Lentiviral Vector Gene Therapy - The Guard1 Trial of AVR-RD-02 for Subjects With Type 1 Gaucher Disease

NCT04145037 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: AVRO-RD-02-201
• Study Type: interventional
• Target: 8
• Locations: 2 countries
• Sites: 5

Brief Summary

This was a multinational, open-label study to assess the safety and efficacy of AVR-RD-02 in approximately 8 to 16 subjects (male or female) who are ≥18 and ≤50 years of age and post pubertal at Screening with a confirmed diagnosis of Type 1 Gaucher disease (based on clinical phenotype, genotyping, and deficient GCase enzyme activity in whole blood).

Conditions

Gaucher Disease

Keywords

Type 1 Gaucher; Guard1

Outcome Measures

Primary Outcomes (8)

• Number of Clinically Significant Adverse Events (AEs) and Serious Adverse Events (SAEs) of AVR-RD-02

  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The AE/SAE are also inclusive of any abnormalities in Clinical Laboratory Tests, Vital Signs and in Electrocardiographs (ECGs). AE/SAE can either be related to AVR-RD-02 infusion or attributed to the conditioning agent, mobilization agent(s), study procedures, and the underlying disease.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

• Vector Copy Number (VCN) in Peripheral Blood as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)

  VCN, defined as the average number of copies of the therapeutic gene (transgene) in a sample of cells, is conventionally reported as the number of vector copies found in a sample, relative to copies of a reference gene in the human genome. This is an estimate of the number of integration sites per cell (on average). A VCN of 1 would signify that a sample of cells evaluated contains on average at least one \[working\] copy of the therapeutic transgene per cell. This measurement was for VCN in a sample of progenitor cells obtained from a peripheral blood sample.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

• Vector Copy Number (VCN) in Bone Marrow as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)

  VCN is defined as the average number of copies of the therapeutic gene (transgene) in a sample of cells and is a measurement of the number of copies of the vector found in a sample, relative to copies of a reference gene in the human genome. This is an estimate of the number of integration sites per cell (on average). A VCN of 1 would signify that a sample of cells evaluated contains on average at least one \[working\] copy of the therapeutic transgene per cell. This measurement was for VCN in a sample of bone marrow progenitor cells obtained from an aspirate.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

• Change From Baseline in Spleen Volume Assessed by Abdominal MRI

  Percent change in spleen volume = (\[spleen volume at Week 52 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100. A reduction in the percent change from baseline (%CFB) in spleen volume (mL) is a positive indicator of efficacy.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

• Change From Baseline in Liver Volume Assessed by Abdominal MRI

  Percent change in liver volume = (\[liver volume at Week 52 minus liver volume at baseline\] divided by \[liver volume at baseline\]) multiplied by 100. A reduction in the percent change from baseline (%CFB) in liver volume (mL) is a positive indicator of efficacy.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

• Change From Baseline in Hemoglobin Concentration

  Ratio to baseline indicates the percent change in hemoglobin concentration. The baseline value is defined as 1 or 100%. A ratio to Baseline \<1 indicates a reduction in hemoglobin concentration and a ratio to Baseline \>1 indicates an increase in hemoglobin concentration.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

• Change From Baseline in Platelet Count

  Ratio to baseline indicates the percent change in platelet count. The Baseline value is defined as 1 or 100%. A ratio to Baseline \<1 indicates a reduction in platelet count and a ratio to Baseline \>1 indicates an increase in platelet count.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

• Change From Baseline in Plasma Lyso-Gb1 Levels by Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS)

  Glucosylsphingosine (lyso-Gb1) is the substrate that accumulates in the lysosomes of patients affected by Gaucher disease as a result of deficiencies in GCase enzyme activity. Treatment with AVR-RD-02 is intended to replace the missing GCase enzymatic activity, which allows degradation of accumulated lyso-Gb1 substrate in the lysosomes. Negative values (decrease from Baseline) are an indicator of efficacy.

