Gene Therapy FLT201 Shows Promise in Early-Stage Study of Gaucher Disease

Pamela Foulds, MD, chief medical officer at Spur

Newly reported data from the phase 1/2 GALILEO-1 trial (NCT05324943) showed that treatment with FLT201 (Spur Therapeutics), an adeno-associated virus (AAV) gene therapy candidate, resulted in durable reductions in glucosylsphinosine (lyso-Gb1) and improvements or maintenance in blood counts and organ volume among patients with Gaucher disease. Spur plans to release more data from the Phase 1/2 GALILEO-1 trial in the first half of 2025 and begin a Phase 3 trial for FLT201 in adults with Gaucher disease type 1 later that year.¹

Gaucher disease, a rare genetic disorder, is caused by a mutation in the GBA1 gene that results in abnormally low levels of glucocerebrosidase (GCase), an enzyme needed to metabolize a certain type of lipid. Presented at the European Society of Gene and Cell Therapy (ESGCT) 31st Annual Congress, the study featured 6 patients who had been treated with a single infusion of FLT201 at a dose of 4.5e11 vg/kg. All patients comprised the safety analysis, while 1 patient was excluded from the efficacy analysis due to detectable pre-existing neutralizing antibodies to the AAVS3 capsid below the protocol cut-off.

In the multicenter study, treatment with the gene therapy led to durable reductions, ranging from 42% to 96%, in lyso-Gb1 levels, considered one of the best predictors of clinical response in Gaucher disease. Notably, these patients had come into the trial with persistently high levels of lyso-Gb1 despite years of treatment with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Above all, FLT201 was considered safety and tolerable, with no infusion reactions or dose limiting toxicities, and treatment-related adverse events that were mild to moderate in severity.

"Gaucher disease is a debilitating chronic disorder, and despite treatment with currently approved therapies, many patients continue to have serious symptoms," Pamela Foulds, MD, chief medical officer at Spur, said in a statement.¹ "Consistent with what is seen in real-world practice, patients entered our trial with different unmet needs."

She added, "All of them had bone disease, which current therapies poorly address. Most had high levels of harmful substrate accumulation. Some also had an enlarged spleen, low platelets, pain or fatigue. What is exciting is that after a single infusion of FLT201, patients improved in areas their disease was poorly controlled and remained well-controlled in areas their disease was controlled. These data underscore FLT201’s potential to set a new standard of care for Gaucher disease type 1."

Gaucher disease has been known to cause several neurological complications, including developmental delays, cognitive problems, eye issues, poor coordination, seizures, muscle spasms, and quick, jerky movements. In addition, some patients with type 1 of the disease may experience behavioral disorder, microcephaly, and increased deep tendon reflexes. The severity and onset of neurological symptoms can vary depending on the type of Gaucher disease.

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In the analysis, low lyso-Gb1 levels were maintained for more than a year as of the cut-off date after the withdrawal of prior therapy in the 1 patient who entered the trial with well-controlled levels. In addition, all 5 patients in the efficacy analysis, including those with severe bone involvement, showed substantial improvements in bone marrow burden through treatment. Furthermore, treated patients demonstrated an improvement or maintenance of spleen and liver volume.

FLT201 leverages Spur’s proprietary and potent AAVS3 capsid to deliver GCase85, a rationally engineered longer-acting version of the enzyme deficient in patients with Gaucher disease. In the trial, patients treated with the gene therapy maintained hemoglobin levels beyond a year post withdrawal of treatment with ERT or SRT. Notably, the improvement or maintenance of platelet counts was also observed post withdrawal or treatment with ERT or SRT.

"FLT201 exemplifies our focus on developing the next generation of gene therapies, optimizing each component of our gene therapy candidates with the aim of changing the course of disease and changing people’s lives," Michael Parini, chief executive officer at Spur, said in a statement.¹ "Our more stable GCase85 enzyme, combined with our potent and proprietary capsid, is leading to improvements in bone, pain and fatigue, all of which are key areas of ongoing need in Gaucher disease. These data highlight FLT201’s potential to provide better outcomes than current standard of care while dramatically reducing the treatment burden for patients, and we are actively engaging with regulators to advance FLT201 into a Phase 3 trial."

Currently, the standard-of-care treatments for patients with Gaucher disease type 1 comprise ERT and SRT. ERT consists of delivering exogenous, functional GCase enzyme to patients at regular intervals by intravenous infusion. Currently available GCase ERT formulations include the following: imiglucerase (Cerezyme; Sanofi/Genzyme), which is derived from Chinese-hamster-ovary cells; velaglucerase alfa (VPRIV™, Shire), which is derived from human fibroblasts; and taliglucerase alfa (Elelyso™, Protalix/Pfizer), which is derived from carrot plant root cells.²

REFERENCE
1. Spur Therapeutics Showcases Positive New Data from Phase 1/2 GALILEO-1 Trial of FLT201, Its Novel Gene Therapy Candidate for Gaucher Disease, in Oral Presentation at ESGCT 31st Annual Congress. News release. Spur Therapeutics. October 23, 2024. Accessed October 23, 2024. https://spurtherapeutics.com/static/Spur-Therapeutics-ESGCT-Data-Release-10-23-24.pdf
2. Hughes DA, Ferrante F. GALILEO-1: a phase 1/2 safety and efficacy study of FLT201 gene therapy for Gaucher disease type 1. Future Rare Diseases. 2023;3:1. doi:10.2217/frd-2022-0019