24 February 2025
An exciting new clinical trial targeted at patients who were not eligible for the recent CFTR modulator therapies has begun at Royal Brompton hospital.
The first trial of its kind, the trial aims to introduce correct genes into the DNA of patients with cystic fibrosis, via inhalation.
Cystic fibrosis and CFTR modulators
Cystic fibrosis is a lifelong inherited condition that progresses in severity over time. It is characterised by the production of sticky, thick mucus which clogs the airways and causes long-lasting lung infections, limiting the ability to breathe over time.
The disease is caused by mutations in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR), which affects the production of the CFTR protein. The CFTR protein is responsible for the balance of salt and fluids inside and outside of the cell, but when it is not made correctly this balance is affected.
There are more than 2,000 known mutations of the CFTR gene which lead to different levels of severity of the disease, depending on the specific mutations that have occurred.
A new class of drugs known as CFTR modulators which target the underlying defects in the CFTR protein, has revolutionised how cystic fibrosis is treated in people with specific mutations.
Unfortunately, these treatments are not suitable for about 10-15% of people with cystic fibrosis, either because of their mutation type or due to intolerance to the modulator drugs.
A possible new treatment
The UK Respiratory Gene Therapy Consortium (GTC) developed an inhaled gene therapy using a lentiviral vector, which aims at inserting a correctly functioning copy of the CFTR gene into the DNA of cells that line the airway.
This therapy aims to improve lung function and reduce exacerbations for people with CF irrespective of their mutations, including those who genetically cannot benefit from CFTR modulators.
The GTC licensed the novel therapy to Boehringer Ingelheim in 2021 and the partnership has developed the world’s first trial of such a product. Trial participants will be those in the approximately 10-15% of people with CF who are not eligible for modulators.
The first part of the trial will test increasing doses of the treatment to evaluate safety, tolerability, and dosage. The second part of the trial will be a randomised trial focusing on clinical efficacy and safety and is expected to be completed in early 2027.
Professor Eric Alton, consultant physician at Royal Brompton hospital who is leading on the trial globally said:
“We’re very excited to have reached this milestone after 24 years of focused effort and in close collaboration with our partners. While the immediate target are those patients, who are not eligible for CFTR modulators, this novel therapy has the potential to achieve long-lasting CFTR function improvement and disease modification for people with CF irrespective of their mutation type and has the potential for re-dosing if needed.
“We are very grateful to our wonderful team, our partners and funders and those with CF who have and continue to support us in many ways, including taking part in the multiple trials.”
Professor Jane Davies, paediatric respiratory consultant and lead investigator for the UK said:
“It’s been incredible to witness the health benefits afforded by CFTR modulators, but those who cannot benefit from these drugs urgently need alternative treatments. We’re breaking new ground in this trial with a gene therapy which has the potential for long-lasting CFTR expression.
“I’d like to acknowledge the people living with CF who are prepared to give their time to trials of new drugs, without whom we’d be unable to make this sort of progress.”
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