Kidney function stays stable 5 years after Fabry gene therapy: Trial
Final FACTs results support larger, broader clinical trial, researchers say
Five years after receiving the experimental Fabry disease gene therapy AVR-RD-01, kidney function in all five participants remains relatively stable, according to the final results of the Canadian FACTs study, which tested the treatment candidate in men with the condition.
All five patients had significant and sustained increases in blood alpha-Gal A activity, an enzyme deficient in people with Fabry. At the same time, four of the patients showed a marked drop in blood lyso-Gb3, a biomarker that reflects alpha-Gal A activity.
The team of North American researchers noted that alpha-gal A activity “was observed at day 6-8 in each patient following infusion [of the gene therapy] and has remained durable for 5+ years,” with “all 5 patients … eligible to come off biweekly enzyme therapy.” Three of the men did stop enzyme treatment, the researchers noted.
With these results, “we demonstrate that this therapeutic approach has merit, is durable, and should be explored in a larger clinical trial,” the team wrote.
The study, “Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial,” was published in the journal Clinical and Translational Medicine.
FACTs tested Fabry gene therapy AVR-RD-01 in 5 patients in Canada
In Fabry disease, mutations in the GLA gene result in a lack of functional alpha-galactosidase, or alpha-Gal A, an enzyme needed to break down the fatty compound globotriaosylceramide, known as Gb3. This enzymatic defect leads to the accumulation of Gb3 in the blood and cells, causing damage to various tissues and organs, especially the kidneys and heart.
AVR-RD-01 is a one-time gene therapy designed to deliver a working copy of the GLA gene to a patient’s hematopoietic stem cells, or HSCs, which give rise to different types of blood cells. Treatment involves harvesting HSCs from a patient and exposing them to the viral vector used to carry the functional GLA gene. After a procedure to eliminate existing bone marrow cells, the modified stem cells are returned to the same patient via a transplant.
Canadian FACTs was a five-year Phase 1 trial (NCT02800070) that tested the gene therapy in five men, ages 29-48, with classic Fabry. All of the participants had been previously treated with enzyme replacement therapy (ERT), used to manage Fabry.
Interim results reported in 2021 showed that alpha-Gal A rose to near-normal levels within a week of receiving AVR-RD-01. Although enzyme activity decreased over time, almost three years later, such activity remained above levels typically found in Fabry patients. In 2024, a follow-up analysis showed sustained reductions in Gb3 and lyso-Gb3 in treated patients.
Meanwhile, the FAB-GT Phase 1/2 open-label trial (NCT03454893) was launched to evaluate AVR-RD-01 in males with Fabry, ages 16-50, who had not received previous treatment. However, some patients showed unexpected drops in alpha-Gal A activity and signs that the modified stem cells were not growing in the bone marrow as expected.
Given these findings, Avrobio, the developer of AVR-RD-01, deprioritized its Fabry program in early 2022, and enrollment in the FAB-GT trial was stopped.
Pausing ERT for 3 patients saved public health care system about $5M
In this report, Canadian FACTs investigators presented the final results of the study, focusing on years one through five, as earlier time points already were reported.
The data showed that blood levels of alpha-Gal A significantly increased in all five patients up to five years after their stem cell transplant. Still, those levels remained below the normal range in all patients except for one, who had sustained normal levels. Enzyme activity levels in white blood cells followed a similar pattern.
Throughout the study, blood Gb3 levels dropped in all patients, remaining in the normal range at year five. While all participants were eligible to do so, three chose to stop ERT during the trial.
The researchers noted that pausing ERT in those three participants had saved the Canadian public health care system about $5 million at the time of the last patient visit. Moreover, ERT cost savings continue to increase as all five patients are involved in a 15-year follow-up.
Blood lyso-Gb3, a recognized metabolite of interest in Fabry that correlates with disease outcomes, significantly decreased in four patients. Half had stopped ERT, and half had continued. The fifth patient, who had also stopped ERT, had a small but significant increase in lyso-Gb3.
Signs of heart muscle inflammation seen after Fabry gene therapy
Kidney function remained relatively stable for up to five years in all patients, as measured by the estimated glomerular filtration rate (eGFR), which measures how well the kidneys work.
Three patients’ kidney function slightly decreased throughout the study, but their eGFR values remained normal. One patient with mild kidney disease at the time of transplant maintained kidney function without eGFR decline, while another who started with moderate kidney disease experienced a more rapid and variable decline.
All patients showed slightly increasing levels of troponin, a biomarker of heart muscle inflammation. Three patients, two of whom remained on ERT, had a short-term increase in the left ventricular mass index, a measure of the heart’s left ventricle mass, which resolved at five years. No signs of heart fibrosis, or scarring, were seen in any evaluable patient, and all blood pressures were in the normal range.
Although antibodies against alpha-Gal A increased in three patients after the transplant, all remained at or near pretreatment levels beyond 18 months, or 1.5 years.
Future clinical trials … would aim to expand the patient cohort examined in this study as well as include female Fabry disease patients and younger male [patients].
Two adverse events occurring during the treatment phase were previously reported: One patient experienced fever with a low white blood cell count, known as febrile neutropenia, and another had a catheter-related infection. Since then, one patient experienced a moderate incident of vomiting and another of wheezing/asthma.
“Treating patients with [HSCs] engineered to express [alpha-Gal A] continues to be a safe therapy for Fabry disease patients,” the researchers wrote.
The team noted that FACTs was designed as a safety study.
“Future clinical trials in this area would aim to expand the patient cohort examined in this study as well as include female Fabry disease patients and younger male [patients],” the team wrote, adding that “the fact that all five treated patients responded positively to the gene therapy bodes well for outcomes in a larger study.”
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