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

A Phase I/II Clinical Study to Evaluate the Safety and Efficacy of ZVS101e Administered as a Single Monocular Subretinal Injection in Subjects With Bietti's Crystalline Dystrophy (BCD)

The purpose of this study was to evaluate the safety and efficacy of ZVS101e administered by subretinal injection in subjects with Bietti's crystalline dystrophy (BCD) and to select the optimal effective dose.

Study Overview

• Status: Recruiting
• Conditions: Bietti's Crystalline Dystrophy
• Intervention / Treatment: Drug: ZVS101e

Detailed Description

This is a single-arm, open-label, and multi-center study of ZVS101e in patients with BCD. Up to 24 subjects are expected to be enrolled. Each participant will receive ZVS101e by subretinal injection in one eye on a single occasion. Safety, efficacy and vector shedding characteristics of ZVS101e are then measured over 180 days. Participants will subsequently enter a long-term follow-up study over a 4.5-year period.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jinlu Zhang, MD; Phone Number: 15810570898; Email: zhangjinlu@chinagene.cc

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100191
      • Not yet recruiting
      • Peking University Third Hospital
      • Principal Investigator: Hongliang Dou, MD
      • Contact: Tingting Wu; Phone Number: 18500191916; Email: wutingting@chinagene.cc
  • Guangdong
    • Guangzhou, Guangdong, China
      • Not yet recruiting
      • Zhongshan Ophthalmic Center,Sun Yat-Sen University
      • Contact: Tingting Wu; Email: wutingting@chinagene.cc
      • Principal Investigator: Bingqian Liu, MD
  • Sichuan
    • Chengdu, Sichuan, China
      • Not yet recruiting
      • West China Hospital, Sichuan University
      • Contact: Bingqian Cong; Email: congbingqian@chinagene.cc
      • Principal Investigator: Fang Lu, MD
  • Tianjin
    • Tianjin, Tianjin, China, 300392
      • Recruiting
      • Tianjin Medical University Eye Hospital
      • Principal Investigator: Xiaorong Li, MD
      • Contact: Tingting Wu; Phone Number: 18500191916; Email: wutingting@chinagene.cc
      • Contact: Siyuan Ma; Phone Number: 13102055471; Email: siyuan.ma@taiji-medicine.com
      • Sub-Investigator: Dongjun Xing, MD
      • Sub-Investigator: Boshi Liu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Fully understand the purpose and requirements of this trial, voluntarily participate in the clinical trial, sign the informed consent form, and be able to complete the whole trial processes as required by the protocol;
• 2. Patients with clinical diagnosis of Bietti's crystalline dystrophy (BCD) (age ≥ 18 years) (including the critical value, and the age is based on the time of signing the informed consent form);
• 3. Genetic test confirmed to carry two pathogenic variants of CYP4V2 and carry no pathogenic mutations of other ophthalmic genetic diseases;
• 4. The study eye must meet the following requirements: Best-corrected visual acuity between 2.3 LogMAR and 0.5 LogMAR (including 2.3 LogMAR and 0.5 LogMAR).

Exclusion Criteria:

• 1. Subjects with insufficient viable retinal cells, or macular retinal less than 100 μm thick;
• 2. Pre-existing eye conditions in the study eye that the investigator determines could interfere with ocular evaluation, preclude surgery, interfere with interpretation of study endpoints or pose surgical complications;
• 3. The study eye has been treated with the following intraocular procedures: retinal detachment surgery, vitrectomy;
• 4. 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);
• 5. Currently taking or may require systemic medications that can cause ocular toxicity, such as psoralen, risedronate, or tamoxifen;

• 6. Those with the following laboratory abnormalities which are clinically significant:

  • Liver function: chronic liver disease, ALT increased > 2 times the upper limit of normal;
  • Hypertension, mean SBP ≥ 160 mmHg or mean DBP ≥ 100 mmHg;
  • 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;
• 7. Patients with rAAV8 neutralizing antibody titer ≥ 1:1000;
• 8. Complicating systemic diseases (such as medical conditions causing immunosuppression) that would preclude the gene transfer, ocular surgery and drug in vivo activity;
• 9. Known drug allergy to the drug planned to be used in the study;
• 10. Patients who cannot communicate or cooperate with medical staff due to neurological, mental illness or language disorder, which affects patient compliance;
• 11. Treatment of either eye with gene therapy drugs for BCD and other ocular diseases, including but not limited to other viral vector gene therapies, mRNA therapy, etc.;
• 12. Has or has had a systemic immune-compromising disease;
• 13. Subjects of reproductive age without any effective contraception and female subjects who have tested positive for pregnancy or are lactating at screening or baseline;
• 14. A condition that, in the opinion of the investigator, would preclude participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Dose escalation and expansion of ZVS101e. All patients enrolled in the study will receive a single subretinal injection of ZVS101e in one eye.	Drug: ZVS101e; ZVS101e contains recombinant adeno-associated virus serotype 8 (rAAV8) vectors which carry human wild type CYP4V2 gene.; Other Names: rAAV2/8-hCYP4V2; rAAV8-hCYP4V2; AAV8-hCYP4V2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to day 180
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.	Up to day 180
Mean change from baseline in BCVA (LogMAR)	BCVA of both eyes will be assessed using the early treatment of diabetic retinopathy study (ETDRS) chart.	Up to day 180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in visual field	Visual field will be assessed by Humphrey perimetry, changes in retinal light sensitivity will be analyzed.	Up to day 180
Change from Baseline in contrast sensitivity	Change from baseline in contrast sensitivity at all spatial frequency will be measured using the CSV-1000E instrument.	Up to day 180
Change from Baseline in microperimetry	Microperimetry will be measured using MP-3，changes in retinal sensitivity (dB) will be analyzed.	Up to day 180
Change from Baseline in mfERG	The measurement will be performed based on the standards of international society for clinical electrophysiology of vision (ISCEV). Response Amplitude Density will be analyzed.	Up to day 180
Change from Baseline in retinal thickness	Retinal thickness will be assessed for both eyes using OCT.	Up to day 180
Change from Baseline in NEI VFQ-25 total score	National eye institute 25-item visual function questionnaire (NEI VFQ-25) consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs. 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.	Up to day 180
Change from Baseline in color vision	Subjects' color vision was classified and graded by having them identify the pictures within Color Vision Examination Plates.	Up to day 180

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in multi-luminance mobility test (MLMT)	MLMT was assessed using both eyes at 1 or more of 7 levels of illumination, ranging from 400 lux (a brightly lit office) to 1 lux (a moonless summer night).	Up to day 180

Collaborators and Investigators

• Sponsor: Chigenovo Co., Ltd
• Investigators: Principal Investigator: Xiaorong Li, MD, Tianjin Medical University Eye Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2023
• Primary Completion (Anticipated): December 1, 2028
• Study Completion (Anticipated): December 1, 2028

Study Registration Dates

• First Submitted: April 2, 2023
• First Submitted That Met QC Criteria: April 16, 2023
• First Posted (Actual): April 27, 2023

Study Record Updates

• Last Update Posted (Actual): April 27, 2023
• Last Update Submitted That Met QC Criteria: April 16, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Genetic Diseases, Inborn; Eye Diseases, Hereditary; Corneal Diseases; Retinal Diseases; Corneal Dystrophies, Hereditary
• Other Study ID Numbers: ZYA-2022-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No