A Study of the Safety, Tolerability and Prelinminary Efficacy of BD111 in Herpes Simplex Virus Type I Stromal Keratitis

A Multicenter, Open-label, Single Dose, Phase Ⅰ Trial to Evaluate the Safety, Tolerability and Prelinminary Efficacy of BD111 in Patients With Herpes Simplex Virus Type I Stromal Keratitis in China

This Phase I study is intended to evaluate the safety, tolerability, PK/PD profiles and preliminary efficacy via corneal intrastromal administration in patients with herpes simplex virus-1 stromal keratitis (HSK), with a dose exploration of four ascending doses of BD111 (investigative drug product).

Study Overview

• Status: Active, not recruiting
• Conditions: Herpes Simplex Virus Type I Stromal Keratitis
• Intervention / Treatment: Genetic: BD111 Injection (Investigative New Drug); Combination product: Triple-drugs therapy of HSV-1 stromal keratitis

Detailed Description

Herpes simplex keratitis is an infectious diseases of the cornea that is primarily caused by Herpes Simplex Virus 1 (HSV-1). The stromal type, also known as HSV-1 stromal keratitis (HSK), is characterized by recurrent or chronic inflammation attributed to residual virus-triggered antigen-antibody-complement cascade reactions. BD111 is a lentivirus-like particle that is an active drug substance delivering gRNA-expressing cassettes and SpCas9 mRNA.The mechanism of action (MOA) is based on CRISPR/Cas9 gene editing technology.

This is a multicenter, open-label, dose-escalation, Phase I trial to evaluate the safety, tolerability, PK/PD profiles and preliminary efficacy of BD111 in patients with herpes simplex virus-1 stromal keratitis (HSK) in China. About 16 patients will be enrolled, dividing into open-label, four dose groups and one positive control (triple-drugs therapy) group. A rapid titration dose group combined with "3+3" dose escalation is designed for dose exploration.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai City
    • Shanghai, Shanghai City, China, 200000
      • Huashan Hospital, Fudan University
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • The Second Affiliated Hospital, Zhejiang University School of Medicine
    • Wenzhou, Zhejiang, China, 310009
      • Eye Hospital of Wenzhou Medical University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria: Participants must meet all of the following inclusion criteria to be enrolled in this study

1. Aged 18 to 70 years old;
2. Clinically diagnosed patients with recurrent herpes simplex virus type I stromal keratitis (HSK). Definition of recurrence: the patient had been diagnosed with HSK and received "local antiviral eye drugs and oral antiviral drugs + local glucocorticoid eye drops" for 3 weeks with successful clinical efficacy. Before enrollment, the clinical recurrence of HSK occurred again with symptoms including tearing, photophobia, pain, blurred vision and foreign body sensation, and signs as recurrence of active inflammatory lesions examined by slit lamp;
3. HSV-1 nucleic acid test (qPCR method) positive;
4. No use of other systemic antiviral drugs or corticosteroids within 48 hours before enrollment;
5. No systemic immune diseases;
6. Good eyelid structure and blinking function;
7. Eye structure and function assessment showing potential for visual recovery;
8. No retinal detachment;
9. No history of corneal trauma;
10. The best visual acuity in the fellow eye (BCVA) ≥ 38 (ETDRS);
11. Fertile males or females must use highly effective contraceptive methods, such as, oral contraceptives, intrauterine devices, abstinence, or barrier contraception combined with spermicides, during the trial and continue contraception for 12 months after administration;
12. Participants voluntarily join the study, sign an informed consent form, have good compliance, and cooperate with follow-up visits.

Exclusion Criteria: Patients with any of the following conditions cannot be enrolled in this study

