Trial in progress: Galileo-3, a Phase 3 safety and efficacy trial of FLT201 gene therapy in patients with gaucher disease type 1

Abstract Background and Significance Gaucher disease (GD) is a rare genetic lysosomal storage disorder caused by variants in the GBA1 gene, resulting in deficient glucocerebrosidase (GCase) and impaired breakdown of glycosphingolipids. Gaucher disease Type 1 (GD1), the most common form, is characterized by hepatosplenomegaly, bone disease, anemia, thrombocytopenia, fatigue, pain, and pulmonary pathology. Current options for therapy include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). ERT requires intravenous (IV) infusions every 2 weeks for life, however due to its short half-life GCase levels become undetectable in target cells within 1–2 days leading to substrate reaccumulation. SRT is an alternative oral option for some patients that inhibits glucosylceramide synthesis but requires chronic daily dosing. FLT201 is a clinical-stage, liver-directed gene therapy candidate designed to overcome the limitations of ERT with a single infusion. It leverages a rationally designed liver-selective adeno-associated virus capsid (AAVS3) to deliver a transgene encoding GCase85, a novel, engineered GCase variant with enhanced stability. This approach enables continuous systemic and intracellular expression of GCase85, providing sustained enzyme exposure beyond what is achievable with ERT. In the first-in-human GALILEO-1 trial (NCT05324943) and its long-term extension study GALILEO-2 (NCT06545136), FLT201 provided durable long-term GCase85 expression out to at least two years, enabling continuous intracellular enzyme activity and sustained glucosylsphingosine (lyso-Gb1) clearance following a single low dose (4.5 x 1011vg/kg) IV administration in all participants who discontinued ERT/SRT. These subjects continue to remain off their background therapy. No treatment-related serious adverse events occurred and only mild (<2xULN) transient elevations in alanine aminotransferase considered related to therapy were observed in the 6 participants treated with FLT201. Study Design and Methods GALILEO-3 (EU CT 2025-520765-50) is an open label, non-randomized, global, multicenter, phase 3 study designed to evaluate the safety and efficacy of FLT201. The study will enroll approximately 45 adults with GD1 who have been on stable ERT/SRT treatment for at least 2 years. Participants will receive a single IV infusion of FLT201 at a dose of 4.5 x 1011 vg/kg, discontinue ERT/SRT treatment after week 4, and will be followed for a period of 5 years. A primary analysis will occur at Week 52 with the option for an interim analysis to occur at Week 24 and a final analysis at the end of study. The primary endpoint for the study is the proportion of participants with stable hemoglobin concentration (decrease from baseline of no more than 1.5 g/dL) at Week 52. Key secondary efficacy endpoints include change from baseline in lyso-Gb1 levels and the proportion of participants with stable platelet count, spleen volume, and liver volume at Week 52. Further efficacy endpoints will evaluate bone health, and various patient reported outcome measures (PROMs) to assess quality of life, Gaucher disease severity (DS3), and fatigue. Secondary safety endpoints will include the incidence of treatment emergent adverse events and serious adverse events, change from baseline in vital signs and laboratory assessments, and incidence of clinically significant abnormalities upon physical examination and 12-lead ECG assessments. Key inclusion criteria include having a clinical diagnosis of GD1, being age 18 or older prior to screening, having stable hemoglobin concentration and platelet count at baseline, and receiving ERT or SRT without interruption for at least 2 years. Key exclusion criteria include being diagnosed or suspected to have Gaucher disease type 2 or 3, positivity for AAVS3 neutralizing antibodies, having abnormal lab values or conditions that would make the subject unsuitable for the study, having a positive pregnancy test or lactating, a history of hematopoietic stem cell transplantation or solid organ transplant, history of receiving a previous gene or cell therapy, and history of total splenectomy. Conclusions GALILEO-3 is a pivotal phase 3 switch study that is designed to evaluate the safety and efficacy of FLT201 in adult GD1 participants on stable ERT/SRT therapy. This study is intended to support the registration of FLT201 in the adult GD1 population.