Robust increases of up to 700-fold over baseline in plasma GCase enzyme activity in first two patients treated with FLT201

Normalization of leukocyte GCase in both patients demonstrates cellular uptake from plasma

FLT201 has been well tolerated, with no serious adverse events

LONDON, UK I October 04, 2023 IFreeline Therapeutics Holdings plc (Nasdaq: FRLN) today reported positive initial safety, tolerability and enzyme activity data from the ongoing Phase 1/2 GALILEO-1 trial evaluating FLT201, its adeno-associated virus (AAV) gene therapy candidate, in Gaucher disease. Gaucher disease is a debilitating genetic disorder in which a deficiency of the GCase enzyme leads to a buildup of harmful substrates, causing symptoms including enlarged spleen and liver, low blood counts, bone pain and reduced lung function. In addition to demonstrating a favorable safety and tolerability profile, data from the first two patients in GALILEO-1 show that a single infusion of FLT201 led to several hundred-fold increases in GCase activity in plasma and normalization of GCase activity in leukocytes.

“These initial clinical data are very compelling,” said Pilar Giraldo, M.D., Ph.D., hematologist at the Spanish Foundation for the Study and Therapy of Gaucher Disease, Quirónsalud Hospital – Zaragoza, and an investigator in the GALILEO-1 trial. “While existing therapies have had a significant impact on the disease, many patients continue to experience symptoms and current therapies come with a heavy lifelong treatment burden. People with Gaucher disease deserve better treatment options. FLT201 represents a promising new approach as a one-time investigational gene therapy, and based on the emerging clinical data, I am excited about its potential.”

“FLT201 is a highly differentiated gene therapy candidate for Gaucher disease with the opportunity to provide better outcomes for patients, while dramatically reducing the burden that comes with existing therapies,” said Pamela Foulds, M.D., Freeline’s Chief Medical Officer. “The magnitude of the increases in plasma GCase activity in the first two patients treated with FLT201, together with the normalization of GCase activity in cells, further strengthen our belief in its therapeutic potential. Given the strong response and clean safety and tolerability to date, we have decided to treat a third patient at this dose rather than a higher dose as initially planned.”

“Our goal at Freeline is to unlock the true potential of gene therapy by optimizing every component of our product candidates,” said Michael Parini, Freeline’s Chief Executive Officer. “FLT201 exemplifies that approach. It leverages our proprietary capsid designed to deliver high expression at low doses and our novel GCase variant engineered to overcome the short half-life of wildtype GCase. Our preclinical data for FLT201 show robust increases in plasma GCase, which is then taken up by disease-affected tissues, clearing harmful substrate more effectively than the existing standard-of-care. These clinical data show the preclinical data are starting to translate, and we are committed to expeditiously advancing FLT201.”

Positive Initial Clinical Data for FLT201
The data reported today include assessments of safety, tolerability and GCase activity from the first two patients in GALILEO-1, which is a first-in-human, international, multicenter Phase 1/2 dose-finding study in people with Gaucher disease Type 1. Both patients were treated with a dose of 4.5×1011 vg/kg and have successfully come off their prior therapies.

As of the September 27 data cutoff, the data demonstrated:

  • Favorable safety and tolerability, with no infusion reactions and no serious adverse events as of 13 weeks post-dosing for patient 1 and six weeks post-dosing for patient 2. All treatment-related adverse events were Grade 1 and resolved without intervention.
  • No elevations in liver transaminase levels during the same time periods. Alanine-transaminase (ALT) and aspartate-transaminase (AST) levels remained in the normal range in both patients.
  • Robust increases in plasma GCase levels. Patient 1 showed a nearly 700-fold increase over baseline to more than 70 μmol/L/h as of 12 weeks post-dosing. Patient 2 showed a similarly robust response, with a greater than 300-fold increase over baseline to approximately 30 μmol/L/h as of four weeks post-dosing. Normal plasma GCase levels range from 0.3 to 1.2 μmol/L/h (mean: 0.58 μmol/L/h).
  • Normalization of leukocyte GCase activity, demonstrating cellular uptake of GCase from the plasma. Leukocyte GCase activity reached normal levels in patient 1 within four weeks of dosing and remained normal as of the last measurement. Similarly, leukocyte GCase activity in patient 2 reached normal levels within four weeks of dosing. Leukocytes are validated markers for broad cellular uptake in Gaucher disease.
  • Both patients had normal hemoglobin levels at baseline and have remained in the normal range at each weekly assessment, including those taken after coming off enzyme replacement therapy or substrate replacement therapy.

Given the compelling safety profile and robust enzyme activity at the 4.5×1011 vg/kg dose, a third patient has been scheduled for dosing in this first cohort to gather additional data before deciding whether to continue at the current dose or explore a higher dose. Three additional study patients have been identified and are in the process of being scheduled for dosing.

Webcast/Conference Call Information
Freeline Therapeutics will host a webcast presentation at 8 a.m. ET today to discuss these initial clinical data for FLT201 in Gaucher disease.

A live webcast of the event will be available on the Investors section of Freeline’s website at Participants may access the event by registering here. While not required, it is recommended that participants join 10 minutes prior to the scheduled start. An archived replay will be available on Freeline’s website for at least 90 days.

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 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 (NCT05324943).

About Freeline Therapeutics
Freeline is a clinical-stage biotechnology company focused on developing transformative gene therapies for chronic debilitating diseases. Freeline uses its proprietary, rationally designed AAV vector and capsid (AAVS3), along with novel promoters and transgenes, to deliver a functional copy of a therapeutic gene into human liver cells, thereby expressing a persistent functional level of the missing or dysfunctional protein into a patient’s bloodstream. The company 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. For more information, visit or connect with Freeline on LinkedIn and Twitter.

SOURCE: Freeline Therapeutics