1. Active ocular infection caused by other pathogens in the target eye or the fellow eye within 30 days before enrollment, including but not limited to infectious conjunctivitis, keratitis, scleritis, and endophthalmitis;
2. Patients with bilateral viral keratitis
3. Previous corneal transplant surgery in the study eye;
4. Any medicine or food allergic history;
5. Absence of tear film and blinking function;
6. Severe dry eye disease;
7. Ocular surface tumor;
8. Glaucoma;
9. Patients with systemic autoimmune diseases;
10. Signs of systemic infection before enrollment, including fever and receiving antibiotic treatment (systemic infection in this trial is defined as abnormal values in white blood cells, lymphocytes, and neutrophils in routine blood tests);
11. Severe diseases in the major organs including but not limited to cardiovascular, lung, liver, kidney, or other uncontrolled diseases;
12. HIV infection;
13. Pregnant and lactating women (pregnancy in this trial is defined as a positive urine or blood pregnancy test);
14. Participation in other drug or medical device clinical trials at present;
15. Alcohol or drug abuse;
16. Lack of compliance with the trial or the ability to sign an informed consent form;
17. Other situations deemed unsuitable for participation in the trial by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BD111 dose 1 group; 1.25E+06 TU/eye	Genetic: BD111 Injection (Investigative New Drug); BD111 Injection (Investigative New Drug) is a type of lentiviral-like particle, which can simultaneously deliver SpCas9 and gRNA targeting the HSV-1 virus gene, also known as HSV-1-erasing lentiviral particles (HELP).; Other Names: HELP; BD111 Lentivirus-like particles; HSV-1-erasing lentiviral particles
Experimental: BD111 dose 2 group; 2.5E+06 TU/eye	Genetic: BD111 Injection (Investigative New Drug); BD111 Injection (Investigative New Drug) is a type of lentiviral-like particle, which can simultaneously deliver SpCas9 and gRNA targeting the HSV-1 virus gene, also known as HSV-1-erasing lentiviral particles (HELP).; Other Names: HELP; BD111 Lentivirus-like particles; HSV-1-erasing lentiviral particles
Experimental: BD111 dose 3 group; 5.0E+06TU/eye	Genetic: BD111 Injection (Investigative New Drug); BD111 Injection (Investigative New Drug) is a type of lentiviral-like particle, which can simultaneously deliver SpCas9 and gRNA targeting the HSV-1 virus gene, also known as HSV-1-erasing lentiviral particles (HELP).; Other Names: HELP; BD111 Lentivirus-like particles; HSV-1-erasing lentiviral particles
Experimental: BD111 dose 4 group; 10E+06 TU/eye	Genetic: BD111 Injection (Investigative New Drug); BD111 Injection (Investigative New Drug) is a type of lentiviral-like particle, which can simultaneously deliver SpCas9 and gRNA targeting the HSV-1 virus gene, also known as HSV-1-erasing lentiviral particles (HELP).; Other Names: HELP; BD111 Lentivirus-like particles; HSV-1-erasing lentiviral particles
Active Comparator: Positive control group; Triple-drugs therapy group: "Ganciclovir Eye gel+Valacilovir Tablets+Prednisolone Acetate Eye Drops" for 3 weeks.	Combination product: Triple-drugs therapy of HSV-1 stromal keratitis; Triple-drugs therapy: "Ganciclovir Eye gel+Valacilovir Tablets+Prednisolone Acetate Eye Drops" for 3 weeks.; Other Names: Ganciclovir Ophthalmic Gel; Valacyclovir Hydrochloride Tablets; Prednisolone Acetate Ophthalmic Suspension

