Gene Therapy ST-920 Shows Favorable Impact on Fabry Disease in Phase 1/2 Study


In a dose-ranging study, the gene therapy achieved 78% Gb3 substrate clearance at 6 months and 77% reduction in urine podocyte loss in 1 of the first kidney biopsies.

Robert Hopkin, MD, associate professor of clinical pediatrics, Cincinnati Children’s Medical Center

Robert Hopkin, MD

Newly announced findings from the phase 1/2 STAAR study (NCT04046224) assessing the safety and tolerability of isaralgagene civaparvovec, or ST-920 (Sangamo Therapeutics), a gene therapy candidate in patients with Fabry disease, showed a favorable safety profile with the treatment, coupled with elevated expression of alpha-galactosidase A (a-Gal A) activity that suggests favorable impact on progression of Fabry neuropathy. The company has already begun plans to move the agent in a phase 3 study, which is expected to begin by the end of 2023.

The single-dose, dose-ranging, multicenter study featured 13 patients with Fabry disease, aged between 22 and 67 years old, who received a one-time administration of ST-920. Presented at the 19th Annual WORLDSymposium, treatment with the agent resulted in maintained supraphysiological a-Gal-A activity that was sustained for over 2 years. Throughout this period, all dose escalation patients had been withdrawn from enzyme replacement therapy (ERT) and remain off ERT today.

"Fabry is a debilitating disease with life-long impact," lead investigator Robert Hopkin, MD, associate professor of clinical pediatrics, Cincinnati Children’s Medical Center, said in a statement. “The combination of the first kidney biopsy results and the associated urine podocyte data are highly encouraging and compelling. As a whole, this exciting dataset shows that ST-920 has the potential to improve the lives of patients without the need for burdensome ERT treatment."

Main Takeaways

  • ST-920 has shown a favorable safety profile over 2 years in a phase 1/2 study including 13 patients.
  • Results suggest that ST-920 has the potential to improve the lives of patients with Fabry disease without the need for ERT.
  • Increases were observed in a-Gal-A activity, as were reductions in plasma lysosomal Gb3 levels.
  • A phase 3 clinical trial is expected to begin by the end of 2023.

ST-920, an AAV2/6 human a-Gal-A gene therapy, continued to show promising results in the highest dosed cohort. At November 22, 2022, the supplemental cutoff, doses of 5 x 1013 vg/kg, the dosage being used for the proposed phase 3 study, resulted in rapid, predicable, and sustained increases in a-Gal A activity across all participants, regardless of sex. Across the 4 dose cohorts of 0.5 x 1013 vg/kg, 1 x 1013 vg/kg, 3 x 1013 vg/kg, and 5 x 1013 vg/kg, a-Gal A activity ranged from nearly 4-fold to 68-fold of mean normal over the 2-year period.

For naïve and pseudo-naïve patients with initially high levels of lysosomal Gb3 (>80 ng/mL), treatment with ST-920 resulted in plasma reductions that ranged from 40% to 65%. For the first time, at the high dose, there was a further reduction of 54% in lysosomal Gb3 for those with baseline plasma levels that were lower than 25 ng/mL. Across the dose escalation and expansion phases, plasma lysosomal Gb3 continued to decrease in 2 participants, and were stable for up to 25 months.

In 1 particular patient, Participant 9, ST-920 biomarkers of nephropathy significantly improved, as demonstrated by a clearance of 78% in Gb3 inclusions from peritubular capillaries. This individual, on the highest dose of the gene therapy, also saw reductions in urinary podocyte loss by 77%. Overall, the significant decrease in renal Gb3 inclusions and the reduction in urine podocyte loss supported a potential favorable impact on progression of Fabry neuropathy, the investigators concluded.

In another patient, Participant 8, investigators observed stable renal Gb3 inclusions and reduced podocyturia. Also on the highest dose of ST-920, this individual had reduced urinary podocyte loss by 97%. Additionally, this individual exhibited significant increases in a-Gal A activity and reductions in lysosomal Gb3.

"We are thrilled with these data, which we believe demonstrate the importance of ST-920 as a potential gene therapy to treat the underlying pathology of Fabry disease. Taken together, the updated biomarker data, kidney biopsy improvements and SF-36 results suggest a promising path forward in our efforts to develop a gene therapy that has the potential to transform the lives of patients living with Fabry disease," Nathalie Dubois-Stringfellow, PhD, senior vice president and chief development officer, Sangamo, said in a statement. "We believe that we have a potential best-in-class gene therapy and are excited to advance this program into a Phase 3 clinical trial as the next step in our mission to deliver an important potential treatment to patients as quickly as possible."

In the dose escalation phase, investigators observed a clinically meaningful and statistically significant change in SF-36 general health scores at week 52 (mean, 19.6; 95% CI, 7.8-31.4; P = .010). Regarding safety, ST-920 was generally well tolerated at all doses, with no requirement for prophylactic corticosteroids or other immune modulating agents. There were no treatment-emergent adverse events greater than Grade 2 reported, as well as no serious treatment-related AEs.

1. Sangamo Therapeutics announces evidence of clinical benefit in phase 1/2 STAAR study in Fabry disease. News release. Sangamo Therapeutics. February 22, 2023. Accessed February 27, 2023.
2. Hopkin RJ, Ganash J, Deegan P, et al. STAAR, a phase 1/2 study of isaralgagene civaparvovec (ST-920) gene therapy in adults with Fabry disease. Presented at: WORLDSymposium 2023; February 22-26. Orlando, FL.
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