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

Study Overview
=================
Brief Summary
-----------------
This is 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 postpubertal at Screening with a confirmed diagnosis of Type 1 Gaucher disease (based on clinical phenotype, genotyping, and deficient GCase enzyme activity in whole blood).

Detailed Description
-----------------
Five study periods (Screening, Baseline, Pre-gene Therapy Infusion, Gene Therapy Infusion, and Post-gene Therapy Infusion Follow-up) comprise the study. During the Screening Period (approximately 60 days), written informed consent will be obtained and the subject will complete other Screening procedures to confirm study eligibility. Once study eligibility is confirmed, subjects will enter the Baseline Period (up to 7 days) during which time assessments will be performed to establish Pre-gene Therapy Infusion baseline. Once baseline assessments are complete, the subject will enter 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, conditioning regimen administration, and conditioning washout period will take place. Enzyme replacement therapy must be discontinued at least 2 weeks before the scheduled Gene Therapy Infusion Day. Following completion of the Pre-gene Therapy Infusion Period, the subject will enter the Gene Therapy Infusion Period (1 day) during which AVR-RD-02 infusion will take place. After AVR-RD-02 Gene Therapy Infusion, the subject will enter the Post-gene Therapy Infusion Follow-up Period (approximately 52 weeks) during which time periodic safety and efficacy assessments will be performed to assess measures of safety, engraftment, and clinical response Post-gene Therapy Infusion. During the Post- gene Therapy Infusion Period, subjects will not receive ERT unless pre-specified laboratory and clinical criteria, which suggest the need for ERT initiation, are met.

Official Title
-----------------
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

