Safety and Tolerability of ZVS101e in Patients With Bietti 's Crystalline Dystrophy

NCT05714904 | Unknown Early Phase 1

• 1 other identifier: ZVS101e-01
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to evaluate the safety and tolerability of an adeno-associated virus vector expressing CYP4V2 in patients with Bietti's crystalline dystrophy (BCD).

Conditions

Bietti's Crystalline Dystrophy

Outcome Measures

Primary Outcomes (3)

• Incidence of ocular and systemic adverse events (AEs) after ZVS101e treatment.

  An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product; the event will not need to have a causal relationship with the treatment.

  Baseline up to Week 52

• Incidence of ocular and systemic serious adverse events (SAEs) after ZVS101e treatment.

  A serious adverse event (SAE) is any untoward medical occurrence at any dose that leading to the following: Results in death; Life-threatening, refers to an event in which the patient is at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe; Significant or permanent disability/incapacity, where disability refers to a serious disruption and damage of a person's ability to perform normal life functions; Requires inpatient hospitalization or prolongation of existing hospitalization; Congenital anomaly or birth defect; Other medically important events.

  Baseline up to Week 52

• Type and severity of ocular and systemic AEs and SAEs after ZVS101e treatment.

  Safety as the primary endpoint will be assessed by best-corrected visual acuity (BCVA), slit-lamp examination, ophthalmoscopy, fundus photography, intraocular pressure (IOP), optical coherence tomography (OCT), laboratory tests, vital signs, physical examinations, electrocardiogram (ECG), immunopathology and biodistribution of ZVS101e.

  Baseline up to Week 52

Secondary Outcomes (12)

• Mean change from baseline in BCVA after ZVS101e treatment;

  Baseline up to Week 52

• Change from Baseline in visual field

  Baseline up to Week 52

• Change from Baseline in contrast sensitivity

  Baseline up to Week 52

• Change from Baseline in color vision

  Baseline up to Week 52

• Change from Baseline in retinal thickness

  Baseline up to Week 52

Study Arms (1)

Dose escalation

EXPERIMENTAL

2 cohorts of 3 patients each. All the patients enrolled in the study will receive a single subretinal injection in one eye. Cohort 1: Subretinal administration of a single low dose ZVS101e at Day 0. Cohort 2: Subretinal administration of a single high dose ZVS101e at Day 0.

Drug: ZVS101e

Interventions

ZVS101e DRUG

ZVS101e is developed by Chigenovo Co., Ltd., it contains recombinant adeno-associated virus serotype 8 (rAAV8) vectors which carry human CYP4V2 gene.

Also known as: rAAV2/8-hCYP4V2, rAAV8-hCYP4V2

Dose escalation

Eligibility Criteria

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

You may qualify if:

• Willingness to adhere to protocol as evidenced by written informed consent;
• Patients with clinical diagnosis of Bietti's crystalline dystrophy (BCD) (age ≥ 18 years) (the age is based on the time of signing the informed consent form);
• Genetic test confirmed to carry two pathogenic variants of CYP4V2 and carry no pathogenic mutations of other ophthalmic genetic diseases;
• Agree to use reliable barrier contraception for 2 year after administration of ZVS101e;
• The study eye must meet the following requirements: BCVA between 2.3 LogMAR and 0.5 LogMAR (including 2.3 LogMAR and 0.5 LogMAR); No refractive medium turbidity that affects fundus examination; Visible photoreceptor (outer nuclear) layer on a standard optical coherence tomography (OCT) scan.

You may not qualify if:

• Lack of sufficient viable retinal cell. Specifically, if indirect ophthalmoscopy reveals less than I disc area of retina which is not involved by complete retinal degeneration, these eyes will be excluded. In addition, in eyes where OCT scans of sufficient quality can be obtained, areas of retina with thickness measurements less than 100 μm, or absence of neural retina, will not be targeted for delivery of AAV2-hCYP4V2;
• Existing or pre-existing of choroidal neovascular (CNV) lesions that were secondary to BCD, or other eye conditions interfering with the surgery or the interpretation of the clinical endpoint, in the investigators' opinion;
• The study eye has been treated with other drugs within 3 months that could affect the evaluation of the investigational drug (such as ranibizumab, bevacizumab, aflibercept, conbercept);
• The study eye has been treated with the following intraocular procedures: retinal detachment surgery, vitrectomy;
• Pre-existing eye conditions that the investigator evaluates could interfere with ocular evaluation, preclude surgery, interfere with interpretation of study endpoints or surgical complications (such as glaucoma, high refractive error, diabetes retinopathy or retinal vasculitis );
• Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen;
• Patient with allergic constitution (such as those allergic to two or more drugs and food);
• Those with the following laboratory abnormalities which are clinically significant:
• Liver function: chronic liver disease, ALT increased \>3 times the upper limit of normal; With uncontrolled hypertension, mean systolic blood pressure ≥ 160 mmHg or mean diastolic blood pressure ≥ 100 mmHg; With uncontrolled diabetes, HbA1c\>10%; Patients with abnormal coagulation function (prothrombin time ≥ upper limit of normal (3 seconds' longer), activated partial thromboplastin time ≥ upper limit of normal (10 seconds' longer)); Serum virology test: Active hepatitis B, hepatitis C virus antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab) or syphilis antibody positive; Abnormality of tumor markers (alpha fetoprotein, carcinoembryonic antigen, CA125 carbohydrate antigen, CA153 carbohydrate antigen, CA199 carbohydrate antigen)
• Having any past or present medical history that may affect the safety of the trial or the in vivo process of the drug, especially the medical history of cardiovascular, hepatic, renal, endocrine, gastrointestinal, pulmonary, neurological, hematological, oncologic, immunological or metabolic disorders and others that are thought clinically significant by the investigator, such as diabetes, severe cardiac failure (New York Heart Association Class III and IV);
• Participation in any medicine or medical device clinical trials within 3 months prior to enrollment;
• Neutralizing antibodies to rAAV\> 1:1000 by immunologic test;
• For females in pregnancy or lactation period;
• Any other conditions which leads the investigator to determine the participant is unsuitable for this study.

Sponsors & Collaborators

• Peking University Third Hospital: lead

Study Sites (1)

Peking University Third Hospital

Beijing, Beijing Municipality, 100191, China

RECRUITING

Related Publications (1)

• Jia R, Meng X, Chen S, Zhang F, Du J, Liu X, Yang L. AAV-mediated gene-replacement therapy restores viability of BCD patient iPSC derived RPE cells and vision of Cyp4v3 knockout mice. Hum Mol Genet. 2023 Jan 1;32(1):122-138. doi: 10.1093/hmg/ddac181.

  PMID: 35925866 BACKGROUND

MeSH Terms

Conditions

Bietti Crystalline Dystrophy

Study Officials

• Hongliang Dou, MD

  Peking University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hongliang Dou, MD

CONTACT

010-82266563; douhongliang3736@sina.com

Xuefeng Feng, PhD

CONTACT

xue168feng@sina.com

Study Design

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

Study Record Dates

• First Submitted: December 13, 2022
• First Posted: February 6, 2023
• Study Start: September 23, 2022
• Primary Completion: March 31, 2025
• Study Completion: March 31, 2025
• Last Updated: February 6, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)