AVROBIO Announces 87% Substrate Reduction in First Kidney Biopsy and Additional Positive Data from Clinical Trials of AVR-RD-01 Investigational Gene Therapy in Fabry Disease
– 87% reduction in average number of Gb3 inclusions in first kidney biopsy taken one year post-treatment, the primary efficacy endpoint in the Phase 2 trial
– Plasma lyso-Gb3 consistently reduced 33% to 41% below baseline enzyme replacement therapy (ERT) levels in the first four Phase 1 patients
– Durability observed across multiple biomarkers, sustained at more than two years for the first Phase 1 patient
– No SAEs related to AVR-RD-01 drug product; SAEs and AEs reported have been consistent with conditioning regimen, underlying disease or pre-existing conditions across both studies
– Company to host a conference call to discuss these additional data today,
AVR-RD-01 Summary of Interim Clinical Data
The primary efficacy endpoint for the Phase 2 FAB-201 trial is the change from baseline in the average number of Gb3 inclusions per peritubular capillary (PTC)3 as measured in a kidney biopsy one year post-treatment with AVR-RD-01. Gb3, or globotriaosylceramide, is a substrate (or fat) that accumulates in the cells of Fabry patients and can result in damage to multiple organs including the kidneys and heart.
In addition to safety, the FAB-201 and Phase 1 clinical trials are examining a number of secondary efficacy and other endpoints, including biomarkers, such as measurements in the plasma of Gb3 and lyso-Gb3 (the toxic metabolite of Gb3), AGA enzyme activity levels in leukocytes and plasma, vector copy number (VCN), as well as indicators of kidney and cardiac function.
The following is a summary of key observations from the most recent interim clinical data set:
- Substantial Gb3 substrate reduction in kidney biopsy. The kidney biopsy for the first treatment-naïve patient dosed in the FAB-201 trial, as reviewed by two independent examiners, showed a reduction from an average of 3.55 Gb3 inclusions per PTC at baseline to an average of 0.47 inclusions per PTC one year after administration of the Company’s AVR-RD-01 investigational gene therapy, representing an 87% reduction.
- Sustained plasma lyso-Gb3 reductions. The first Phase 2 patient had an 87% reduction in plasma lyso-Gb3 at one year. The first four Phase 1 patients have seen their plasma lyso-Gb3 levels reduced between 33% and 41% versus their ERT pre-treatment levels. In particular, the 41% reduction level has stabilized at more than two years for the first Phase 1 patient.
- Durability data for AVR-RD-01 continues to show sustained results across multiple parameters. All six patients across the trials for whom data are reported at six months or longer post-treatment with AVR-RD-01 show sustained AGA enzyme activity in leukocytes and plasma and exhibit consistent VCN trends, with VCN levels for the first Phase 1 patient stable at more than two years post-treatment.
- Kidney and cardiac functions stable. Kidney and cardiac functions, as measured by GFR4 and cardiac MRI Left Ventricular Mass parameters, were stable and in a normal range in the first Phase 2 patient at one year.
- Phase 1 patients who have discontinued ERT remain off ERT. The two patients in the Phase 1 trial who discontinued ERT post-AVR-RD-01 treatment remain off ERT to date. These patients have now been off ERT for 10 and 9 months, respectively. A third patient is in the process of discontinuing ERT.
- No unexpected trends or safety events were identified. Serious adverse events (SAEs) and adverse events (AEs) reported were generally consistent with myeloablative conditioning, underlying disease or pre-existing conditions.
