Trial of Boehringer's cystic fibrosis gene therapy imminent

An inhaled gene therapy for cystic fibrosis developed by Boehringer Ingelheim is due to start clinical testing shortly, hoping to become a first-in-class treatment for the genetic disorder.

Boehringer's lentiviral vector-based BI 3720931 candidate will be tested in a phase 1/2 trial, called LENTICLAIR 1, that will be conducted by the company in collaboration with the UK Respiratory Gene Therapy Consortium (GTC) and contract development and manufacturing organisation OXB, with results due in 2027.

Considering the cystic fibrosis transmembrane conductance regulator (CFTR) gene responsible for cystic fibrosis was sequenced way back in the late 1980s – and was considered a landmark as the first disease-causing gene to be identified in any illness – it could be viewed as remarkable that no gene therapy has emerged in the intervening decades.

One reason for that is that around 2,000 mutations in the CFTR gene can lead to CF, a disease caused by an imbalance in chloride and sodium ions in the body that results in thick, sticky mucus building up in the lungs, pancreas, and other organs.

Another is that other treatment approaches - i.e., exon-skipping antisense oligonucleotides pioneered by Vertex Pharma that modulate CFTR - subsequently reached the market and provided therapy that can alleviate symptoms in around 90% of patients.

However, their high cost – Vertex charges more than $300,000 a year at list prices for its latest triple therapy Kaftrio/Trikafta (elexacaftor/ivacaftor/tezacaftor) – has reinvigorated interest in gene therapies that could correct mutations with one-off treatment.

With BI 3720931, Boehringer and its partners are hoping to fulfil that need and provide an option for the estimated 10% to 15% of patients for whom there are no suitable CFTR modulators available.

It is designed to insert a functional copy of the CFTR gene in the DNA of airway epithelial cells, improving lung symptoms – the most debilitating caused by CF – and reduce the sudden worsening in symptoms (exacerbations) that are a feature of the disease.

"The GTC is very excited to have reached this milestone after 24 years of focused effort and in close collaboration with our partners and people with CF," commented Professor Eric Alton of Imperial College London's National Heart and Lung Institute, who coordinates the group.

"While the immediate target [is] those adult 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 mutation type and has the potential for re-dosing if needed," he added.

Photo by Rana Mirzayeva on Unsplash