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

The Guard1 Trial, an Open-Label, Multinational Phase 1/2 Study of the Safety and Efficacy of Ex Vivo, Lentiviral Vector-Mediated Gene Therapy AVR-RD-02 for Subjects With Type 1 Gaucher Disease

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).

Study Overview

• Status: Terminated
• Conditions: Gaucher Disease
• Intervention / Treatment: Drug: AVR-RD-02

Detailed Description

Five study periods (Screening, Baseline, Pre-gene Therapy Infusion, Gene Therapy Infusion, and Post-gene Therapy Infusion Follow-up) comprised the study. During the Screening Period (approximately 60 days), written informed consent was obtained and the subject completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, subjects entered the Baseline Period (up to 7 days) during which time assessments were performed to establish Pre-gene Therapy Infusion baseline. Once baseline assessments were completed, the subject entered the Pre-gene Therapy Infusion Period (approximately 8 to 10 weeks) during which time mobilization, apheresis, AVR-RD-02 investigational product preparation and testing for release, busulfan conditioning regimen administration took place. Enzyme replacement therapy was discontinued at least 2 weeks before the scheduled Gene Therapy Infusion Day. Following completion of the Pre-gene Therapy Infusion Period, the subject entered the Gene Therapy Infusion Period (1 day) during which AVR-RD-02 infusion took place. After AVR-RD-02 Gene Therapy Infusion, the subject entered the Post-gene Therapy Infusion Follow-up Period (approximately 52 weeks) during which time periodic safety and efficacy assessments were performed to assess measures of safety, engraftment, and clinical response following AV-RD-02 infusion.

In August 2023, the study was terminated early by the Sponsor, which was not based on any safety or medical reasons and therefore, one subject did not complete the study (i.e., Week 52). Subsequently, in August 2023, the sponsor's long-term follow-up study (AVRO-RD-02-LTF01), was also terminated early for the same reason as the AVRO-RD-02-201 study, and therefore, no subjects completed the 15-year long-term follow-up study.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: AVROBIO MedInfo; Phone Number: 617-914-8419; Email: medinfo@avrobio.com

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • University Health Network
• United States
  • California
    • San Diego, California, United States, 92103
      • University of California San Diego
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA for all Enrolled (Switch-stable and Treatment-naïve) Subjects:

Note: No treatment-naïve subjects enrolled in this study.

1. Subject was ≥18 and ≤50 years old and post pubertal

2. 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.

3. 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
4. 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.

5. 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.

   1. For male subjects and for male spouses/partners of female subjects, condoms were an acceptable method of barrier contraception
   2. For female subjects and for female spouses/partners of male subjects, acceptable methods of barrier contraception included diaphragm, cervical cap, or contraceptive sponge.
6. Male and female subjects agreed to refrain from donating sperm and eggs, respectively, after undergoing conditioning.
7. Subject was willing to refrain from donating blood, organs, tissues, or cells for gene therapy infusion any time after AVR-RD-02 treatment.
8. 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.

9. Subject was willing to receive blood or blood products transfusion to manage adverse events (AEs).

   Additional Inclusion Criteria for Switch-stable Subjects (in addition to criteria 1-9 above):

10. 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

11. Subject had normal or near-normal hematologic values at Screening defined as one or more of the following:

    1. Hemoglobin concentration ≥10 g/dL
    2. Platelet count ≥80 x 10^9/L

12. Subject had stable Gaucher disease during the 6 months immediately preceding Screening defined by:

    1. Stable hemoglobin concentration (i.e., within a range of ±2 g/dL of the Screening value) based on documented historical clinical laboratory results and
    2. Stable platelet count (within ±20% of the Screening value) based on documented historical clinical laboratory results

13. Subject had not received SRT for Gaucher disease within 12 months of Screening

    Additional Inclusion Criteria for Treatment-naïve Subjects (in addition to inclusion criteria 1 through 9, above, treatment-naïve subjects must meet the following inclusion criteria for participation in this study):

14. Subject had neither received ERT nor SRT for Gaucher disease nor has received neither ERT nor SRT for Gaucher disease within 12 months of Screening.

