LONDON, England — Freeline Therapeutics today announced new clinical data from its ongoing Phase 1/2 GALILEO-1 trial of FLT201, its adeno-associated virus (AAV) gene therapy candidate for Gaucher disease, showing substantial reductions in glucosylsphinogsine (lyso-Gb1), one of the best predictors of clinical response, in patients with persistently high levels despite years of treatment with currently approved therapies, as well as early signs of clinical improvements in bone marrow burden and fatigue. FLT201 continues to demonstrate a favorable safety and tolerability profile. These data are being showcased in a late-breaking oral presentation at the American Society of Gene and Cell Therapy (ASGCT) 27th Annual Meeting taking place in Baltimore, Maryland.
Gaucher disease is caused by a mutation in the GBA1 gene, which leads to a deficiency of the glucocerebrosidase (GCase) enzyme. As a result, substrates build up in cells and organs throughout the body, causing symptoms including enlarged spleen and liver, low blood counts, bone pain, fatigue and reduced lung function. FLT201 delivers a rationally engineered version of the GCase enzyme (GCase85) with greater stability than wildtype GCase, designed to stay in cells longer to more effectively clear substrates and penetrate difficult-to-reach tissues, including bone, that currently approved therapies poorly address. Reductions in lyso-Gb1 levels in the blood are highly correlated with substrate reduction in disease-affected tissues and positive clinical outcomes in Gaucher disease.
“Gaucher disease, the most common lysosomal storage disorder, is severe and progressive when not treated. Currently approved treatments have made a significant difference for people with Gaucher disease, but there is not an existing cure. Patients require life-long treatment and many continue to experience symptoms, including enlarged organs, chronic bone pain and fatigue,” said Ozlem Goker-Alpan, M.D., founder and CEO of the Lysosomal and Rare Disorder Research and Treatment Center (LDRTC) and an investigator in the Phase 1/2 GALILEO-1 trial of FLT201. “A gene therapy that could deliver the same or better efficacy than currently available treatments, while freeing people from an ongoing treatment burden, would mark a significant advance in the treatment paradigm for Gaucher disease. I am very encouraged by the clinical data to date for FLT201.”
Positive New Clinical Data for FLT201
Today’s presentation will include updated data on safety, tolerability, GCase activity and lyso-GB1, hemoglobin and platelet levels, as well as new data on bone marrow burden and fatigue from GALILEO-1, a first-in-human, international, multicenter dose-finding study in adults with Gaucher disease Type 1. The data being reported are from the four patients in the trial who have come off their prior therapies as of the February 19, 2024 data cutoff. These four patients have remained off their prior therapies and range in follow up from 14 to 32 weeks after dosing. All patients were treated with a single dose of 4.5×1011 vg/kg.
The data demonstrated:
- Favorable safety and tolerability, with no infusion reactions and no serious adverse events. Modest alanine-transaminase (ALT) elevations in some patients were managed with immune therapy, with no impact to efficacy. Non-serious adverse events were all mild or moderate in severity.
- Robust and continuous expression in plasma GCase, with clear evidence of cellular uptake of GCase from the plasma as measured by GCase activity in the leukocytes. Leukocytes are established indicators for broad cellular uptake in Gaucher disease.
- Substantial reductions in lyso-Gb1 in patients who entered the trial with persistently high lyso-Gb1 levels despite years on prior treatment with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Low lyso-Gb1 levels were maintained in one patient who entered the trial with well-controlled levels.
- Maintenance of hemoglobin levels, an established endpoint for Gaucher disease clinical trials, was observed post withdrawal of treatment with ERT or SRT. Improvement or maintenance of platelet counts was also seen post withdrawal of treatment with ERT or SRT.
Emerging late-breaking data as of April 8, 2024, also demonstrated:
- Reductions in bone marrow burden in the first four patients as of 12 to 38 weeks post-dosing, indicating clearance of substrate from the bone marrow and reappearance of healthy, fatty marrow.
- Clinically meaningful improvement in fatigue in the first patient dosed, which led to increased functioning and ability to perform daily activities. The patient demonstrated a 21-point improvement on the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale, with a 2.8 to 6.8-point improvement being considered clinically meaningful in chronic illnesses. As of the data cut, this patient was the only patient with sufficient follow-up data for a meaningful FACIT assessment.
Freeline today also announced that FLT201 has been granted Regenerative Medicine Advanced Therapy (RMAT) designation by the US Food and Drug Administration and Priority Medicines (PRIME) Designation by the European Medicines Agency (EMA). Both RMAT and PRIME designations are designed to expedite the drug development and review process for investigational therapies intended to treat, modify, reverse or cure a serious or life-threatening disease. The investigational therapy must be supported by preliminary clinical evidence that the therapy has the potential to address unmet medical needs for the disease. RMAT and PRIME provide the benefits of intensive guidance from the FDA and EMA, respectively, on efficient drug development, including the ability for early interactions to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, and potential priority review of the biologics license application.
