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
4.5x1011 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 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 FLT201FLT201 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
DiseaseGaucher 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
DiseaseParkinson’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
TherapeuticsFreeline 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.
For more information, visit www.freeline.life or connect with
Freeline on LinkedIn and X.
Media Contact:Naomi
Aokinaomi.aoki@freeline.life+ 1 617 283 4298