15. Subject had a hemoglobin level ≤2 g/dL below the lower limit of normal (LLN) for age and sex at Screening and at least one of the following at Screening:

    1. Platelet count <120 x 10^9/L
    2. Enlarged liver by palpation, confirmed on abdominal MRI
    3. Moderate splenomegaly by palpation, confirmed on abdominal MRI
16. For any subject who was treatment-naïve, ERT peri-procedurally (from the Screening Period throughout 2 weeks prior to Gene Therapy Infusion) was considered in consultation with the PI and Sponsor Medical Monitor.

EXCLUSION CRITERIA:

1. 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:

1. Hemoglobin value <9.0 g/dL, or
2. Platelet count <70 x 10˄9/L, or
3. Spleen volume >10 x normal, or

4. Pulmonary hypertension 3. Subject had experienced a prior anaphylactic or anaphylactoid reaction (of any severity) to ERT.

   4. Treatment-naïve subject had history of clinically significant (CS) anti-GCase antibodies.

   5. 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.

   7. Subject presented with iron, folic acid, and/or vitamin B12 deficiency sustained anemia during Screening.

   8. 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.

   9. 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.

   10. Subject was a pregnant and/or lactating female. 11. Subject was unable to understand the nature, scope, and possible consequences of the study.

   12. 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.

   15. 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.

   16. 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.

   18. Subject had a prior history of (or current) cancer or precancerous lesion or has a known genetic predisposition to cancer. The one exception was a prior history of resected squamous cell carcinoma.

   19. Subject had any other medical condition that predisposes him/her to (or conveys increased risk of) malignancy, in the opinion of the Investigator - including history of (or current) monoclonal gammopathy of undetermined significance (MGUS).

   20. Subject had a history of alcohol or illicit drug abuse, according to the Investigator's judgment.

   21. Subject had undergone, or was scheduled to undergo, bone marrow transplant, HSC transplant, and/or solid organ transplant. NOTE: Subjects who were otherwise eligible for the study but were scheduled for bone marrow or HSC transplant to treat Type 1 Gaucher disease may have been enrolled in the study (instead of receiving an allogeneic transplant) and undergo gene therapy infusion with AVR-RD-02.

   22. Subject had white blood cell count (WBC) < 3.0 x 10˄9/L and/or uncorrected bleeding disorder from enrollment (i.e., signing of informed consent at Screening) through the Gene Therapy Infusion Period of the study (i.e., the day of AVR-RD-02 gene therapy infusion).

   23. Subject had clinically significant immunosuppressive disease or condition, in the opinion of the Investigator, at Screening.

   24. Subject was on (or requires treatment with) cytotoxic or immunosuppressive agents from 60 days prior to signing informed consent at Screening (i.e., study enrollment) through the Week 52 study visit; the one exception was treatment with cytotoxic or immunosuppressive agents required per protocol for stem cell transplant.

   25. Subject was on (or requires treatment with) red blood cell (RBC) growth factor (e.g., erythropoietin) from 6 months prior to enrollment (i.e., signing of informed consent at Screening) through the Week 52 study visit.

   26. Subject had any condition that made it impossible to perform MRI studies. 27. Subject had medical condition(s) and/or was receiving medication(s) that would contraindicate ability to undergo mobilization (including contraindication to granulocyte colony-stimulating factor (G-CSF) and/or plerixafor), apheresis, or conditioning.

   28. Busulfan was contraindicated for the subject. 29. Subject had previously received treatment with AVR-RD-02 or any other gene therapy.

