeks 12, 26，52, 78, 104, 130, 156, 182, 208, 234 and 260 ]
    The SF-36 questionnaire is a universal tool for evaluating patient-reported QoL outcome. SF-36 comprises 36 questions which cover eight domains of health: 1) limitations in physical activities because of health problems; 2)limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6)limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The scale score of each domain will be calculated based on the total score of the items included in the said domain and re-adjusted to 0-100,higher scores mean a worse outcome

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Age

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 Type of Subject and Disease Characteristics
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 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)
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 visual acuity (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 Sex

8. Male or female

   1. Male subjects:

      A male subject must agree to take contraceptive measures at least 6 months after the treatment visit, see Appendix 5 for details

   2. 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

9. 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)
10. 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) (Polman C H 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 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 clinical-related ocular surgery (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 NFS-02 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 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

Contacts and Locations

Contacts

Contact: Bin LI; +86 027 65524119; info@neurophth.com

Locations

United States, Colorado

University of Colorado- Dept of Ophthalmology; Recruiting

Aurora, Colorado, United States, 80045

Contact: Prem Subramanian, Doctor 720-848-2020 prem.subramanian@cuanschutz.edu

China, Beijing

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

Beijing, Beijing, China

Contact: Shihui Wei, Doctor +86 13910079431 weishihui706@hotmail.com

China, Guangdong

Zhongshan Ophthalmic Center, Sun Yat-sen University; Recruiting

Guangzhou, Guangdong, China

Contact: Xiaoyan Ding, Doctor +86 13535022222 dingxiaoyan@gzzoc.com

China, Zhejiang

Optometry Affiliated to Wenzhou Medical University; Recruiting

Wenzhou, Zhejiang, China

Contact: Jia Qu, Doctor +86 13806898805 13806898805@163.com

Sponsors and Collaborators

Neurophth Therapeutics Inc

More Information

• Responsible Party: Neurophth Therapeutics Inc
• ClinicalTrials.gov Identifier: NCT05820152
• Other Study ID Numbers: NFS-02-101
• First Posted: April 19, 2023
• Last Update Posted: December 12, 2023
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Optic Nerve Diseases; Optic Atrophy, Hereditary, Leber; Nervous System Diseases; Cranial Nerve Diseases; Eye Diseases; Optic Atrophies, Hereditary; Optic Atrophy; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Eye Diseases, Hereditary; Genetic Diseases, Inborn; Mitochondrial Diseases; Metabolic Diseases