Gene Therapy ST-920 Leading to Long-term Benefits in STAAR Trial

One-time therapy is sustaining higher alpha-GalA enzyme activity in patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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One-time treatment with ST-920 (isaralgagene civaparvovec), an experimental gene therapy being developed by Sangamo Therapeutics, continues to be generally well-tolerated among people with Fabry disease, according to new data from the Phase 1/2 STAAR clinical trial.

Trial data show that the gene therapy leads to long-term increases in activity of the alpha-GalA enzyme. Fabry disease is caused by genetic mutations that impair the functionality of this enzyme, leading to a toxic accumulation of certain fatty molecules such as lyso-Gb3 in cells.

“I’m encouraged by these results, showing isaralgagene civaparvovec gene therapy has reassuring safety data to date, with no requirement for corticosteroid therapy,” Patrick Deegan, MD, from Cambridge University Hospitals NHS Foundation Trust, and a study investigator, said in a press release. “ST-920 has the potential to provide an alternative to enzyme replacement therapy for patients with Fabry disease. I look forward to seeing additional data as we continue to progress this important program.”

Scientists at Sangamo and other institutions shared the findings earlier this month at the NORD Summit in Washington, DC, and at the 29th Congress of the European Society of Gene & Cell Therapy, in Edinburgh, Scotland, in the poster “Preliminary results of STAAR, a Phase I/2 study of isaralgagene civaparvovec (ST-920) gene therapy in adults with Fabry disease and long-term follow-up.

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ST-920 Gene Therapy Continues to Show Safety, Efficacy in Trial

How does ST-920 work?

ST-920 uses a viral vector to deliver a healthy copy of the gene encoding the alpha-GalA enzyme to cells in the liver. These cells can “read” this gene to produce a functional enzyme that is secreted into the blood and pumped out to the rest of the body.

“The constant production of [alpha]-Gal A should lead to a reduction and potentially the clearance of Fabry disease substrates such, as globotriaosylsphingosine (lyso-Gb3), from target organs,” according to the researchers.

The STAAR clinical trial (NCT04046224), sponsored by Sangamo, is investigating multiple doses of ST-920 in adults with Fabry disease. The study is still recruiting participants at locations in the U.S., Canada, Australia, Italy, and the U.K.

The presentation included data from the first nine participants in STAAR, comprising four dose groups: 5 trillion vector genomes per kg of body weight (vg/kg), 10 trillion vg/kg, 30 trillion vg/kg, and 50 trillion vg/kg. All the dose groups included two patients except the 30 trillion vg/kg group, which had three patients.

All participants are being followed for one year (52 weeks) in the main STAAR study. The four participants in the two lower-dose groups have completed a year of follow-up and have entered into a long-term follow-up study (NCT05039866).

As of the most recent assessment (July 21, 2022), all nine participants have alpha-GalA activity that is higher than what would be expected in someone without Fabry disease. Enzyme activity “increased rapidly after dosing and remained elevated until the last sampling timepoint,” the researchers wrote.

Five of the nine patients had been on enzyme replacement therapy (ERT) at the start of the trial. So far, four of these patients — one each in the two lowest dose groups, and two in the 30 trillion vg/kg dose group — have discontinued ERT. Alpha-GalA activity remained high after ERT discontinuation in all four of these patients.

Levels of lyso-Gb3 remain above normal thresholds in all nine patients, and some individuals experienced a slight increase in lyso-Gb3 levels after stopping ERT, but in most patients, levels of lyso-Gb3 are not substantially elevated and none have resumed ERT.

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Two patients with very high (over 60 ng/ml) levels of lyso-Gb3 at the start of the study both experienced a marked drop (40%–55% reduction) in levels of this fatty molecule within the first few months after treatment with ST-920.

In terms of safety, ST-920 has been generally well-tolerated: all of the reported side effects of the medication were judged mild in severity, except for one case of treatment-related fever deemed moderate in severity.

Based on positive findings from STAAR, Sangamo is planning to conduct a Phase 3 clinical trial to further explore the safety and efficacy of ST-920.

“We continue to be excited by the promising data coming from our wholly owned Fabry program,” said Nathalie Dubois-Stringfellow, PhD, senior vice president and chief development officer at Sangamo. “The sustained levels of α [alpha]-Gal A activity after ERT withdrawal suggest that ST-920 has the potential to provide an alternative to the current standard of care. As we prepare for a potential Phase 3 trial, we look forward to sharing additional data from the nine dose escalation patients as well as our newly initiated expansion phase.”