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

Secondary Outcomes (8)

• Change From Baseline in GCase Enzyme Activity Level in Plasma

  Weeks 13, 26, 39, and 52

• Change From Baseline in GCase Enzyme Activity Level in Peripheral Blood Leukocytes

  Weeks 13, 26, 39, and 52

• Number of Subjects Who Restarted ERT

  Between Week 26 and Week 52 post-AVR-RD-02 treatment

• Change From Baseline in Presence of Anti-GCase Total Antibodies

  At Weeks 5, 13, 26, 39, and 52

• Change From Baseline in Bone Mineral Density (BMD) Assessed by Bone Density Scan (DXA)

  Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

Study Arms (2)

Switch Stable

EXPERIMENTAL

Switch-stable arm: Subjects who had undergone ERT ≥15 U/kg and ≤60 U/kg every other week (or equivalent; i.e., any combination of infusions resulting in a total monthly ERT dose of \>30 U/kg and \<120 U/kg) for ≥24 consecutive months for Type 1 Gaucher disease at the time of Screening. Switch-stable subjects must have discontinued ERT at least 2 weeks before the scheduled AVR-RD-02 infusion. Switch-stable subjects who had been and substrate reduction therapy (SRT) must not have received SRT within 12 months of Screening.

Drug: AVR-RD-02

Treatment-naïve

EXPERIMENTAL

Treatment-naïve arm: Subjects with Type 1 Gaucher disease who had never received either ERT or SRT for Gaucher disease or had not received either ERT or SRT for Gaucher disease within 12 months of Screening (i.e., treatment-naïve subjects). Enrollment followed a similar scheme as for the switch-stable subjects. Note: No subjects enrolled in this arm.

Drug: AVR-RD-02

Interventions

AVR-RD-02 DRUG

AVR-RD-02 Drug product: active substance is autologous CD34+ enriched hematopoietic stem cells (HSCs) that have been genetically modified ex vivo with a lentiviral vector (LV) to contain a ribonucleic acid (RNA) transcript that, after reverse transcription, results in codon-optimized, complementary deoxyribonucleic acid (cDNA) that, upon its integration into human genome, encodes for functional human glucocerebrosidase (GCase).

Switch Stable; Treatment-naïve

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Note: No treatment-naïve subjects enrolled in this study.
• Subject was ≥18 and ≤50 years old and post pubertal
• Subject had a confirmed diagnosis of Type 1 Gaucher disease based on deficient GCase enzyme at Screening.
• a. For switch-stable subjects, documentation of GCase enzyme activity prior to having been started on ERT or if GCase levels prior to ERT were not available, deficient trough GCase enzyme activity in peripheral blood at Screening.
• Female subjects of reproductive potential were counseled regarding the risks, benefits, limitations, and alternatives associated with female fertility preservation. Oocyte harvesting and cryopreservation were offered
• Male subjects were willing to refrain from donating sperm at any time after receiving conditioning therapy. For subjects planning on (or for whom there is a possibility of) fathering children in the future, sperm cryopreservation before administration of the conditioning regimen was recommended.
• All subjects who had not undergone successful surgical sterilization (ie, vasectomy, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) agreed to remain sexually abstinent or use two effective methods of contraception while sexually active from the day of conditioning administration until 52 weeks post-gene therapy infusion. Two methods of contraception were required even with documented medical assessment of surgical success of sterilization.
• For male subjects and for male spouses/partners of female subjects, condoms were an acceptable method of barrier contraception
• For female subjects and for female spouses/partners of male subjects, acceptable methods of barrier contraception included diaphragm, cervical cap, or contraceptive sponge.
• Male and female subjects agreed to refrain from donating sperm and eggs, respectively, after undergoing conditioning.
• Subject was willing to refrain from donating blood, organs, tissues, or cells for gene therapy infusion any time after AVR-RD-02 treatment.
• Subject was willing and able to provide written informed consent for the study in accordance with applicable regulations and guidelines and to comply with all study visits and procedures, including the use of any data collection device(s) that may be used to directly record subject data.
• Subject was willing to receive blood or blood products transfusion to manage adverse events (AEs).
• Subject had undergone a stable dose (within 75% to125% of the prescribed dose) of ERT ≥ 15 U/kg and ≤ 60 U/kg every other week (or equivalent) for ≥ 24 consecutive months with no significant interruptions, in dosing over the last 6 months, in the opinion of the Investigator, prior to Screening
• Subject had normal or near-normal hematologic values at Screening defined as one or more of the following:

