A Factor IX Gene Therapy Study (FIX-GT)
Research type
Research Study
Full title
A Phase I/II, Open label, Multicentre, Ascending Single Dose, Safety Study of a Novel Adeno-associated Viral Vector (FLT180a) in Patients With Haemophilia B
IRAS ID
225130
Contact name
Pratima Chowdary
Contact email
Sponsor organisation
University College London
Eudract number
2017-000852-24
Duration of Study in the UK
1 years, 4 months, 1 days
Research summary
Research Summary
Severe haemophilia B is a bleeding disorder where a protein made by the body to help make blood clot is either partly or completely missing. This protein is called a clotting factor; with severe haemophilia B, levels of clotting factor IX (FIX) (nine) are very low and affected individuals can suffer life threatening bleeding episodes. HB mainly affects boys and men (normally one in every 30,000 males). Current treatment for HB involves intravenous infusions of factor IX as regular treatment (Prophylaxis) or 'on demand'. On demand treatment is highly effective at stopping bleeding but cannot fully reverse long-term damage that follows after a bleed. Regular treatment can prevent bleeding, however can be invasive for patients and also expensive.
This research study aims to test the safety and effectiveness of a high activity version of the Factor IX gene (Factor IX Padua) which can produce Factor IX protein in the body. The gene will be given by using an inactivated virus called “the vector” named as FLT180a, in a single infusion. The vector has been developed from a virus known as an adeno-associated 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 Factor IX gene and to make its way within liver cells where Factor IX protein is normally made.
FLT180a is a new, unproven gene treatment and this trial is the first time it has been used in man. Up to three different doses of FLT180a will be tested, in up to 18 patients with severe haemophilia B. Patients will be recruited from haemophilia centres in the EU and US. Patients will be in the trial for approximately 40 weeks and will undergo procedures including physical examinations, bloods tests, ECGs and liver ultrasounds.
Summary of Results
UCL 15/0552 Clinical Study Results
Research sponsor: University College London (UCL) Treatment studied: FLT180a gene therapy (also called AAV2/S3-HLP2-Ti-FIXco1) Study purpose: A study to learn about the safety of FLT180a in adults with haemophilia B and to measure levels of clotting Factor IX, which are low in people with haemophilia B
Thank you
UCL sponsored this study and would like to acknowledge the contribution of the study participants to this research.
What is happening with the study now?
Ten participants in the United Kingdom with haemophilia B were given FLT180a, i.e. gene therapy as a one-off, slow injection through a needle into a vein, also known as an intravenous or IV infusion.
The study is now finished. UCL reviewed the data collected when this study ended and created reports of the results. This is a summary of the main results.
The health of all of the participants who took part is being checked regularly by Freeline Therapeutics for another 15 years, as part of their long term follow study.
Why was the research needed?
Researchers are looking for better ways to treat people with moderate or severe haemophilia B. Before a new treatment can be approved for patients to receive as standard of care, researchers do clinical studies to find out how it works and how safe it is.
Haemophilia B is a bleeding disorder that happens mostly in males. Most cases are inherited, which means it is passed down to someone through their parents’ genes.
Normally, the body uses a protein called “Factor IX” or “Factor 9” to make blood clots when you cut yourself or have an operation. In people with haemophilia B, the body does not make enough Factor IX to make blood clots as the ‘gene’ that provide instructions for making factor IX in the body are missing or faulty. Without enough Factor IX, the blood cannot clot. This can lead to bleeding that does not stop, including bleeding inside the body.
Current treatments for haemophilia B work by replacing the missing Factor IX. Normally, Factor IX replacements need to be given as IV infusions. Getting IV infusions can sometimes cause medical problems such as infections. The infusions can also be very time-consuming and have a major impact on the person’s life.
The study treatment, FLT180a, is a type of treatment called “gene therapy”. Instead of replacing the body’s missing Factor IX , gene therapy introduces a new functioning gene into the body that provides the correct instructions. The body then uses the new instructions to produce its own Factor IX. This could mean that people with haemophilia B might not need to have regular Factor IX replacement infusions.
What kind of study was this?
This study was an ‘open-label’ study. This means the researchers and the participant knew what each participant was getting.
As this was the first time FLT180a has been given to humans, the study used an ascending-dose design which helps decide on the best dose to give to participants.
