Sangamo starts FDA submission seeking approval of Fabry gene therapy
New trial data show gains in kidney, heart health with isaralgagene civaparvovec
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Sangamo Therapeutics has begun seeking accelerated approval from the U.S. Food and Drug Administration (FDA) for isaralgagene civaparvovec (formerly ST-920), its experimental gene therapy for Fabry disease.
Accelerated approval is a type of conditional approval in which the FDA allows a therapy to be sold based on early evidence that it is likely to benefit patients. It requires drug developers to conduct additional testing to demonstrate the treatment’s clinical benefit.
The company is submitting a biologics license application, or BLA, seeking accelerated approval of isaralgagene civaparvovec under a special FDA pathway, which the agency uses to speed the development and review of medicines that have the potential to address unmet needs in the care of serious diseases.
Under this pathway, Sangamo can submit the BLA as a rolling application — that is, it can submit each section of the application as it becomes ready, rather than having to finalize the entire application before submitting as is normally required. Sangamo announced in a company press release that it has started the application process.
“We are pleased to have initiated a rolling submission of a BLA to the FDA seeking approval of [isaralgagene civaparvovec],” said Nathalie Dubois-Stringfellow, PhD, chief development officer at Sangamo.
A genetic disorder, Fabry is caused by mutations in the GLA gene, which provides instructions to make an enzyme called alpha-galactosidase A (alpha-Gal A). Dysfunction of this enzyme leads to the buildup of certain fatty molecules to toxic levels in cells, causing damage to organs such as the kidneys and heart. Current treatments include enzyme replacement therapy (ERT), which works by administering a functional version of the alpha-Gal A enzyme into the body.
For its part, isaralgagene civaparvovec aims to deliver a healthy version of the GLA gene to liver cells, facilitating the production of a functional alpha-Gal A enzyme that can clear disease-driving fatty acid buildup.
Sangamo is hoping the FDA will authorize isaralgagene civaparvovec’s use based on data from the Phase 1/2 STAAR trial (NCT04046224), in which the one-time gene therapy was administered to 33 adults with Fabry disease. Among them, 18 had been on ERT prior to receiving the gene therapy, and 15 had not.
Data from STAAR trial support gene therapy approval request
New data from STAAR were shared in a series of presentations at the 22nd Annual WORLDSymposium, held this week in San Diego. Dubois-Stringfellow said the data “demonstrate how [isaralgagene civaparvovec] can alter the underlying [disease biology] of Fabry disease to provide meaningful clinical benefit across all types of adult Fabry disease patients.”
Kidney function in the STAAR trial was measured by tracking estimated glomerular filtration rate (eGFR), a standard test that basically measures how efficiently the kidneys filter blood. In people with Fabry, the rate of change in eGFR over time is usually negative, reflecting how the kidneys become less efficient as the disease progresses and organs sustain more damage. Available treatments like ERT can help slow this decline, but patients usually still have a negative eGFR rate, indicating worsening as time goes on.
Contrasting this typical picture, top-line data from the STAAR trial showed that, at one year after isaralgagene civaparvovec treatment, the average eGFR rate was positive. Those results suggest kidney health is actually improving over time in these patients. In 19 patients with available data, the average eGFR rate remained positive two years after gene therapy.
“These encouraging data demonstrate the potential for [isaralgagene civaparvovec] to improve kidney function, a notable departure from the historical renal decline characteristic of the disease,” said John A. Bernat, MD, PhD, an investigator on the STAAR study at University of Iowa Health Care.
Alongside a well-tolerated safety profile, the ability to withdraw from current enzyme replacement therapy and a range of other clinical benefits, [isaralgagene civaparvovec] shows the potential as a one-time, durable treatment option for Fabry disease.
Cardiac data suggest that measures of heart health were also stable over the two years following isaralgagene civaparvovec treatment. The gene therapy led to sustained increases in alpha-Gal A enzyme activity as intended, the data also showed.
“These data demonstrate the potential for the endogenous production of [alpha]-Gal A activity following [isaralgagene civaparvovec] administration to transform the Fabry treatment landscape,” said Robert J. Hopkin, MD, study investigator at Cincinnati Children’s Hospital Medical Center in Ohio.
According to Hopkin, “the stabilization in cardiac function, including stability of cardiac structure and cardiac biomarkers, is particularly encouraging, given that cardiovascular disease is the most common cause of death in Fabry disease patients.”
Isaralgagene civaparvovec has generally shown a favorable safety profile, according to the developer. Most adverse events, or side effects and other safety issues, were non-serious, the company noted. As of the latest follow-up, all patients who had been on ERT prior to gene therapy have discontinued enzyme replacement therapy.
“Alongside a well-tolerated safety profile, the ability to withdraw from current enzyme replacement therapy and a range of other clinical benefits, [isaralgagene civaparvovec] shows the potential as a one-time, durable treatment option for Fabry disease,” Bernat said.
