NEW YORK – Sangamo Therapeutics is planning a Phase III clinical trial of its investigational Fabry disease gene therapy, isaralgagene civaparvovec, and may propose a study protocol to the US Food and Drug Administration by year-end.
Patients with Fabry disease have a buildup of globotriaosylceramide (Gb3) in their cells, which damages numerous organs. The rare, inherited genetic disorder is caused by mutations in the GLA gene that lead to a deficiency in alpha-galactosidase A (alpha-Gal A) enzymes, without which patients are unable to metabolize Gb3. Fabry disease patients experience pain, hearing loss, skin issues, organ problems, and sometimes even progressive kidney and heart failure.
There's currently no cure for Fabry disease, although there are therapies that try to address its symptoms. Standard care typically involves enzyme replacement therapy (ERT), such as Sanofi's Fabrazyme (agalsidase beta), Takeda Pharmaceuticals' Replagal (agalsidase alfa), or Chiesi Global Rare Diseases/Protalix BioTherapeutics' Elfabrio (pegunigalsidase alfa), which supply patients with needed levels of alpha-Gal A. But ERTs require hourslong IV infusions every two weeks, said Sangamo Chief Development Officer Nathalie Dubois-Stringfellow. Combined with travel time to and from a healthcare facility, patients can end up spending an entire day every other week getting this treatment.
With isaralgagene civaparvovec, Brisbane, California-based Sangamo aims to increase production of alpha-Gal A for Fabry disease patients by delivering a functional copy of the GLA gene to the liver, which, hopefully, can then begin producing functional alpha-Gal A that's released into the bloodstream after just one infusion. The gene therapy is delivered via an IV infusion with a recombinant adeno-associated virus serotype 2/6 vector (rAAV 2/6).
Sangamo is currently testing the safety and tolerability of ascending doses of this gene therapy in a first-in-human, open-label, global Phase I/II trial, dubbed STAAR, in which it aims to enroll about 50 adult Fabry disease patients and follow them for one year. Investigators plan to expand enrollment based on patients' specific renal and cardiac symptoms and levels of anti-alpha-Gal A antibodies. There's also a long-term follow-up portion, in which Sangamo will track patients' outcomes on the gene therapy for four years.
Anjay Rastogi, a nephrologist and director of UCLA Health's Fabry's Disease Program, said that while ERT has been an effective therapy for Fabry disease for more than two decades, it can be burdensome for patients and their families. And the other standard treatment, Amicus Therapeutics' Galafold (migalastat), an oral medication designed to repair alpha-Gal A, is only available to patients with certain GLA mutations.
"These are not cures," Rastogi said. "The ultimate goal would be if we can replace the defective gene." While Rastogi is not involved in Sangamo's ongoing Phase I/II STAAR study of its gene therapy, he is considering making UCLA a trial site for the Phase III trial the company is planning to do next.
The STAAR study is open to patients who are on ERT as well as those who aren't. However, they cannot take Galafold or a similar drug during the study.
So far, investigators on the STAAR study have observed increases in alpha-Gal A activity in participants within eight weeks of treatment. An early readout at a lysosomal disease research conference in February from the first 13 participants in this trial suggests patients are maintaining enzyme activity. Investigators also observed clearance or stabilization of renal Gb3 inclusions and reductions in urine podocyte loss in some patients.
In the initial dose-escalating portion of the study, all ERT-treated participants successfully ceased ERT, and none had to resume the therapy.
Roger Hajjar, director of Mass General Brigham's Gene and Cell Therapy Institute, who is also not involved in the STAAR trial, found this early data on Sangamo's gene therapy impressive. However, he would like to see more data on the durability of patients' outcomes on the treatment and how disease-affected organs fare, such as the kidney, heart, and liver.
While Sangamo intends for its gene therapy to be a one-time infusion, Dubois-Stringfellow acknowledged that there's more to learn about how long the effects of the gene therapy last and whether re-dosing will be needed after a few years. "This is not unique to Fabry," she said. "It is an early field," she said of gene therapy.
Isaralgagene civaparvovec has been well tolerated in the Phase I/II trial, according to investigators, with patients commonly experiencing fever, headache, chills, and increased pain. The FDA and the European Medicines Agency have deemed the treatment an orphan drug. Isaralgagene civaparvovec also has fast-track designation from the FDA, which could allow Sangamo the chance to seek accelerated approval or priority review for a biologics license application.
The basis for such an application will be the Phase III trial that Sangamo is now preparing for. The company is also considering partnerships to support commercialization of the gene therapy should the late-stage study be successful, Dubois-Stringfellow said. Sangamo has struck commercialization partnerships for other products, including a collaboration and license agreement with Pfizer to develop and commercialize a hemophilia A gene therapy in an ongoing Phase III trial.
"We're very optimistic," she said. "We have the potential to be first and best-in-class" in Fabry disease.
It's still early in the development cycle for this gene therapy, but Rastogi said that publicly shared results on isaralgagene civaparvovec have been promising so far, particularly the substantial enzyme activity, reductions in Gb3, and the more than two years of data collected on the longest treated participant. But "the proof is in the pudding," he added. "We'll be watching very carefully to see how patients do."
Rastogi said he would also like to see data on morbidity and mortality, including whether the gene therapy decreases rates of organ failure and the need for organ transplants, in addition to biomarker results. Those "are long-term endpoints," Rastogi said. "Only time will show that."