A Fabry Disease Gene Therapy Study (MARVEL 1)
Research type
Research Study
Full title
A Phase 1/2, Baseline-controlled, Non-randomised, Open-label, Single-ascending Dose Study of a Novel Adeno-associated Viral Vector (FLT190) in Patients With Fabry disease
IRAS ID
251125
Contact name
Derralynn Hughes
Contact email
Sponsor organisation
Freeline Therapeutics Limited
Eudract number
2018-002097-51
Duration of Study in the UK
1 years, 11 months, 23 days
Research summary
Summary of Research
Fabry disease is an inherited disorder caused by a mutation in the gene encoding the α-galactosidase A (αGLA) enzyme. Patients with Fabry disease do not have enough of this αGLA enzyme in their body. This enzyme normally breaks down fatty substances, and if the enzyme is missing or is defective, these fatty substances are not broken down and build up in the body’s cells, such as in the heart and kidney cells. Patients with Fabry disease have a wide range of signs and symptoms, including severe conditions such as kidney failure, heart problems and increased risk of stroke.
Current treatment for Fabry disease is limited to the management of pain, conventional management of complications, and methods to increase the availability of functional αGLA.
This clinical trial with a novel Gene Therapy (FLT190) for treatment of Fabry disease is designed to be expressed in the liver, leading to the production of functional αGLA enzymes in the body. The GLA gene will be given by using an inactivated virus called “the vector” named as FLT190, in a single infusion. The vector has been developed from a virus known as an adenoassociated virus, that has been changed so that it is unable to cause a viral infection in humans. This “inactivated” virus is further altered to carry the GLA gene and to make its way within liver cells where αGLA enzyme is made.
The study is designed in two parts: in the first part up to 9 participants, who have been previously treated for Fabry disease, will be enrolled in the study across 3 dose cohorts (low, medium, high) and in part two 3 participants, who have been previously untreated, will be enrolled at the most effective dose identified following Part 1. Participants will be in the trial for approximately 12 months.
Summary of Results
Freeline Therapeutics Ltd (“Freeline”) sponsored this trial and would like to acknowledge the contribution of the trial participants to this research.What were the trials about?
In the first trial (FLT190-01), 2 participants in the United Kingdom and 1 participant in Germany with Fabry disease were given the gene therapy known as FLT190. FLT190 was administered as a one-time, slow injection through a needle into a vein, also known as an intravenous (IV) infusion. The participants were checked at regular visits for up to 38 weeks and then transferred into the second trial (FLT190-02). In the second trial, the health of all participants was to be monitored by Freeline for up to 5 years.The trials were stopped early by Freeline for commercial reasons, with participants completing approximately 1 to 4 years of follow-up. Freeline reviewed the data collected when the trials ended and created a report of the results. This is a summary of the main results from both trials.
Why was the research needed?
Fabry disease is a rare lysosomal storage disorder that happens mostly in men. Most cases are inherited, which means it is passed down to someone through their parents’ genes. Normally, the α-galactosidase A (α-Gal A) enzyme helps break down certain types of fatty substances in your blood vessels and tissues. In people with Fabry disease, the “gene” that produces α-Gal A is faulty. This results in much less enzyme available to break down the fatty substances, leading to their buildup in the body’s cells and organ complications. Fabry disease symptoms generally appear in childhood, with organ issues starting in young adulthood. The average life expectancy for men with Fabry disease is approximately 50 years.Current treatments for Fabry disease may be used to treat symptoms or to treat the disease directly by increasing the availability of the α-Gal A enzyme through pharmacological chaperone therapy (PCT) or enzyme replacement therapy (ERT). PCT can only be taken by people with a specific mutation in the α-Gal A gene, meaning it will not be suitable for 50-65% of people with Fabry disease. For ERT, a manufactured version of the α-Gal A enzyme is given to patients by IV infusions, usually at a hospital or clinic, every 2 weeks. PCT or ERT treatment is generally continued life-long.
Researchers are looking for better ways to treat people with Fabry disease. Before a new treatment can be approved for patients to receive as standard of care, researchers do clinical trials to find out how well it works and how safe it is.
The trial treatment, FLT190, is a type of treatment called a “gene therapy”. Instead of giving a patient replacement α-Gal A enzyme, gene therapy introduces a working copy of the gene into the body that provides the correct instructions for making the α-Gal A enzyme. The body then uses the new instructions to produce its own α-Gal A enzyme. If successful, this could mean that people with Fabry disease might not require PCT or ERT.
What kind of trials were these?
The first trial (FLT190-01) was an “open-label” trial. This means the researchers and the participant knew what treatment the participant received.This was the first trial in which FLT190 was studied in humans, so this trial primarily aimed to determine the safety of FLT190, whilst also collecting information about how effective it was for treating Fabry disease. Participants received a single infusion of FLT190; the dose was calculated based on their body weight. Gene therapy doses are often written using the number of vector genomes (vg) or modified viral particles per kilogram of the patient’s body weight; for example, 1.0 × 10^12 vector genomes per kilogram (vg/kg).
Participants who were on PCT before the trial had to stop treatment at least 7 days before receiving FLT190. If participants were on ERT before the trial, they continued receiving ERT for the first 4 weeks after receiving FLT190 or until their α-Gal A levels had increased above their pre-FLT190 treatment levels. If their doctor agreed, they then could stop receiving ERT infusions.
