“These data in Fabry Disease and Gaucher Disease are very promising and underscore the confidence we have in our proprietary gene therapy platform, using our next-generation AAV technology,” said Chris Hollowood, Executive Chairman of Freeline. “This comes just a few days after the data Freeline announced at the European Association for Haemophilia and Allied Disorders (EAHAD) conference in the Phase 1/2 trial of its Haemophilia B programme, FLT180a. That trial has shown the potential for the Freeline platform to deliver sustained high protein levels and provides encouragement that higher αGLA levels could be achievable in Fabry Disease as we dose escalate.”
Freeline’s programme, FLT190, is an investigational liver-directed adeno-associated viral (AAV) gene therapy for the treatment of Fabry Disease. The programme is the first clinical-stage AAV gene therapy study globally in Fabry Disease. FLT190 is an in-vivo gene therapy administered by a one-time short intravenous infusion. Preliminary data were presented today on the starting dose in a dose escalation study. The infusion was well tolerated. A 3 to 4-fold increase in plasma αGLA activity was achieved by week 4 (0.3 → 1 ± 0.2 nmol/hr/ml) and sustained through the data cutoff at week 20.
The study, named MARVEL1, is a multi-centre, international, dose-escalating Phase 1/2 study in adult males with classic Fabry Disease. The study is focused on assessing the safety of FLT190, and its ability to transduce liver cells to produce continuous high levels of αGLA. In addition to safety, endpoints in the study include clearance of Gb3 and LysoGb3 from the plasma and urine, baseline renal and skin biopsies (repeated in long term follow up), renal and cardiac function, αGLA immune response, viral shedding and quality of life.
Prof. Derralynn Hughes, Royal Free Hospital, London, UK
“We are pleased to be sharing early clinical information that shows for the first time that AAV gene therapy can deliver sustained levels of αGLA from a single infusion. The dose escalation will allow us to explore the levels required to bring a meaningful therapeutic benefit to patients suffering from the disease. I am hopeful that this trial will translate into the potential for better outcomes for the Fabry community.”
As of the data cutoff date, there have been no infusion-related adverse events. Two Grade 1 or 2 serious adverse events have been reported in the study. The patient had, similar to those observed in other programs using AAV-based gene therapy, clinically asymptomatic elevations in ALT levels and levels returned to normal range within 3 weeks following immune suppression. A grade 2 myocarditis of unknown aetiology was observed but repeat MRI scans showed no evidence of changes compared to base line and it resolved without specific intervention.
Freeline’s Gaucher Disease program, FLT200, is a liver-directed AAV gene therapy for the treatment of Gaucher Disease type 1 and is designed to increase levels of beta-glucocerebrosidase (GCase). It is expected that the normal glucocerebrosidase (GBA) gene delivered to the liver by FLT200 will be able to produce a fully functioning GCase enzyme and prevent the accumulation of fat molecules, specifically the substrate glucosylceramide, to toxic levels inside the cells affected by the disease. The pre-clinical data suggested that, after a single injection of Freeline’s AAV-based GBA construct, long term sustained steady state levels of fully active GCase can be achieved in the bloodstream. In addition, GCase uptake by macrophages in key organs was observed, as well as significant substrate clearance in GBA deficient animal models. There was also a greater bioavailability than bi-weekly infusions of velaglucerase alfa; a medication indicated for long-term Enzyme Replacement Therapy (ERT) for patients with Gaucher Disease type 1. These pre-clinical data suggest that AAV liver-directed gene therapy has therapeutic potential for Gaucher Disease providing sustained levels of GCase in the bloodstream at all times and with greater bioavailability than existing ERT.
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Freeline is a privately-held clinical-stage biotechnology company focused on AAV based gene therapy targeting the liver. Our vision is to create better lives for people suffering from chronic systemic diseases using the potential of gene therapy as a one-time curative treatment. Freeline is headquartered in the UK and has operations in Germany and the US.
About Fabry Disease
Fabry Disease is an inherited, X-linked disease characterised by the progressive accumulation of glycosphingolipids in lysosomes throughout the body. It is caused by mutations in the gene encoding of the α-galactosidase A enzyme (αGLA) responsible for the breakdown of globotriaosylceramide (Gb3), a type of glycosphingolipid.
The condition ranges from mild to severe and may appear anytime from childhood to adulthood. The progressive accumulation of Gb3 leads to organ damage, major disability and often early mortality. Symptoms and signs include neuropathic pain, impaired sweating, gastrointestinal symptoms, renal failure, heart disease and increased risk of stroke. Current treatment consists of ERT and chaperone therapy to temporarily clear Gb3 accumulation and alleviate symptoms.
The MARVEL1 study is the first clinical-stage adeno-associated virus (AAV) gene therapy study globally for Fabry Disease. The programme leverages Freeline’s proprietary gene therapy platform, including its novel capsid, which has already shown clinical benefit for Haemophilia B patients.
MARVEL1 is a multi-centre, international, dose-escalating Phase 1/2 study in adult males with classic Fabry Disease. The study is focused on assessing the safety of FLT190, and its ability to lead to continuous high levels of αGLA production. In addition to safety, endpoints in the study include clearance of Gb3 and LysoGb3 from the plasma, changes in renal and skin biopsies, renal and cardiac function, αGLA immune response, viral shedding and quality of life.
About Gaucher Disease
Gaucher Disease is a genetic disorder in which a fatty substance called glucosylceramide accumulates in macrophages in certain organs due to the lack of functional GCase. The disorder is hereditary and presents in various subtypes. Freeline is currently focused on Type 1 Gaucher Disease, the most common type, which impacts the health of the spleen, liver, blood system and bones. The current standard of care is intravenous infusion of ERT every two weeks, which is a significant treatment burden on the patient. The aim of Freeline’s investigational gene therapy programme is to deliver a one-time treatment of a long-lasting gene therapy that will provide a consistent and therapeutically relevant level of constant endogenous GCase, thus eliminating the need for ERT.
About gene therapy
Gene therapy may be classified depending on whether the therapy is administered to cells inside the body or out of the body. In vivo gene therapy means that therapy is administered directly to the patient to the targeted cells in the body of the patient. In contrast, with ex vivo gene therapy, the targeted cells are removed from the patient and gene therapy is administered to the cells in vitro before they are returned to the patient’s body as a treatment.
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