An Open-Label, Multinational Study Of The Efficacy And Safety of Ex Vivo, Lentiviral Vector-Mediated Gene Therapy AVR-RD-01 For Treatment-Naive Subjects With Classic Fabry Disease
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- AVROBIO
- 入组人数
- 15
- 试验地点
- 5
- 主要终点
- Evaluation of Aberrant Clonal Expansion
研究概览
简要总结
This was a multinational, open-label study to assess the efficacy and safety of AVR-RD-01 in approximately 15 male subjects, who were 16 years of age or older and postpubertal with a confirmed diagnosis of classic Fabry disease based on deficient alpha galactosidase A (AGA) enzyme activity who were considered treatment naïve, i.e., had not previously received treatment with enzyme replacement therapy (ERT) and/or chaperone therapy within 3 years of the time of Screening.
详细描述
The duration of each subject's participation in this study was approximately 64 weeks (or 1 year, 12 weeks), comprised of five study periods (Screening, Baseline, Pre-transplant, Transplant, and Post-transplant Follow-up). During the Screening Period (approximately 8 weeks), written informed consent (and assent, if applicable) was obtained and the subject had completed other Screening procedures to confirm study eligibility. Once study eligibility was confirmed, the subjects entered the Baseline Period (up to 3 days) during which time assessments would have been performed to establish a pre-transplant baseline. Once baseline assessments were completed, the subject entered the Pre-transplant Period (approximately 6 weeks) during which time mobilization, apheresis, AVR-RD-01 investigational drug product preparation and testing for release, and conditioning regimen administration to achieve myeloablation took place. Following completion of the Pre-transplant Period, the subject entered the Transplant Period (1 day) during which time AVR-RD-01 infusion took place. After AVR-RD-01 infusion, the subject entered the Post-transplant Follow-up Period (approximately 48 weeks), during which time periodic safety and efficacy assessments were performed to assess measures of engraftment, clinical response, and safety post-transplant.
In January 2022, the study was terminated early due to a decision by the study sponsor, to deprioritize its Fabry disease development program, and therefore, some subjects (n=5) did not complete the study (i.e., Week 48). Subsequently, in August 2023, the long-term follow-up study (AVRO-RD-01-LTF01), was also terminated early due to the decision by the sponsor to terminate the development program for Fabry disease, and therefore, no subjects completed the 15-year long-term follow-up study. This decision to terminate was not based on any safety or medical reasons.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 50 Years（Child, Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Subject was male, 16 years of age or older (18 years of age or older in the US), and post pubertal,(minimum age by region)
- •Subject had a confirmed diagnosis of classic Fabry disease based on deficient AGA enzyme activity (defined as < 1% of normal).
排除标准
- •Subject had a galactosidase alpha (GLA) gene mutation associated with late-onset cardiac variant Fabry disease.
- •Subject had previously received ERT and/or chaperone therapy within 3 years for treatment of Fabry disease.
- •Subject had tested positive for anti-AGA antibodies at the time of screening.
- •Subject had eGFR < 60 mL/min/1.73 m² (ie, chronic kidney disease [CKD] stage ≥ 3) at Screening.
- •Subject had a prior history of myocardial infarction (MI).
- •Subject had a history of coronary artery disease (CAD) with angina requiring percutaneous transluminal coronary angioplasty (with or without stent placement) and/or coronary artery bypass graft (CABG).
- •Subject had a history of moderate to severe valvular heart disease requiring valve replacement.
- •Subject had a history of heart failure, moderate to severe diastolic dysfunction, and/or left ventricular ejection fraction (LVEF) ≤ 45% on echocardiogram (ECHO) performed at rest at Screening.
- •Subject had a history of clinically significant cardiac arrhythmia (eg, heart block [second or third degree], atrial fibrillation requiring therapy, ventricular fibrillation, ventricular tachycardia, supraventricular tachycardia, or cardiac arrest).
- •Note [history of intermittent atrial fibrillation not requiring treatment was allowed].
- •Subject had a prior history of stroke and/or transient ischemic attack (TIA).
- •Subject had aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) at Screening.
- •Subject had a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma.
- •Subject had previously received treatment with AVR-RD-01 or any other gene therapy.