“FLT201 is a potentially first- and best-in-class gene therapy for Gaucher disease,” said Pamela Foulds, M.D., Freeline’s Chief Medical Officer. “It is designed to deliver a continuous supply of the enzyme missing in people with Gaucher disease and to deliver a more stable version of that enzyme, with the aim of getting enzyme into all disease-affected tissues and increasing the amount of time the enzyme is in those tissues to do its job of clearing harmful substrates. The clinical data to date strengthen our conviction in the life-changing potential of FLT201. They also support our strategy of extending the therapeutic potential of our GCase85 enzyme into a genetically linked subset of Parkinson’s disease patients with GBA1 mutations, and we are excited to share promising new data from that program.”
Highlights from GBA1 Parkinson’s Disease Research Program
In a separate poster presentation at ASGCT, Freeline is presenting in vitro and in vivo data from its Parkinson’s disease research program. The program builds on its work with Gaucher disease, leveraging the enhanced stability of GCase85 to develop a gene therapy candidate for a subset of Parkinson’s disease patients with mutations in the GBA1 gene. As in Gaucher disease, the GBA1 mutations lead to a deficiency of GCase and the accumulation of harmful substrates, greatly increasing the risk of developing Parkinson’s disease. GBA1 mutations are also associated with earlier onset of disease, more severe symptoms and increased likelihood of progression to dementia.
The findings demonstrate that:
- GCase85 results in an order of magnitude higher GCase activity compared to wildtype in both in vitro and in vivo studies.
- Direct injection into the caudate putamen region of the brain using an AAV9 vector is effectively distributed to the target cells of the substantia nigra, which is a key area of the brain affected by Parkinson’s disease.
- An AAV9-GBA1-85 construct results in stronger expression and broader GCase distribution in the brain than a wildtype AAV9-GBA1 construct when directly injected into the brain in mice.
Both the late-breaking oral presentation and the poster presentation are now available on the News & Events section of Freeline’s website.
About FLT201
FLT201 is an adeno-associated virus (AAV) gene therapy candidate that is currently being investigated in the Phase 1/2 GALILEO-1 clinical trial in adults with Gaucher disease Type 1. FLT201 is designed to generate durable increases in glucocerebrosidase (GCase) and reduce the accumulation of harmful substrates, with the aim of providing a one-time treatment that can stop disease progression, improve outcomes, and free people from lifelong treatment. FLT201 uses Freeline’s proprietary AAVS3 capsid to introduce a novel transgene into liver cells to produce a rationally engineered GCase variant. In preclinical studies, the GCase variant has demonstrated a greater than 20-fold increase in half-life at lysosomal pH conditions compared to wildtype human GCase. Preclinically, FLT201 has shown robust GCase expression, leading to significant GCase uptake and substrate reduction in key tissues. For more information about the GALILEO-1 trial, please visit clinicaltrials.gov (NCT05324943).
About Gaucher Disease
Gaucher disease 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. As a result, harmful substrates glucosylceramide (Gb-1) and glucosylsphingosine (lyso-Gb1) build up in cells that then accumulate in various organs, causing inflammation and dysfunction. Gaucher disease is hereditary and presents in various subtypes. Freeline is currently focused on Gaucher disease Type 1, the most common form of the disease, which affects the health of the spleen, liver, bone and lung. Despite treatment with existing therapies, many people with Gaucher disease continue to experience symptoms and disease progression. Gaucher disease affects approximately 18,000 people in the United States, United Kingdom, France, Germany, Spain, Italy and Israel.
About GBA1-linked Parkinson’s Disease
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that results in tremors, muscle rigidity, difficulty walking, anxiety, depression and cognitive impairments. Approximately 5-15% of PD patients have mutations in the GBA1 gene, which encodes for the glucocerebrosidase (GCase) enzyme. The most common genetic risk factor for PD, GBA1 mutations increase the risk of developing PD by 5- to 30-fold. GBA1 mutations are also associated with earlier onset and more severe disease. There are no approved disease-modifying therapies for PD, and current treatments, which focus on managing symptoms, become less effective over time. Freeline estimates GBA1-linked PD affects approximately 190,000 patients in the United States, United Kingdom, France, Germany, Spain and Italy.
About Freeline Therapeutics
Freeline is a clinical-stage biotechnology company focused on developing transformative gene therapies for chronic debilitating diseases. Freeline is currently advancing FLT201, a highly differentiated gene therapy candidate that delivers a novel transgene, in a Phase 1/2 clinical trial in people with Gaucher disease type 1. Freeline has additional programs in research, including one focused on GBA1-linked Parkinson’s disease that leverages the same novel transgene as FLT201. Freeline is headquartered in the UK and has operations in the United States.
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