The second trial (FLT190-02) was a long-term follow-up trial, which means that participants were monitored to examine the safety and efficacy of FLT190 for a long period of time after they received FLT190 in the first trial. Participants were invited to enter this second trial immediately after their participation in the first trial was completed. The 3 participants who entered this trial were followed-up for approximately 1 to 4 years before the trials were stopped early.
For these trials, participants completed follow-up visits where information on their overall health, medical problems, and response to treatment was collected.
Who did the trials enroll?
The participants in these trials were males with Fabry disease between the ages of 29 and 46 years of age. All 3 participants had been receiving a stable dose of ERT for at least 1 year before receiving FLT190.What questions did the trials want to answer?
The main questions the researchers wanted to answer in these trials were:
• What, if any, medical problems or adverse events did participants have during the trial?
• What α-Gal A levels were achieved after participants were given FLT190?What type of treatments did the participants receive?
Two participants received 0.75 × 10^12 vg/kg FLT190 and 1 participant received 1.5 × 10^12 vg/kg FLT190, each administered through an IV infusion. The amount of FLT190 each participant received was based on information that the researchers already had about FLT190.What happened during the trials?
Before participants received any trial treatment, the doctors checked their overall health to make sure they could join the trial. The doctors checked the participants’ vital signs (heart rate, blood pressure, breathing rate, and body temperature), physical measurements, and took blood and urine samples. They also asked about the participants’ medical histories. Participants had scans to check their heart, brain, and liver. The participants were asked to answer questionnaires about their symptoms and quality of life and to agree to keep a diary during the trial. Once participants were deemed eligible, a small sample (biopsy) of their skin and liver was taken for examination under a microscope.During the first trial (FLT190-01), participants were given FLT190 by staff at the trial site. After receiving FLT190, the participants’ vital signs were measured every 15 minutes until the end of the infusion and then once per hour for 6 hours. At 8 hours after treatment with FLT190, blood samples were taken and vital signs were measured. If the doctor thought it was necessary, vital signs were then taken every 2 hours until they were stable. Once the doctor was satisfied the participant was well enough, they were allowed to go home from the hospital. Participants then returned for check-ups to check their health, medical changes, their heart and liver, and collect blood samples regularly for up to 38 weeks until they transferred into the second trial.
During the second trial (FLT190-02), participants had follow-up visits every 6 months to assess their health and any medical changes, check their heart and liver, and collect blood samples. The last visit took place at the trial site approximately 1 to 4 years after the participants were treated with FLT190 in the first trial. Freeline decided to stop the trials early for commercial reasons.
What were the results of the trials?
This is a summary of the main results from these 2 trials overall. The results each participant had might be different from the overall summary results.A full list of the questions the researchers wanted to answer can be found on the websites listed at the end of this summary. Once a full report of the trial results is available, it may also be found on these websites.
What medical problems or adverse events did any participants have during the trials?
This section is a summary of the “adverse events” that happened during the trials. An adverse event is any new sign or symptom that participants have, which may or may not be caused by the treatments in the trials. An adverse event is called “serious” when it is life-threatening, causes lasting problems, is medically significant, requires hospital care, or results in death.
• All 3 participants experienced at least 1 adverse event; there were 67 adverse events in total.
• There were 13 adverse events which were deemed related to FLT190, the most common of which was alanine aminotransferase (ALT) increased (2 events; ALT is an enzyme produced by the liver and found in the blood. It can be raised for several reasons including damage to the liver). All FLT190-related adverse events were of mild or moderate severity.
• There were 5 serious adverse events. One participant had serious adverse events of myocarditis (inflammation of the heart muscle) and ALT increased (reported as transaminases increased). Another participant had serious adverse events of pyrexia (fever), urinary tract infection, and ALT increased. All serious adverse events were considered FLT190-related, except the event of urinary tract infection. All serious adverse events were of moderate severity.
• No adverse events were life-threatening or fatal.
• All adverse events resolved with no long-term consequences.Most trial participants’ immune systems reacted to FLT190, which is common in gene therapy studies. In some cases, this caused adverse events. These events were treated with a medicine (called an immunosuppressant) that decreased the body’s immune response.
What α-Gal A activity levels were achieved after participants were given FLT190?
In these trials, α-Gal A levels increased after receiving FLT190. By the end of their participation in the trials, 2 participants had higher α-Gal A levels compared to their pre-FLT190 levels and 1 participant had α-Gal A levels that had gone back down to the level seen before FLT190 was given.How has this trial helped patients and researchers?
This trial helped researchers learn more about the short- and long-term safety of FLT190 and how effective it is when given to people with Fabry disease. The results of this trial showed that the safety and tolerability of FLT190 was satisfactory in the context of a gene therapy. Researchers look at the results of many trials to decide which treatments work best and are safest for patients. This summary shows only the main results from two trials. Other trials may provide new information or different results. Always talk to a doctor if you have any questions about any of the medicines you are taking.REC name
Scotland B REC
REC reference
18/SS/0115
Date of REC Opinion
1 Nov 2018
REC opinion
Further Information Favourable Opinion