   30. Subject was participating in (or plans to participate in) any other investigational drug trial or plans to be exposed to any other investigational agent, device and/or procedure, from 30 days prior to enrollment (i.e., signing of informed consent at Screening) through study completion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Switch Stable; 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; 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).
Experimental: Treatment-naïve; 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; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in GCase Enzyme Activity Level in Plasma	Treatment-naïve Gaucher patients are deficient in glucosylcerebrosidase (GCase) enzyme activity due to mutations in the GBA gene. AVR-RD-02 is intended to increase the amount of GCase enzyme activity in the lysosomes of treated subjects. A positive value (increase from Baseline in GCase enzyme activity) is a positive indicator of efficacy.	Weeks 13, 26, 39, and 52
Change From Baseline in GCase Enzyme Activity Level in Peripheral Blood Leukocytes	Treatment-naïve Gaucher patients are deficient in glucosylcerebrosidase (GCase) enzyme activity due to mutations in the GBA gene. AVR-RD-02 is intended to increase the amount of GCase enzyme activity in the lysosomes of treated subjects. A positive value (increase from Baseline in GCase enzyme activity) is a positive indicator of efficacy.	Weeks 13, 26, 39, and 52
Number of Subjects Who Restarted ERT	The absence of the need to re-start ERT post treatment is a positive indicator of efficacy.	Between Week 26 and Week 52 post-AVR-RD-02 treatment
Change From Baseline in Presence of Anti-GCase Total Antibodies	Number of subjects with changes in anti-GCase antibodies from Baseline to post infusion timepoints. Unit of measure: Number of subjects negative at baseline but positive at post-treatment timepoints. A negative or zero result (titer lower or unchanged at post-infusion timepoints compared to Baseline) indicates no immune response to the therapeutic protein.	At Weeks 5, 13, 26, 39, and 52
Change From Baseline in Bone Mineral Density (BMD) Assessed by Bone Density Scan (DXA)	An increase in BMD is a positive indicator of efficacy. Subjects had T-scores reported for change from baseline in Bone Mineral Density in the Femoral Neck and Lumbar Spine regions assessed by Bone Mineral Density (DXA). The T-score on the subject's bone density report shows how many standard deviations the subject's bone mass differs from the bone mass of an average healthy 30-year-old adult. If the bones are more dense than the average 30-year-old adult, the bone mass will be indicated as a positive T-score. Higher positive T-score indicates greater bone density. If the bones are less dense than the average 30-year-old adult, the bone mass will be indicated as a negative T-score. Lower negative T-score indicates lesser bone density.	Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Change From Baseline in Bone Mineral Density (BMD) Assessed by Bone Density Scan (DXA)	An increase in BMD is a positive indicator of efficacy. Subjects had Z-scores reported for change from baseline in Bone Mineral Density in the Femoral Neck and Lumbar Spine regions assessed by Bone Mineral Density (DXA). A Z-score compares the subject's bone density to the average bone density of people their own age and gender. If the bones more dense than the average person their own age and gender, the bone mass will be indicated as a positive Z-score. Higher positive Z-score indicates greater bone density. If the bones are less dense than the average person their own age and gender, the bone mass will be indicated as a negative Z-score. Lower negative Z-score indicates lesser bone density.	Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Change From Baseline in Plasma Chitotriosidase Activity Levels Measured by Fluorometric Enzyme Assay	Chitotriosidase enzyme is part of an inflammatory response originating in macrophages, which are the primary cell type affected in Gaucher disease. Gaucher disease patients typically have elevated Chitotriosidase enzyme activity in their plasma compared to healthy population. A reduction from Baseline in chitotriosidase enzyme activity is a positive indicator of efficacy.	Baseline to 52 weeks post-AVR-RD-02 treatment follow-up
Change From Baseline in Bone Marrow Burden (BMB) Score as Assessed by Bone Magnetic Resonance Imaging (MRI)	Bone Marrow Burden Score is a semi-quantitative MRI scoring system for assessing the extent of bone marrow involvement in Gaucher disease. A BMB score from 0 to 8 could be given for the lumbar spine, and a BMB score from 0 to 8 could be given to the femurs. Thus, a total BMB score of up to 16 is obtained by adding the lumbar and femoral BMB scores. A higher total BMB-score indicates more severe bone marrow involvement. A reduction in BMB score is a positive indicator of efficacy.	Baseline to 52 weeks post-AVR-RD-02 treatment follow-up

Collaborators and Investigators

• Sponsor: AVROBIO
• Investigators: Study Director: Milena Veselinovic, MD, AVROBIO

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2019
• Primary Completion (Actual): August 21, 2023
• Study Completion (Actual): August 21, 2023

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: October 28, 2019
• First Posted (Actual): October 30, 2019

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Guard1; Type 1 Gaucher
• Additional Relevant MeSH Terms: 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; Gaucher Disease
• Other Study ID Numbers: AVRO-RD-02-201

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: Yes
• Studies a U.S. FDA-regulated device product: No