You may not qualify if:

• Subject had Type 2 or 3 Gaucher disease, had severe neurological signs and symptoms, defined as complete ocular paralysis, overt myoclonus or history of seizures, characteristic of neuronopathic Gaucher disease, or had a tremor, peripheral neuropathy or symptoms of Parkinson's disease.
• Subject had any one of the following:
• Hemoglobin value \<9.0 g/dL, or
• Platelet count \<70 x 10˄9/L, or
• Spleen volume \>10 x normal, or
• Pulmonary hypertension 3. Subject had experienced a prior anaphylactic or anaphylactoid reaction (of any severity) to ERT.
• \. Treatment-naïve subject had history of clinically significant (CS) anti-GCase antibodies.
• \. Subject had a contraindication to ERT, in the opinion of the Investigator. 6. Subject had a contraindication to HSC transplantation (HSCT), in the opinion of the Investigator.
• \. Subject presented with iron, folic acid, and/or vitamin B12 deficiency sustained anemia during Screening.
• \. Subject had idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), thrombocytopenia, anemia, hepatomegaly, splenomegaly, and/or osteoporosis, unrelated to Gaucher disease, in the opinion of the Investigator.
• \. Subject had a clinical co-morbidity such as neurologic, cardiovascular, pulmonary, hepatic, gastrointestinal, renal, hematologic, endocrine, metabolic, genetic, immunologic, neoplastic, or psychiatric disease, other medical condition(s), or intercurrent illnesses that may have confounded the study results or, in the opinion of the Investigator, may have precluded participation in the study.
• \. Subject was a pregnant and/or lactating female. 11. Subject was unable to understand the nature, scope, and possible consequences of the study.
• \. Subject had diabetes mellitus (Type 1 or Type 2). 13. Subject had active, progressive bone necrosis. 14. Subject had an active chronic infection during the Screening, Baseline, or Pre-gene Therapy Infusion Period of the study.
• \. Subject had an active uncontrolled acute bacterial, viral, fungal, parasitic, or prion-associated infection during the Screening, Baseline, or Pre-gene Therapy Infusion Period of the study.
• \. Subject had a history of (or current) tuberculosis. 17. Subject tested positive for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV, Type 1 or 2), human T-cell lymphotropic virus (HTLV)-1, HTLV-2, and/or syphilis on Venereal Disease Research Laboratory (VDRL) test, chemiluminescent microplate immunoassay (CMIA), or enzyme immunosorbent assay (EIA) at Screening.

Sponsors & Collaborators

• AVROBIO: lead

Study Sites (5)

University of California San Diego

San Diego, California, 92103, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

University Health Network

Toronto, Ontario, M5G 2C4, Canada

Location

MeSH Terms

Conditions

Gaucher Disease

Condition Hierarchy (Ancestors)

Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Limitations and Caveats

GCase PBL results were not available at many timepoints due to sample instability. CFB in chitotriosidase was calculated for only 2 subjects because timepoints for the other 2 subjects exceeded ULOQ of the assay and could not be quantified. BMA samples were collected and batched for VCN analysis, but due to study termination, they were not analyzed and thus discarded. Change from baseline BMD scores were not able to be evaluated for some subjects due to missing baseline and/or Week 52 data.

Results Point of Contact

• Title: AVROBIO MedInfo
• Organization: AVROBIO, Inc

medinfo@avrobio.com

617-914-8419

Study Officials

• Milena Veselinovic, MD

  AVROBIO

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2019
• First Posted: October 30, 2019
• Study Start: May 30, 2019
• Primary Completion: August 21, 2023
• Study Completion: August 21, 2023
• Last Updated: January 18, 2024
• Results First Posted: January 18, 2024

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1); US (4)