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity (DLT)	DLT is defined as toxicity related to BD111 observed by the investigator and sponsor during the treatment period, specifically: a) Endophthalmitis; b) Corneal perforation; c) Hypopyon; d) Other toxicities that are significantly worse than baseline or defined as ≥ Grade 4 ocular toxicity and persist for 14 days or longer, which require trial termination after discussion with the investigator and sponsor; e) Any non-ocular Grade ≥ 3 abnormality that persists for more than 1 week or requires hospitalization for medical intervention; f) death.	12 months
Maximum tolerated dose (MTD)	The highest dose at which ≤1/3 of the subjects experience DLT during the DLT observation period. The MTD dose must be confirmed in at least 6 subjects.	12 months
Recommended Phase 2 dose (RP2D)	The RP2D is determined by integrating safety, pharmacokinetic, and efficacy data from the comprehensive dose escalation. Typically, the MTD (DLT incidence ≤ 1/3) is used as the RP2D when it is confirmed, or a dose lower than the MTD is selected as the RP2D based on comprehensive data.	12 months
Incidence and characteristics of adverse events (AE) and serious adverse events (SAE) during the study	AE and SAE are recorded and evaluated, including eye-related AEs after treatment, such as AE at the corneal injection site.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tear fluid vector RNA	Tear fluid vector RNA copy numbers detected by real-time qPCR test, is one of Pharmacokinetics indicators of main components of BD111, and analysizing results will be used to evaluated the PK profile of tear fluid vector RNA and dose-response relationship of BD111.	12 months
Tear fluid vector circular DNA	Tear fluid vector circular DNA copy numbers detected by real-time qPCR test, is another Pharmacokinetics indicator of main components of BD111, and analysizing results will be used to evaluated the PK profile of tear fluid vector RNA and dose-response relationship of BD111.	12 months
Blood vector circular DNA	Real-time qPCR test will be used to detect copy number of vector circular DNA in blood, analysizing the PK profile of blood vector circular DNA and dose-response relationship of BD111.	12 months
Blood p24 protein	P24 protein concentration in blood will be assayed using ELISA p24 kit at preseted timepoints, analysizing the PK profile of Blood p24 protein.	12 months
Blood Cas9 protein	Cas9 protein concentration in blood will be assayed using ELISA p24 kit at preseted timepoints, analysizing the PK profile of Blood p24 protein.	12 months
Off-target Detection (Not applicable to comparison group)	BD111 off-target test of eye swabs samples will be conducted by DNA deep sequencing at Day 0, Day6 and Day 180 post-administration.	12 months
Antibodies to BD111-related ingredients (anti-drug antibodies, no applicable to comparison group)	Including: a) Anti-p24 antibody in the participants' blood samples at Day 0, Day 14, Day 28, Day 180 and Day 365; b) Anti-Cas9 antibody in the participants' blood samples at Day 0, Day 14, Day 28, Day 180 and Day 365; c) Anti-BD111 antibody in the participants' blood samples at Day 0, Day 14, Day 28, Day 180 and Day 365.	12 months
The percentage of participants with successful clearance of HSV-1 viral genome in tear at Day 14, Day 28, Day 70, Day 112, Day 180, and Day 365 post-administration	The definition of successful HSV-1 clearance: negative results in tear swab HSV-1 nucleic acid tests on two consecutive samplings (interval ≥14 days). The definition of a negative result in tear swab HSV-1 nucleic acid test: single qPCR Ct value = 40 or "undetected", or Ct value of the first qPCR test "36 < Ct value < 40", and the Ct value of repetitive qPCR test is 40 or "undetected".	12 months
The percentage of participants with failed clearance of HSV-1 viral genome in tears at Day 14, Day 28, Day 70, Day 112, Day 180, and Day 365 post-administration	The failure of HSV-1 viral genome clearance is determinated by HSV-1 positive results of qPCR test. HSV-1 positive definition of qPCR test: qPCR Ct value ≤ 36, or qPCR Ct value is "36 < Ct value < 40" and the Ct value of repetitive qPCR test is ≤ 36, or results of both qPCR tests are "36 < Ct value < 40".	12 months
Clinical cure rate of HSK at Day 70 and Day112 post-administration	Definition of HSK clinical cure: disappearance of the subject's clinical symptoms, disappearance of active inflammatory lesions on ophthalmologic examinations, and successful clearance of the HSV-1 viral genome.	12 months
The percentage of participants with HSK recurrence at Day 180, and Day 365 post-administration	Definition of HSK recurrence: HSV-1 nucleic acid qPCR test is positive, and clinical symptoms presents again, and ophthalmic examinations find active inflammatory lesions on interventional eye.	12 months
The score change of corneal inflammation scale post-administration	The score changes of corneal inflammation scale will be essessed at Day 70, Day 112, Day 180, and Day 365 post-administration.	12 months
The improvement in best corrected visual acuity (BCVA)	From baseline to Day 70, Day 112, Day 180, and Day 365 post-administration.	12 months
The improvement in corrected distance visual acuity (CDVA) post-administration	From baseline to Day 70, D11ay 2, Day 180, and Day 365 post-administration.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-p24 antibody in blood	At Day 14, Day 28, Day 180, and Day 365 post-administration.	12 months
Anti-Cas9 antibody in blood	At Day 14, Day 28, Day 180, and Day 365 post-administration.	12 months
Anti-BD111 antibody in blood	At Day 14, Day 28, Day 180, and Day 365 post-administration.	12 months

Collaborators and Investigators

• Sponsor: Shanghai BDgene Co., Ltd.
• Investigators: Principal Investigator: Wei Chen, M.D., No. 270, West Academy Road, Wenzhou, Zhejiang, China

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2023
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): March 13, 2026

Study Registration Dates

• First Submitted: June 13, 2024
• First Submitted That Met QC Criteria: June 19, 2024
• First Posted (Actual): June 25, 2024

Study Record Updates

• Last Update Posted (Actual): May 18, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Herpes Simplex Virus Type I; Stromal Keratitis; Herpes simplex keratitis
• Additional Relevant MeSH Terms: Infections; Virus Diseases; Eye Diseases; DNA Virus Infections; Skin Diseases; Corneal Diseases; Skin Diseases, Infectious; Herpesviridae Infections; Skin Diseases, Viral; Herpes Simplex; Keratitis; Anti-Infective Agents; Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antiviral Agents; Protective Agents; Neuroprotective Agents; Methylprednisolone Acetate; Valacyclovir; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Ganciclovir
• Other Study ID Numbers: BD-HSK-111002-Ⅰ

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No