Conditions
-----------------
Gaucher Disease

Intervention / Treatment
-----------------
* Drug: AVR-RD-02


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA for all Enrolled (Switch-stable and Treatment-naïve) Subjects: Subject is ≥18 and ≤50 years old and post pubertal Subject has 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 are not available, deficient trough GCase enzyme activity in peripheral blood at Screening. Female subjects of reproductive potential will be counseled regarding the risks, benefits, limitations, and alternatives associated with female fertility preservation. Oocyte harvesting and cryopreservation will be offered Male subjects must be 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 will be recommended. All subjects who have not undergone successful surgical sterilization (ie, vasectomy, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) must agree 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 are required even with documented medical assessment of surgical success of sterilization. For male subjects and for male spouses/partners of female subjects, condoms are an acceptable method of barrier contraception For female subjects and for female spouses/partners of male subjects, acceptable methods of barrier contraception include diaphragm, cervical cap, or contraceptive sponge Male and female subjects must agree to refrain from donating sperm and eggs, respectively, after undergoing conditioning. Subject must be willing to refrain from donating blood, organs, tissues, or cells for gene therapy infusion any time after AVR-RD-02 treatment. Subject must be 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 must be 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): Subject has 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 has normal or near-normal hematologic values at Screening defined as one or more of the following: Hemoglobin concentration ≥10 g/dL Platelet count ≥80 x 10^9/L Subject has stable Gaucher disease during the 6 months immediately preceding Screening defined by: Stable hemoglobin concentration (i.e., within a range of ±2 g/dL of the Screening value) based on documented historical clinical laboratory results and Stable platelet count (within ±20% of the Screening value) based on documented historical clinical laboratory results Subject has 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): Subject has neither received ERT nor SRT for Gaucher disease nor has received neither ERT nor SRT for Gaucher disease within 12 months of Screening. Subject has 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: Platelet count <120 x 10^9/L Enlarged liver by palpation, confirmed on abdominal MRI Moderate splenomegaly by palpation, confirmed on abdominal MRI For any subject who is treatment-naïve, ERT peri-procedurally (from the Screening Period throughout 2 weeks prior to Gene Therapy Infusion) will be considered in consultation with the PI and Sponsor Medical Monitor. EXCLUSION CRITERIA: Subject has Type 2 or 3 Gaucher disease, has severe neurological signs and symptoms, defined as complete ocular paralysis, overt myoclonus or history of seizures, characteristic of neuronopathic Gaucher disease, or has a tremor, peripheral neuropathy or symptoms of Parkinson's disease. Subject has 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 Subject has experienced a prior anaphylactic or anaphylactoid reaction (of any severity) to ERT. Treatment-naïve subject has history of clinically significant (CS) anti-GCase antibodies. Subject has a contraindication to ERT, in the opinion of the Investigator. Subject has a contraindication to HSC transplantation (HSCT), in the opinion of the Investigator. Subject presents with iron, folic acid, and/or vitamin B12 deficiency sustained anemia during Screening. Subject has 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 has 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 confound the study results or, in the opinion of the Investigator, may preclude participation in the study. Subject is a pregnant and/or lactating female. Subject is unable to understand the nature, scope, and possible consequences of the study. Subject has diabetes mellitus (Type 1 or Type 2). Subject has active, progressive bone necrosis. Subject has an active chronic infection during the Screening, Baseline, or Pre-gene Therapy Infusion Period of the study. Subject has 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 has a history of (or current) tuberculosis. Subject tests 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. Subject has a prior history of (or current) cancer or precancerous lesion or has a known genetic predisposition to cancer. The one exception is a prior history of resected squamous cell carcinoma. Subject has 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). Subject has a history of alcohol or illicit drug abuse, according to the Investigator's judgment. Subject has undergone, or is scheduled to undergo, bone marrow transplant, HSC transplant, and/or solid organ transplant. NOTE: Subjects who are otherwise eligible for the study but are scheduled for bone marrow or HSC transplant to treat Type 1 Gaucher disease may be enrolled in the study (instead of receiving an allogeneic transplant) and undergo gene therapy infusion with AVR-RD-02. Subject has 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). Subject has clinically significant immunosuppressive disease or condition, in the opinion of the Investigator, at Screening. Subject is 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 is treatment with cytotoxic or immunosuppressive agents required per protocol for stem cell transplant. Subject is 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. Subject has any condition that makes it impossible to perform MRI studies. Subject has medical condition(s) and/or is receiving medication(s) that would contraindicate ability to undergo mobilization (including contraindication to G-CSF and/or plerixafor), apheresis, or conditioning. Busulfan is contraindicated for the subject. Subject has previously received treatment with AVR-RD-02 or any other gene therapy. Subject is 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Switch Stable<br>Switch-stable arm: Subjects who have undergone ERT ≥15 U/kg and ≤60 U/kg every other week (or equivalent; ie, 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 discontinue ERT at least 2 weeks before the scheduled transplant day. Switch-stable subjects who have been on ERT and substrate reduction therapy (SRT) must not have received SRT within 12 months of Screening. | Drug: AVR-RD-02<br>* 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).<br>|
| Experimental: Treatment-naïve<br>Treatment-naïve arm: Subjects with Type 1 Gaucher disease who have never received either ERT or SRT for Gaucher disease or have not received either ERT or SRT for Gaucher disease within 12 months of Screening (ie, treatment-naïve subjects). Enrollment will follow a similar scheme as for the switch-stable subjects. | Drug: AVR-RD-02<br>* 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).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of clinically significant Adverse Events and Serious Adverse Events of AVR-RD-02 |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Number of participants with clinically relevant abnormalities, as assessed by clinical laboratory tests |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Number of participants with clinically relevant abnormalities, as assessed by vital signs |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Number of participants with clinically relevant abnormalities, as assessed by electrocardiograms (ECGs) |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Average Vector Copy Number (VCN) in peripheral blood as assessed by quantitative polymerase chain reaction (qPCR) and/or droplet digital polymerase chain reaction (ddPCR) |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Average Vector Copy Number (VCN) in bone marrow as assessed by quantitative polymerase chain reaction (qPCR) and/or droplet digital polymerase chain reaction (ddPCR) |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Change from Baseline in spleen volume assessed by abdominal MRI |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Change from Baseline in liver volume assessed by abdominal MRI |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Change from Baseline in hemoglobin concentration |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Change from Baseline 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) |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from average of Screening and Baseline over time in glucocerebrosidase (GCase) enzyme activity |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Incidence of Enzyme Replacement Therapy (ERT) utilized following treatment with AVR-RD-02 |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Change from Baseline in anti-GCase total antibodies and subsequent titers by an electrochemiluminescence method |  | 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) |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 
| Change from Baseline in plasma Chitotriosidase activity levels measured by fluorometric enzyme assay |  | 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) |  | Baseline to 52 weeks post-AVR-RD-02 treatment follow-up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 1 Gaucher, Guard1