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

Phase 1Active Not RecruitingNCT06474416

Shanghai BDgene Co., Ltd.16 enrolled

Overview

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).

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Herpes Simplex Virus Type I Stromal Keratitis

Interventions

BD111 Injection (Investigative New Drug)GENETIC

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).

Triple-drugs therapy of HSV-1 stromal keratitisCOMBINATION_PRODUCT

Triple-drugs therapy: "Ganciclovir Eye gel+Valacilovir Tablets+Prednisolone Acetate Eye Drops" for 3 weeks.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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.

Locations (3)

Huashan Hospital, Fudan University

Shanghai, Shanghai City, China

The Second Affiliated Hospital, Zhejiang University School of Medicine

Hangzhou, Zhejiang, China

Eye Hospital of Wenzhou Medical University

Wenzhou, Zhejiang, China

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 12 months

Secondary Outcomes

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.

Time frame: 12 months

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.