Fabry Disease Gene Therapy Demonstrates Favorable Impact in Phase 1/2 Trial
All dose-escalation patients withdrew from enzyme replacement therapy (ERT) and remain off ERT.
This content originally appeared on our sister site, NeurologyLive.
Treatment with Sangamo Therapeutics' isaralgagene civaparvovec (ST-920), an investigational AAV2/6 human a-Gal-A gene therapy for Fabry disease being evaluated in the phase 1/2 STAAR clinical trial (NCT04046224), showed a favorable safety profile and resulted in elevated alpha-galactosidase A (a-Gal A) activity, which suggests a favorable impact on progression of Fabry neuropathy. The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.
The dose-ranging, multicenter study included 13 patients with Fabry disease, aged 22 to 67 years old, who each received a one-time administration of ST-920. The gene therapy effected supraphysiological a-Gal-A activity that was sustained for over 2 years. All dose-escalation patients withdrew from enzyme replacement therapy (ERT) during this period and remain off ERT.
"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."
As of the November 22, 2022, supplemental cutoff date, the trial's highest dose (5x1013 vg/kg) resulted in rapid, predicable, and sustained increases in a-Gal A activity across all participants, regardless of sex. Across the 4 dose cohorts, which included 0.5x1013 vg/kg, 1x1013 vg/kg, 3x1013 vg/kg, and 5x1013 vg/kg, a-Gal A activity ranged from nearly 4-fold to 68-fold of the normal mean over 2 years.
For naïve and pseudo-naïve patients who had initially high levels of lysosomal Gb3 (>80 ng/mL), treatment with the gene therapy effected decreases that ranged from 40% to 65%. At the high dose, there was a further reduction of 54% in lysosomal Gb3 for those with baseline plasma levels 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.
It was noted that ST-920 biomarkers of nephropathy significantly improved in 1 particular patient (Participant 9), as shown by a clearance of 78% in Gb3 inclusions from peritubular capillaries. This individual, who received the highest dose, also saw reductions in urinary podocyte loss by 77%. The investigators concluded that the significant decrease in renal Gb3 inclusions and the reduction in urine podocyte loss indicated a potential favorable impact on progression of Fabry neuropathy.
In another patient, Participant 8, investigators observed stable renal Gb3 inclusions and reduced podocyturia. This individual, who also received the highest dose, 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," Nathalie Dubois-Stringfellow, PhD, senior vice president and chief development officer, Sangamo Therapeutics, added to the statement. "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. 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 (AEs) greater than Grade 2 reported, as well as no serious treatment-related AEs. 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.
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