open label, study of efficacy and safety of avr-rd-01 for treatment-naive subjects with classic fabry disease

Conditions: Fabry Disease

Summary: 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.

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.

Eligibility criteria:
inclusion criteria: 1. 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) 2. subject had a confirmed diagnosis of classic fabry disease based on deficient aga enzyme activity (defined as \< 1% of normal). exclusion criteria: 1. subject had a galactosidase alpha (gla) gene mutation associated with late-onset cardiac variant fabry disease. 2. subject had previously received ert and/or chaperone therapy within 3 years for treatment of fabry disease. 3. subject had tested positive for anti-aga antibodies at the time of screening. 4. subject had egfr \< 60 ml/min/1.73 m² (ie, chronic kidney disease \[ckd\] stage ≥ 3) at screening. 5. subject had a prior history of myocardial infarction (mi). 6. 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). 7. subject had a history of moderate to severe valvular heart disease requiring valve replacement. 8. 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. 9. 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 \[history of intermittent atrial fibrillation not requiring treatment was allowed\]. 10. subject had a prior history of stroke and/or transient ischemic attack (tia). 11. subject had aspartate aminotransferase (ast) and/or alanine aminotransferase (alt) ≥ 3 times the upper limit of normal (uln) at screening. 12. subject had a prior history of (or current) malignancy; the one exception is a prior history of resected basal cell carcinoma. 13. subject had previously received treatment with avr-rd-01 or any other gene therapy. other inclusion/exclusion criteria apply.

Keywords: fabry disease cell therapy gene therapy lysosomal storage disorder lenti-viral