“We are excited by the magnitude of the Gb3 reduction observed in the first patient’s kidney biopsy at 12 months. This is the primary efficacy endpoint in FAB-201 and an efficacy endpoint that has previously been utilized by the
Interim clinical data for all eight patients dosed to date in the FAB-201 and Phase 1 clinical trials appear to indicate that the Company’s AVR-RD-01 investigational gene therapy has been generally well tolerated with no unexpected trends or safety events identified. No serious adverse events (SAEs) related to the AVR-RD-01 drug product were reported as of the safety data cut-off dates of
“With eight Fabry patients across two trials now treated with our investigational gene therapy, we are extremely pleased with the emerging data set and its support for AVR-RD-01 to potentially address the genetic basis of Fabry disease. As these clinical trials progress, we aim to position AVR‑RD‑01 as a first-line therapy,” said
Enrollment in the FAB-201 clinical trial is ongoing, and further details are available on clinicaltrials.gov.
Conference Call and Webcast Information
About Fabry Disease
Fabry disease is a rare lysosomal storage disease associated with significant morbidity and early mortality. It is caused by a defective gene that causes a deficiency in the functional enzyme, α‑galactosidase A (AGA), which breaks down a particular type of fat in the body’s cells known as globotriaosylceramide, or Gb3. As Gb3 and related substrates build up in patients with Fabry disease, Gb3 and its metabolites (principally lyso-Gb3) become toxic to the patient’s cells. The accumulation of Gb3 and other glycosphingolipids results in damage to multiple tissues and organs, especially the kidneys, heart and blood vessels, leading to cerebrovascular complications including stroke. In addition, high levels of Gb3 substrate accumulation in the kidney may cause kidney failure. Gb3 can also accumulate in other tissues, such as the nervous system, where it can lead to debilitating pain. Due to end-stage renal disease and other life-threatening complications associated with Fabry disease, the average life expectancy in affected classic Fabry males is approximately 58 years of age. Most patients with Fabry disease begin experiencing chronic pain in childhood but are often not diagnosed with Fabry disease until their twenties, due to a broad variation in patient symptoms. It is estimated that Fabry disease is diagnosed in approximately one in 40,000 males and one in 118,000 females in
About the AVR-RD-01 Clinical Trials
The investigator-sponsored Phase 1 trial is designed to assess the safety and preliminary efficacy of the Company’s investigational gene therapy, AVR-RD-01, in patients with classic Fabry disease who have been treated with standard-of-care enzyme replacement therapy (ERT) for at least six months; enrollment is complete with five patients dosed. The Phase 1 trial is conducted by the FACTs team (FAbry disease Clinical research and Therapeutics) in
AVR-RD-01 is an investigational, ex vivo lentiviral gene therapy being developed as a single-dose therapy with the potential to provide life-long therapeutic benefit for patients with Fabry disease. AVR-RD-01 employs a state-of-the-art lentiviral vector system that is designed to be an efficient gene transfer system with the goal of permanent integration of functional copies of the AGA transgene5 into the patient’s own stem cells. In patients with Fabry disease, hematopoietic stem cells are collected from the patient and then transduced with lentiviral vector carrying a functional version of the α-galactosidase A (GLA) gene that encodes for active α-galactosidase A (AGA) – the enzyme that is deficient in Fabry disease – to create AVR-RD-01. AVR-RD-01 is then infused back into the patient with the goal of having transduced cells, and their daughter cells, secrete functional AGA into the plasma and tissues, which can then be taken up by other cells in the body. This process is called cross correction.
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1 The official name of the ’FAB-201 Trial’ is AVRO-RD-01-201, which is a Phase 2 trial of AVROBIO’s investigational gene therapy, AVR-RD-01, in Fabry disease.
2 FACTs - FAbry disease Clinical research and Therapeutics in
3 Peritubular capillaries (PTCs), also referred to as kidney interstitial capillaries (KICs), convey blood after filtration in the glomeruli, enabling it to eventually exit the kidneys and return to the circulatory system.
4 Glomerular Filtration Rate (GFR) includes estimated GFR (eGFR) determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, and measured GFR (mGFR) determined using plasma clearance of iohexol.
5 A transgene is an exogenous DNA sequence introduced into the genome, which in the case of AVR-RD-01 encodes for functional AGA enzyme.
Christopher F. Brinzey
The Yates Network