A Clinical Study Evaluating LY-M001 Injection in the Treatment of Adult Patients with Type I Gaucher Disease

Gaucher disease (GD) is caused by mutations in the GBA1 gene, which leads to a lack or reduction of GCase activity. The consequences of this deficiency are generally attributed to the accumulation of the GCase substrate, Glucosylceramide (GlcCer), in macrophages in the liver, spleen, kidney, bone, lung, and even the brain, inducing their transformation into Gaucher cells whose cell cytoplasm presenting a characteristic "crumpled tissue paper" appearance, leading to pathological changes in involved tissues and organs.LY-M001 Injection is an rAAV8 vector gene therapy product. It can specifically transduce the target organ liver after a single intravenous administration and express the GCase protein in liver cells for a long period of time.

The purpose of this study was to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetics and pharmacokinetics of LY-M001 injection in patients with GD1 using a multicenter, open, single-arm, single-dose, dose-escalation and extended clinical design. This study includes the main study phase and the long-term follow-up study phase. Phase I studies enrolled approximately 6 to 12 (up to 12) evaluable subjects, and the total number of participants at RP2D dose levels in Phase II and Phase I studies was approximately 14, ensuring 13 evaluable subjects at the RP2D dose. The primary study period was 52 weeks after LY-M001 infusion, and the long-term follow-up period was 53 weeks to 5 years after LY-M001 infusion.Subjects who complete the 52 weeks follow up period or who prematurely withdraw in this study will enter the long-term follow-up study phase to obtain long-term assessment data. After the completion of the 5-year long-term follow-up in this study, the principal Investigator will discuss with the Sponsor whether to prolong the follow-up period based on available safety and efficacy data.

The study was conducted intravenously with a single dose. The Phase I dose escalation study consists of three preset dose groups, including one rollback dose group and two incremental dose groups, which are: Backdose (5 × 10\^12 vg/kg) group, dose group 1 (1.5 × 10\^13 vg/kg) and dose group 2 (3.0 × 10\^13 vg/kg), where dose group 1 was the starting dose of the Phase I study. Three subjects were enrolled in each dose group one by one, and each subject was added to the next subject after at least 28 days of DLT observation to determine safety.

Eligibility Criteria:
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 confirmed double mutations in the GBA1 allele through laboratory testing, and the glucocerebrosidase activity was reduced to less than 30% of the normal value, and meeting the standard clinical diagnosis criteria for GD1.
4. Patients who meet a) or b) below:

   1. Treated patients with Gaucher disease type I who had previously received enzyme replacement therapy (ERT) or substrate clearance therapy (SRT) with GD, were on stable medication, eluted 5 drugs for a half-life or more before administration, or were comprehensively judged to be stable by the investigator.
   2. Newly treated or untreated GD1 patients who meet one or more of the following criteria at screening:

      * Hemoglobin ≥80g/L and less than the lower limit of normal;
      * Platelets ≥40×109/L and less than the lower limit of normal;
      * Hepatomegaly;
      * Splenomegaly.
5. Negative pregnancy test for female subjects of childbearing potential (WOCBP). Notes: WOCBP is defined as the absence of postmenopausal status (continuous amenorrhea of at least 12 months with no identifiable cause other than menopause), and the absence of surgical (i.e., ovarian, salpingectomy, and/or hysterectomy) or Investigator-determined cause of permanent infertility due to other causes (e.g., lenticular hypoplasia) after menarche in female subjects.
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 positive.
2. Patients with clinically diagnosed Gaucher disease type II or III (GD2 or 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 GD as judged by the Investigator.
5. Treatment or disposal of investigational drugs or investigational devices received in other clinical studies within 28 days prior to screening or within 5 half-lives (drugs only), whichever is older.
6. Evidence of clinically significant liver disease, fragile liver, or history of exposure to hepatotoxins that meets, but is not limited to, any of the following at the time of screening:

   * Progressive hepatomegaly larger than 3 times the normal volume.
   * History of stage 2 or above liver fibrosis.
   * AST, ALT, or TBIL are 1.5 times higher than ULN.
   * A history of alcohol or drug abuse within the previous 2 years (defined as having consumed more than 14 standard units of alcohol per week \[1 standard unit containing 14 g of alcohol, such as 360 mL beer, 45 mL spirits containing 40% or more alcohol, or 150 mL wine\]).
   * Hepatitis B surface antigen (HBsAg) positive and HBV deoxyribonucleic acid (HBV-DNA) positive (HBV-DNA\>103 copy number /mL); Or take hepatitis B drugs (such as interferon, lamivudine, adefovir and entecavir); Or antibodies to hepatitis C virus (HCV) and positive for hepatitis C virus RNA.
7. Human immunodeficiency virus (HIV) antibody positive or Treponema pallidum antibody positive.
8. Severe hyperlipidemia (triglycerides \> 11.29mol/L).
9. Uncontrolled concomitant or infectious diseases (need to be determined by the investigator based on clinical practice).
10. 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.
11. 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.
12. Clinically diagnosed or investigator-determined serious cardiovascular disease (such as heart failure ≥3 from the New York College of Cardiology \[NYHA\]).
13. Hypersensitivity to any component of LY-M001 injection.
14. Previous treatment with any type of gene therapy or cell therapy.
15. Use of systemic immunosuppressive agents or steroid therapy other than those required by the protocol for prophylactic administration within 3 months prior to dosing.
16. History of cancer within 5 years prior to screening, or currently active neoplastic disease, except for basal or squamous cell carcinoma of the skin or carcinoma in situ that has been definitively treated.
17. Has received a live attenuated vaccine within 4 months prior to screening or plans to receive a live attenuated vaccine during the clinical trial.
18. Other conditions that, in the opinion of the Investigator, make the subject unsuitable for the study.