A Study of the Safety and Preliminary Efficacy of LY-M001 Injection in the Treatment of Adult Patients With Gaucher Disease Type I

A Prospective, Single-center, Open-arm, Single-arm Study of the Safety and Preliminary Efficacy of Single Intravenous Infusion Administration of LY-M001 Injection in the Treatment of Adult Patients With Gaucher Disease Type I

This is a prospective single-center, open, single-arm, single-dose intravenous infusion study to evaluate the safety and initial efficacy, pharmacodynamic characteristics, immunogenicity, biodistribution, and viral shedding of LY-M001 injection.This study mainly includes the main study stage and the long-term follow-up study stage.

This study included the screening period (weeks -8 to days -2), the baseline period (days -1), the treatment and safety observation period (days 0 to 28), and the short-term follow-up period (weeks 5 [from day 29] to week 38). Participants eligible for the screening period will be admitted to the study center for a single LY-M001 treatment and a short-term follow-up period after the end of the treatment and safety observation period. Participants who complete all follow-up during the main study phase or who withdraw early from the study are required to complete all assessments required for the End of Study (EOS) visit.The study included up to three adult Gaucher disease type I subjects at preset dose group levels.With 5.0 × 1012 vg/kg as the initial effective dose (first dose group), 1 to 2 subjects are expected to be included. The first dose group was enrolled by sentinel method, and the first subject in this group was observed for at least 28 days after receiving LY-M001 (dose-limited toxicity [DLT] observation period) to enroll the next subject.

Participants enrolled in the long-term follow-up study were those who completed the main study or withdrew early, and the duration of the long-term follow-up study and the main study lasted for a total of 5 years.

Inclusion Criteria:

1. Age ≥ 18 years and ≤ 60 years, male or female.
2. The subjects should fully understand the purpose, nature and method of this study as well as possible adverse reactions, and sign the informed consent form (ICF) voluntarily.
3. Patients with GD1 who have confirmed double mutations in the Gba1 allele by laboratory testing and meet the standard for clinical diagnosis of Gaucher disease (i.e., reduced GCase enzyme activity to less than 30% of normal values).
4. The subjects were type I patients with Gaucher disease. Patients with type I Gaucher disease who had received specific treatment in the past required 5 half-lives of elution
5. Negative pregnancy test for female subjects of childbearing potential 6.6.The subject and his/her partner have no plans to have children during the screening period and within 6 months after the end of the study, and voluntarily take effective contraceptive measures (such as abstinence, condom, etc.); and the subject had no plans to donate sperm or eggs.

7.Subjects are not to donate blood during the study and for at least 1 year after the end of the study.

Exclusion Criteria:

1. AAV8 neutralizing antibody is strongly positive.

2. Patients with clinically suspected Gaucher disease type II (GD2) or Gaucher disease type III (GD3).

3. Active and progressive bone disease that is expected to require surgical treatment within the next 6 months.

4. Subject has idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), thrombocytopenia, anemia, hepatomegaly, splenomegaly, and/or osteoporosis unrelated to Gaucher disease as judged by the investigator.

5. Treatment or disposition of an investigational drug or investigational device for another clinical investigation within 28 days or 5 half-lives (only for drugs), whichever is longer, prior to Screening.

6. Evidence of clinically significant liver disease, fragile liver, or history of hepatotoxin exposure, meeting at screening, but not limited to, any of the following:

   • Progressive hepatomegaly and greater than 3 times normal volume.
   • History of stage 2 or greater liver fibrosis.
   • AST, ALT or TBIL greater than 1.5 times the upper limit of normal (ULN).
   • History of alcohol or drug abuse within the previous 2 years.
   • Hepatitis B surface antigen (HBsAg) positive, and hepatitis B virus DNA positive (HBV-DNA > 103 copies/mL); or taking hepatitis B virus drugs (such as interferon, lamivudine, adefovir and entecavir); or hepatitis C virus (HCV) antibody positive.

7. Human immunodeficiency virus (HIV) antibody positive or Treponema pallidum antibody positive.

8. Severe hyperlipidemia (triglycerides > 1000 mg/dL).

9. Uncontrolled concomitant disease or infectious disease (need to be judged by the investigator based on clinical practice).

10. Subject had undergone splenectomy and were scheduled to undergo splenectomy during the study period.

11. Karnofsky score (KPS) < 70.

12. The subject has received or plans to receive bone marrow transplantation, hematopoietic stem cell transplantation and/or major organ transplantation, including but not limited to liver transplantation, kidney transplantation, etc.

13. Subject has received erythropoietin, transfusion, or red blood cell transfusion within 3 months prior to screening ;or platelet transfusion within 1 month prior to screening.

14. Clinically diagnosed or significant cardiovascular disease as judged by the investigator (e.g., New York Heart Association [NYHA] class ≥ 3 heart failure).

15. Hypersensitivity to any component of LY-M001 Injection.

16. Previous treatment with any type of gene therapy or cell therapy.

17. Use of systemic immunosuppressive agents or steroid therapy other than those required by the protocol for prophylactic administration within 3 months prior to dosing.

18. History of cancer within 5 years of screening, except for completely resected non-melanoma skin cancer, non-metastatic prostate cancer, and completely treated ductal carcinoma in situ.

19. Has received a live attenuated vaccine within 4 months prior to screening or plans to receive a live attenuated vaccine during the clinical trial.

20. Other conditions that, in the opinion of the investigator, make the subject unsuitable for the study.