Phase 1/2 dose confirmation study of FLT180a in haemophilia B
Research type
Research Study
Full title
A dose confirmation study of FLT180a (adeno-associated viral vector containing the Padua variant of a codon-optimized human Factor IX gene) in adult subjects with hemophilia B.
IRAS ID
300194
Contact name
Pratima Chowdary
Contact email
Sponsor organisation
Freeline Therapeutics Ltd
Eudract number
2021-001079-18
Duration of Study in the UK
1 years, 4 months, 31 days
Research summary
Research Summary:
Haemophilia B is a hereditary bleeding disorder where blood cannot clot properly to control bleeding due to a lack of blood clotting factor IX (nine). It is caused by a mutation in the gene for the factor IX (FIX) protein. Individuals with blood levels of FIX < 1% have a severe version of the disease characterised by frequent bleeding episodes that result in chronic, debilitating joint involvement. Keeping plasma FIX levels at or above only 1% of normal can greatly reduce bleeding episodes.Current treatment for haemophilia B involves intravenous infusions of FIX at the time of a bleed or as regular prophylactic infusions. Because FIX does not stay active in the body for long periods, multiple IV infusions a week may be required.
FLT180a is an investigational gene-modified product. A previous study of 10 patients showed improved FIX activity following a single infusion of FLT180a, suggesting potential to eliminate need for replacement infusions.
This is a phase I/II study. Up to 9 male participants, age 18-65, will take part in this study. The study will be performed at multiple sites globally.
This study will enrol 3 participants who will receive a single dose of study medicine based on information from prior studies and body weight. Around 21 days post-treatment, study data will be reviewed and a decision will be made regarding the dose for the next 3 participants, the dose may stay the same or be adjusted. Once all 6 participants have reached 21 days post-treatment or beyond, the data will be reviewed again and a decision will be made whether this is the best dose of the study medicine to test in a bigger study, or whether the dose needs to be confirmed in 3 more participants (possibly after being adjusted).
Lay summary of study results: "Freeline Therapeutics Ltd (“Freeline”) sponsored this trial and would like to acknowledge the contribution of the trial participants to this research.What was the trial about?
Six participants in the United Kingdom and the United States with haemophilia B were given the gene therapy known as FLT180a as a one-time, slow injection through a needle into a vein, also known as an intravenous (IV) infusion.The trial was cancelled by Freeline for commercial reasons, with all participants completing approximately 1 year of follow-up. Freeline reviewed the data collected when this trial ended and created a report of the results. This is a summary of the main results.
Although the trial has ended, the health of all the participants who took part is being checked regularly for 5 years since treatment as part of Freeline’s safety oversight commitments.
Why was the research needed?
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 clot when you cut yourself or have an operation. In people with haemophilia B, the body does not make enough factor IX to make blood clot as the gene that provides instructions for making factor IX in the body is 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, the 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.
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 conduct clinical trials to find out how it works and how safe it is.
The trial treatment, FLT180a, is a type of treatment called a “gene therapy”. Instead of replacing the body’s missing factor IX, gene therapy introduces a working copy of the 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 trial was this?
This trial was an “open-label” trial. This means the researchers and the participants knew what treatment each participant received.Since FLT180a had already been tested on humans, this trial aimed to confirm the best dose to give. Participants received a single dose based on their body weight to determine if it is safe and works well to treat haemophilia B.
After receiving FLT180a, participants remained on their usual factor IX replacement for the first 2 weeks until factor IX levels were greater than or equal to 5% of the normal range. If their doctor agreed, they then stopped receiving factor IX replacement infusions.
Who did the trial enrol?
All participants had either severe or moderately severe haemophilia B and were males between 20 and 51 years of age. To take part in the trial, 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 trial want to answer?
The main questions the researchers wanted to answer in this trial were:
• What medical problems did participants have during the trial?
• How long did the treatment work for?What type of treatments did the participants receive?
All participants received 7.7 × 1011 vg/kg FLT180a through an IV infusion. The amount of FLT180a each participant received was calculated carefully based on information that the researchers already had about FLT180a. Participants were divided into 2 groups and each group was given the same dose of FLT180a.What happened during the trial?
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’ 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. The participants were also required to answer questionnaires about their symptoms and quality of life and to keep a diary during the trial.During the trial, participants were given FLT180a by staff at the trial site. After receiving FLT180a, the participants had their vital signs (heart rate, blood pressure, breathing rate, and internal body temperature) taken once per hour for 4 total hours. Participants then returned for further check-ups regularly throughout the first year and then annually. 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 trial site approximate 47 to 54 weeks (approximately 1 year) after the infusion.
After the trial, participants are continuing to be followed for 5 years for safety oversight purposes only.
What were the results of the trial?
This is a summary of the main results from this trial overall.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 did participants have during the trial?
This section is a summary of the “adverse events” that happened during the trial. An adverse event is any new sign or symptom that participants have, which may or may not be caused by the treatments in the trial. During the trial, all participants experienced at least 1 adverse event within the first year after they were given FLT180a. Most of these adverse events were alanine aminotransferase (ALT) increased, coronavirus 2019 (COVID-19), arthralgia (joint stiffness), and headache.Most trial participants’ immune systems reacted to FLT180a, which in some cases caused adverse events; these events were treated with a medicine (an immunosuppressant) that decreased the body’s immune response.
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.None of the participants experienced a serious adverse event and no participants died during the trial.
How long did the treatment work for?
All the participants were considered clinical responders (which means they showed a positive change in response to their treatment) within 1 month of receiving FLT180a with their responses lasting between 2 months to 1 year.How has this trial helped patients and researchers?
This trial 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 trial showed that FLT180a was well-tolerated in all participants and had a good safety profile."
REC name
London - West London & GTAC Research Ethics Committee
REC reference
21/LO/0467
Date of REC Opinion
17 Aug 2021
REC opinion
Further Information Favourable Opinion