This means the lowest dose was given to 2 study participants 6 weeks apart, and the responses analysed by the researchers before deciding the next step. If these participants had an acceptable response to FLT180a, the next highest dose was given to another 2 participants, 4 weeks later and so on.
After receiving FLT180a, participants remained on their usual Factor IX replacement treatment until their Factor IX levels improved to a specified level (≥3% of normal). If their doctor agreed, they stopped receiving Factor IX replacement infusions. Monitoring of participants’ Factor IX levels and health status continued for 26 weeks (approximately 6 months) until the study ended.
Who did the study enrol?
The participants were males between 25 and 67 years of age. All participants had either severe or moderately severe haemophilia B. To take part in the study, they must have been given at least 150 days of Factor IX replacement treatment in the past. Participants were also tested to check their immune system would not reject the carrier protein used to deliver the treatment.
What questions did the study want to answer?
The main questions the researchers wanted to answer in this study were:
• How many participants responded to the treatment with increased FIX levels (had a clinical response) at a dose of 1.3 × 1012 vg/kg*?
• What medical problems did any participants have during the study?
* The number of vg (vector genomes) is the dose of gene therapy to be given per kg of participant’s body weight.
What type of treatments did the participants receive?
All of the participants received FLT180a through an IV infusion. The amount of FLT180a each participant received was calculated carefully based on information that the scientists already had about FLT180a. Participants were divided into 4 groups and each group was given a different dose of FLT180a.
Between 3 and 20 weeks after getting the FLT180a infusion, participants were given medicines to keep their immune system from rejecting the study treatment. If any of the participants had severe bleeding episodes during the study, they could go back to their previous Factor IX replacement treatment.
What happened during the study?
Before the participants got any study treatment, the doctors checked their overall health to make sure they could join the study. The doctors checked the participants’ blood pressure, joint health and took blood samples. They also asked about the participants’ medical history. Participants also had a liver scan and their heart monitored by a machine called an electrocardiogram. The participants were also required to answer questionnaires about their symptoms and quality of life and to keep a diary during the study.
During the study, the participants were given their FLT180a infusion by staff at the study site. After the infusion, participants had to stay at the study site for between 12 and 24 hours so that their health could be monitored before they went home; 1, 2 and 4 days after the infusion, participants returned to the study site for further check-ups.
After the first week, participants had a weekly check-up at home or at their local medical practice for a total of 25 weeks. In addition, participants had another 1 or 2 blood samples taken each week at home or at their local medical practice.
The last visit took place at the study site 26 weeks (approximately 6 months) after the infusion.
The chart below shows how the study was done:
Before getting treatment
Past medical issues checked
Liver scan
Heart monitoring
Health questionnairesDuring the study
FLT180a given to participants at study site Regular check-ups at home or local medical practice Health diary Final check-up at study siteAfter the study
Participants asked to join long-term follow-up studyWhat were the results of the study?
This is a summary of the main results from this study overall. Ten study participants received 4 different doses of FLT180a: 6 x 1011 vg/kg, 2 x 1012 vg/kg, and 1 x 1012 vg/kg (2 participants each), and 1.3 x 1012 vg/kg (4 participants). 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 study results is available, it may also be found on these websites.
How many participants had a clinical response at the 1.3 × 1012 vg/kg dose?
Researchers answered this question by taking blood samples from each participant after they had been given the study treatment. They measured the amount of Factor IX in the samples to see if the participants had a meaningful response to the treatment.
The researchers counted how many participants had improved Factor IX levels after 6 months. They also counted how many had Factor IX levels which were in the normal range after 6 months.
Six months after treatment, 2 out of the 4 participants who received the 1.3 × 1012 vg/kg dose had normal Factor IX levels, similar to the levels found in people who do not have haemophilia B. The other 2 participants had even higher levels of Factor IX.
What medical problems did any participants have during the study?
This section is a summary of the “adverse events” that happened during the study. An adverse event is any new sign or symptom that participants have, which may or may not be caused by the treatments in this study. The adverse events considered to be related to treatment with FLT180a and which occurred in more than 1 study participant are shown in the table below:Adverse events related to FLT180a in >1 study participant
Adverse event Number of participants
Alanine aminotransferase (ALT)
increased (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) 4
Transaminases increased
(Transaminases are enzymes
produced by the liver and found
in the blood. They can be raised
for several reasons including
damage to the liver) 3
Fatigue (tiredness) 2Most study participants developed an immune response to the FLT180a infusion, and this was treated with immunosuppressants, which in some cases caused adverse events.
