ST-920 gene therapy lowers Fabry disease severity in trial

Interim data show stabilized kidney function, improved quality of life

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The investigational gene therapy ST-920 (isaralgagene civaparvovec) has been well tolerated so far among adults with Fabry disease in the Phase 1/2 STAAR clinical trial, according to new interim data from its developer Sangamo Therapeutics.

One-year data from more than a dozen patients indicate ST-920 stabilized kidney function, reduced disease severity, and improved quality of life. The findings were shared as an oral and poster presentation at the 20th Annual WORLDSymposium in San Diego.

“We remain encouraged by the emerging safety and efficacy data supporting the potential durable benefit that ST-920 could offer patients with Fabry disease as a convenient single-dose treatment option,” Lisa Rojkjaer, MD, chief medical officer of Sangamo, said in a company press release.

Dosing in STAAR is expected to finish soon and Sangamo is gearing up for a Phase 3 trial that could serve to aid ST-920’s approval.

“We expect to complete dosing of the remaining patients in the first half of this year as we continue to explore potential partnerships and other financing options to support the initiation of a registrational trial,” Rojkjaer said.

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 A functional alpha-GalA enzyme

Fabry disease is caused by mutations in the gene that encodes the alpha-GalA enzyme, leading to its reduced activity. Alpha-GalA is normally needed to break down fatty molecules like lyso-Gb3. Without a working version, these fatty molecules build up to toxic levels and cause organ damage.

ST-920 is a one-time gene therapy designed to deliver a healthy version of the gene encoding alpha-GalA to liver cells, allowing the body to produce a functional version of the enzyme to clear toxic fatty buildups.

Sangamo is sponsoring a clinical trial called STAAR (NCT04046224) to evaluate the therapy in Fabry patients. The study’s first part tested several different doses in nine patients and then the highest tested dose was given to all the participants based on the results. As of data cutoff in September, 24 patients have been dosed.

Safety data so far suggest ST-920 is generally well tolerated. The most common side effects and other safety-related issues were fever, headache, COVID-19, fatigue, and the common cold. All were mild or moderate, except one case of severe fever and another of severe muscle pain.

Other gene therapies targeting the liver are known to trigger liver inflammation, which in some cases has required steroid treatment to prevent serious liver damage. None of the patients given ST-920 have shown signs of liver damage that required steroids, however.

Among all the patients dosed so far, data have consistently shown an increase in alpha-GalA enzyme levels, which have been sustained up to three years in the longest followed patient. Most patients given the highest dose have shown supraphysiological activity, meaning alpha-GalA activity is higher than it is in people who don’t have Fabry disease.

Consistent with the increase in alpha-GalA levels, levels of lyso-Gb3 have decreased with gene therapy.

Potential of ST-920

At the time gene therapy was given, 13 of the study participants were on enzyme replacement therapy (ERT).

As of the latest follow-up, 12 of them have stopped ERT and none have had to restart it. Alpha-GalA levels have stayed in the supraphysiological range for all but one of the 12, whose enzyme levels are normal.

“To date, ST-920 has been well tolerated and the preliminary data showing sustained supraphysiologic [alpha]-Gal A activity and the ability to discontinue and remain off ERT are promising,” said Robert Hopkin, MD, investigator of the STAAR study at Cincinnati Children’s Hospital Medical Center.

At the start of STAAR, seven participants had antibodies against alpha-GalA associated with past ERT use. Such antibodies are associated with reduced ERT efficacy. After gene therapy, antibody levels decreased in all seven and five of them no longer have detectable levels of antibodies against alpha-GalA.

One-year data were presented for 13 patients who have been followed for at least 12 months. Results showed stable kidney function with the average rate of decline in estimated glomerular filtration rate (eGFR), a standard measure of kidney function, being only 0.915, as measured in mL/min/1.73 meters squared/year.

Scores on the Fabry Outcome Survey adaptation of the Mainz Severity Score Index (FOS-MSSI), a measure of disease severity, decreased by nearly 4 points on average a year after ST-920, suggesting it reduced disease severity.

Four patients had such dramatic changes in MSSI that their overall category of disease classification changed. One patient who’d had severe disease was reclassified as moderate, while three who’d had moderate disease were changed to mild.

Scores on the Short Form-36 (SF-36), a general measure of quality of life, improved by more than 10 points on average a year after ST-920. Scores on the subsection of the SF-36 that assesses physical health improved by more than 4 points on average, an improvement of about 3 to 5 points being considered clinically meaningful. Patients also reported a small but statistically significant decrease in average scores on the gastrointestinal symptom rating scale (GSRS) a year after gene therapy.

“The early improvements reported in disease severity, quality of life, and gastrointestinal symptoms, together with evidence of reduced immunogenicity, illustrate the potential of ST-920 as a treatment option for adults with Fabry disease,” Hopkin said.