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

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.

Study Overview

• Status: Recruiting
• Conditions: Gaucher Disease Type I
• Intervention / Treatment: Biological: LY-M001 Injection

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 3
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: He Huang, Doctor; Phone Number: 0571-87236703; Email: hehuangyu@126.com

Study Locations

• China
  • Zhejiang
    • Hanzhou, Zhejiang, China, 310003
      • Recruiting
      • The First Affiliated Hospital of Zhejiang University School of Medicine
      • Contact: He Huang, Doctor; Phone Number: 0571-87236703; Email: hehuangyu@126.com

Participation Criteria

Eligibility Criteria

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

Description

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.

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: A Prospective, single-center, open, single-arm study; The study is single-arm. LY-M001 injection is administered by intravenous infusion at a rate of 1 mL per minute.LY-M001 Injection is Clear and colorless liquid.According to the dose cohort of the subject, the required dosage was accurately calculated by the patient's body weight for infusion.

Biological: LY-M001 Injection; With 5.0 × 10^12 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. After the first participant completes the safety evaluation of dosing for at least 28 days, the investigator (PI) and the partner discuss the safety and efficacy data and decide to maintain the first dose or increase/reduce it to another dose group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment- related adverse events	Number and severity of adverse events and serious adverse events and relationship to LY-M001	within 38 weeks after LY-M001 infusion
Incidence of events adjudicated as dose limiting toxicity (DLT)	Number and severity of dose limiting toxicity	within 28 days after LY-M001 infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucocerebrosidase (GCase) protein in plasma and GCase enzyme activity	Change from baseline in plasma GCase protein and GCase enzyme activity level	Within 38 Weeks after LY-M001 infusion
Glucosylsphingosine (Lyso-GL1)in plasma	Change from baseline in plasma Lyso-GL1 level	Within 38 Weeks after LY-M001 infusion

Collaborators and Investigators

• Sponsor: He Huang
• Collaborators: Lingyi Biotech Co., Ltd.

Publications and helpful links

General Publications

• Nabizadeh A, Amani B, Kadivar M, Toroski M, Asl AA, Bayazidi Y, Mojahedian M, Davari M. The Clinical Efficacy of Imiglucerase versus Eliglustat in Patients with Gaucher's Disease Type 1: A Systematic Review. J Res Pharm Pract. 2018 Oct-Dec;7(4):171-177. doi: 10.4103/jrpp.JRPP_18_24.
• Barranger JA, Brady RO, Grabowski GA, Mankin H, Mistry PK, Weinreb NJ. Position statement: National Gaucher Foundation Medical Advisory Board, January 7, 2014. Am J Hematol. 2014 May;89(5):457-8. doi: 10.1002/ajh.23687. Epub 2014 Mar 7. No abstract available.
• Franco M, Reihani N, Marin M, De Person M, Billette de Villemeur T, Rose C, Colin Y, Moussa F, Belmatoug N, Le Van Kim C. Effect of velaglucerase alfa enzyme replacement therapy on red blood cell properties in Gaucher disease. Am J Hematol. 2017 Sep;92(9):E561-E563. doi: 10.1002/ajh.24816. Epub 2017 Jul 19. No abstract available.
• Kuter DJ, Wajnrajch M, Hernandez B, Wang R, Chertkoff R, Zimran A. Open-label, expanded access study of taliglucerase alfa in patients with Gaucher disease requiring enzyme replacement therapy. Blood Cells Mol Dis. 2020 May;82:102418. doi: 10.1016/j.bcmd.2020.102418. Epub 2020 Feb 24.
• Bennett LL, Fellner C. Pharmacotherapy of Gaucher Disease: Current and Future Options. P T. 2018 May;43(5):274-309.
• Tsai P, Lipton JM, Sahdev I, Najfeld V, Rankin LR, Slyper AH, Ludman M, Grabowski GA. Allogenic bone marrow transplantation in severe Gaucher disease. Pediatr Res. 1992 May;31(5):503-7. doi: 10.1203/00006450-199205000-00019.
• Konkle BA, Walsh CE, Escobar MA, Josephson NC, Young G, von Drygalski A, McPhee SWJ, Samulski RJ, Bilic I, de la Rosa M, Reipert BM, Rottensteiner H, Scheiflinger F, Chapin JC, Ewenstein B, Monahan PE. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood. 2021 Feb 11;137(6):763-774. doi: 10.1182/blood.2019004625.
• Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Tschakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014 Nov 20;371(21):1994-2004. doi: 10.1056/NEJMoa1407309.
• Xu YH, Quinn B, Witte D, Grabowski GA. Viable mouse models of acid beta-glucosidase deficiency: the defect in Gaucher disease. Am J Pathol. 2003 Nov;163(5):2093-101. doi: 10.1016/s0002-9440(10)63566-3.
• Sun Y, Zhang W, Xu YH, Quinn B, Dasgupta N, Liou B, Setchell KD, Grabowski GA. Substrate compositional variation with tissue/region and Gba1 mutations in mouse models--implications for Gaucher disease. PLoS One. 2013;8(3):e57560. doi: 10.1371/journal.pone.0057560. Epub 2013 Mar 8.
• Chen RL, Hou JW, Chang PY, Tsai FJ, Wang PJ. Matched unrelated bone marrow transplantation without splenectomy for a child with Gaucher disease caused by homozygosity of the L444P mutation, who also suffered from schizencephaly. J Pediatr Hematol Oncol. 2007 Jan;29(1):57-9. doi: 10.1097/MPH.0b013e3180308793.
• Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, Dolan G, Reiss U, Phillips M, Riddell A, Peralta MR, Quaye M, Patch DW, Tuddenham E, Dane A, Watissee M, Long A, Nathwani A. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med. 2022 Jul 21;387(3):237-247. doi: 10.1056/NEJMoa2119913.

Helpful Links

• a Phase I/II safety and efficacy study of FLT201 gene therapy for Gaucher disease type 1
• A Phase I/II, Open label, Multicentre, Ascending Single Dose, Safety Study of a Novel Adeno associated Viral Vector (FLT180a) in Patients With Haemophilia B 2020
• Package Insert - HEMGENIX
• WHOQOL - Files

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2023
• Primary Completion (Estimated): August 17, 2024
• Study Completion (Estimated): October 17, 2028

Study Registration Dates

• First Submitted: November 20, 2023
• First Submitted That Met QC Criteria: November 30, 2023
• First Posted (Actual): December 8, 2023

Study Record Updates

• Last Update Posted (Actual): December 8, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Disease; Gaucher Disease
• Other Study ID Numbers: LY-M001-GD-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: No
• Studies a U.S. FDA-regulated device product: No