Freeline Therapeutics 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. 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.

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 4.5x1011 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 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.