- •Other inclusion/exclusion criteria apply.
研究组 & 干预措施
Single Assignment AVR-RD-01
AVR-RD-01 is an autologous CD34+-enriched cell fraction transduced with LV/AGA containing an RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into the human genome, encodes for functional human AGA.
干预措施: AVR-RD-01 (Drug)
结局指标
主要结局
Evaluation of Aberrant Clonal Expansion
时间窗: Baseline to Week 48 post gene therapy
Integration Site Analysis (ISA) uses next generation sequencing to identify junction sites between the integrated therapeutic transgene and the host genome. Samples are analyzed for the emergence of clonality (defined as (a single clone accounting for greater than 20% of the population) and whether any integration site is within or near a known oncogene.
Change From Baseline in the Average Number of Gb3 Inclusions (ie, Myelinosomes) Per Kidney Peritubular Capillary (PTC) Per Subject
时间窗: Baseline to Week 48 post gene therapy
Globotriaosylceramide (Gb3) Inclusions in Peritubular Capillaries (PTC) on Kidney Biopsy. Electron microscopic images of kidney biopsy samples were taken and read centrally by two independent renal pathologists, each of whom scored the average number of Gb3 inclusions per kidney PTC per subject using a quantification method. Healthy renal tissue would have no Gb3 inclusions. A reduction from baseline is desirable.
Incidence of and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Baseline to Week 48 post gene therapy
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). Of the 13 serious adverse events, no SAEs reported were considered related to AVR RD 01. Of the 354 adverse events, no AEs were considered related to AVR RD 01. The SAEs and AEs reported in the study were attributed to the conditioning agent used, the underlying disease, comorbid conditions, study procedures and concomitant medications.
Change From Baseline in Immunogenicity of AVR-RD-01
时间窗: Baseline to Week 48 post gene therapy
Number of subjects with changes in anti-AGA antibodies from Baseline to post infusion timepoints. Unite 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 compare to Baseline) indicates no immune response to the therapeutic protein.
Presence of Replication Competent Lentivirus (RCL)
时间窗: Baseline to Week 48 post gene therapy
The "Presence of RCL" is a theoretical risk of lentiviral gene therapy treatment based on the theory that it may be possible for inadvertent generation of RCL caused either by recombination of the lentiviral vector plasmids during the vector production process or by mobilization of proviral DNA in vivo by infectious retroviruses (HIV). The absence of RCL is a positive indicator of safety.
次要结局
- Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Plasma(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Globotriaosylceramide (Gb3) Biomarkers for Fabry Disease in Urine(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Left Ventricular Mass Index (LVMI) as Assessed by Cardiac Magnetic Resonance Imaging (MRI)(Baseline to Week 48 post gene therapy)
- Change From Baseline in Renal Function as Assessed by Measured Glomerular Filtration Rate (mGFR)(Baseline to Week 48 post gene therapy)
- Change From Baseline in Renal Function as Assessed by Urine Albumin Levels(Baseline to Week 24 and Week 48 post gene therapy)
- Average Vector Copy Number (VCN) in Peripheral Blood Leukocytes as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)(At Week 24 and Week 48 post gene therapy)
- Change From Baseline (CFB) in AGA Enzyme Activity Level in Plasma and Peripheral Blood Leukocytes (PBLs)(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Substrate (i.e. Gb3) in Skin Biopsy(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Renal Function as Assessed by Urine Total Protein Levels(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR)(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Abdominal Pain and Stool Consistency as Assessed by the Diary for Irritable Bowel Syndrome Symptoms-Diarrhea (DIBSS-D)(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Brief Pain Inventory-Short Form (BPI-SF) Questionnaire Scores(Baseline to Week 24 and Week 48 post gene therapy)
- Change From Baseline in Physical and Mental Functioning as Assessed by the Short Form 36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores(Baseline to Week 48 post gene therapy)
- Average Vector Copy Number (VCN) in Bone Marrow / Progenitor Cells as Assessed by Quantitative Polymerase Chain Reaction (qPCR) and/or Droplet Digital Polymerase Chain Reaction (ddPCR)(At Week 48 post gene therapy)