How many participants had serious adverse events?
An adverse event is called “serious” when it is life-threatening, causes lasting problems, is medically significant, requires hospital care, or results in death.
7 out of 10 participants had serious adverse events during the study. This was 70% of participants. The researchers thought that the serious adverse events of increased liver enzymes, decreased Factor IX levels, and chest infection were related to FLT180a.
None of the 10 participants died during the study.
How has this study helped patients and researchers?
This study helped researchers to learn more about the safety of FLT180a and how well it works when given to people with haemophilia B.
The results of this study showed that FLT180a was safe and well-tolerated when given to the participants included in this study. Researchers look at the results of many studies to decide which treatments work best and are safest for patients. This summary shows only the main results from one study. Other studies may provide new information or different results. Always talk to a doctor before making any treatment changes.
Further clinical studies with FLT180a are planned.
Where can I learn more about this study?
Full study title: A Phase I/II, Open-label, Multicentre, Ascending Single-dose, Safety Study of a Novel Adeno-associated Viral Vector (FLT180a) in Patients With Haemophilia B National Clinical Trials Number: NCT03369444 EU Clinical Trials Number: 2017-000852-24 UCL protocol number: UCL 15/0552 This summary can be viewed online at https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbURyFnTPO6nSmuOSTUDSzI8-3DBu81_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIL9njkSfUH2b5CdSn3popwztmu4RZZHJT-2F6fIk6nDUF0gEVLr7KPmxvOgxjWaWV1hwV5VJ6mTmkl3tuo-2BYAIRmtB3-2BNdFrHgUxUX84SfZU52CWTRk5SBLgs0D8g-2Bqmdt1cYgD3gARqbzZTz8UKjgTkwGJJrQH3YV72es-2BAHgnndA-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C3a27ef4ea627421e7e8d08da55d01f7e%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637916649610667453%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=gRWN4Wq40dTAkDG5ZgQmUDETTwYsMxFxIGQayRt6pfM%3D&reserved=0
You can find out more about this study by searching on the websites below:
• https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agba4yu73OCS9U-2BkKS40W1kfbzSmdWCVTTDSfM-2Bp8ODc89x9XJ_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIL9njkSfUH2b5CdSn3popw-2Foub0KHIE-2BnC-2F3VFm4qLwyaiiw3O9ywydjgTeh6DAvwr23NHSeio-2FR0ey810G-2B-2FmtLRFfkyztyfJJea1m2UhjJnnJbuzKw-2FaOuAvhBT72GSlb6rc2vnZdc-2BgiqTW6qYAIgFDl6TbDox7RNWYy3e01A-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C3a27ef4ea627421e7e8d08da55d01f7e%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637916649610667453%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=68a%2FFrUPqKUR50Z%2BFUELpjjjXbsMcQ2%2F8zSeERBFit4%3D&reserved=0 Once you are on the website, type ‘NCT03369444’ into the search box and click ‘Search’.
• https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agba4yu73OCS9U-2BkKS40W1kfY5JRtlt1rWQPh9b5eNgwpeVhkq_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIL9njkSfUH2b5CdSn3popw1nGDAVOx7nzzdBqap6S8-2B3fy6HTrzki4y0wsZLTREvbBX5WKRlVkS-2BXK3mywYd4JmaWaX5V22q2CP5bwYKuynVHGB4KFkZaq7Q0MWwNkWUQaJB0n-2BEq1W3UrCCVxcpCcynAnTrJT6hzlBS7Z8oI2vg-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C3a27ef4ea627421e7e8d08da55d01f7e%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637916649610667453%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=c3kwJ4%2FxpXvdCVG%2FfGWiICAwNHx9SYktNNBY5pSCHNQ%3D&reserved=0 Once you are on the website, click ‘Home and Search’ then type ‘2017-000852-24’ in the search box and click ‘Search’.
University College London sponsored this study, and the Joint Research Office is located on the 4th Floor West, 250 Euston Road, London, NW1 2PG.
The email address for the UCL Joint Research Office is CTIMPS@ucl.ac.uk Date this lay summary was prepared: 22 June 2022REC name
London - West London & GTAC Research Ethics Committee
REC reference
17/LO/0801
Date of REC Opinion
23 Aug 2017
REC opinion
Further Information Favourable Opinion