Researcher awarded for development of triple therapy for cystic fibrosis

Marcus A. Mall, MD, whose work led to the development of the first triple therapy for patients with cystic fibrosis, won the Falling Walls Foundation’s Science Breakthrough of the Year in Life Sciences award, according to a press release.

The award acknowledges that Mall, director of the department of pediatric respiratory medicine, immunology and critical care medicine at Charité – Universitätsmedizin in Berlin, Germany, is a leader in his field for his groundbreaking work in creating a triple combination therapy for patients with cystic fibrosis (CF) that significantly improves their lung function and quality of life.

Seeing that therapies targeting symptoms of CF required taking many pills each day with little improvement to patients’ lung function limitations, Mall sought to develop a treatment that went directly to the cause of the disease: deletion of phenylalanine 508, or the F508del mutation, on the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

According to Mall, 90% of patients with CF have at least one allele that has this genetic defect.

“Mucus is a very important protective barrier that entraps and also clears bacteria out of the lung,” Mall said during his presentation at the Falling Walls Science Summit. “In cystic fibrosis cells, we found that this delta F508 mutation causes a misfolding of the protein, so that it is actually recognized by the cell as a wrong protein and degraded so it never gets to the cell membrane. It cannot act as a channel, and that leads to a dehydrated and highly abnormal and sticky mucus that cannot be cleared from the lungs.”

With this knowledge, Mall and his team at Charité – Universitätsmedizin identified three small molecule compounds, elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals), via functional high-throughput screening. According to Mall, by binding to the F508del molecule, this triple combination therapy corrected folding, maturation and function at the cell membrane, which helped in restoration of CFTR chloride function.

In the first large clinical trial of this therapy, Mall and his team evaluated 403 patients with CF to observe how the treatment impacted lung function and quality of life compared with placebo. The trial, published in 2019 in The New England Journal of Medicine, included patients with one allele with a F508del mutation and another allele with a minimal-function mutation that would not react to the pharmacologic therapy.

“We found a very fast and sustained improvement of lung function at a level that has not been observed with any of the other therapies before,” Mall said. “Using MRI imaging techniques that allow to visualize mucus in the lungs, we were also able to show that this therapy effectively removes mucus from the lungs, and using ... questionnaires, we’re able to show that the therapy comes with an unprecedented improvement of the quality of life so that our patients can now make new plans for their lives.”

Both the FDA and European Medicines Agency have approved this triple therapy for patients with CF who are aged 6 years or older and have at least one F508del mutant allele, Mall said.

During his presentation, Mall highlighted the anecdote of one patient with cystic fibrosis who, before treatment with the triple therapy, took “up to 30 pills a day” and yet struggled to keep up with her 3-year-old son. After 4 weeks of treatment with elexacaftor/tezacaftor/ivacaftor, the patient said she “had so much more energy” for her son and family, and she has been able to work again for a few hours a day.

Although Mall’s breakthrough applies specifically to patients with CF, he told the audience at the Science Summit that his work may help in the development of therapies for other rare genetic diseases.

“I do want to make the point here that what we have done and learned from cystic fibrosis could now also be translated and actually used as a blueprint for drug discovery and development for the approximately 8,000 other rare genetic diseases that we currently know of, many of them with very limited therapeutic options that collectively affect millions of people worldwide,” Mall said.

References:

Falling Walls Foundation. Falling Walls Science Breakthroughs of the Year 2022. YouTube. https://falling-walls.com/event/free-livestream-falling-walls-breakthrough-day/. Published Nov. 9, 2022. Accessed Nov. 18, 2022.

Improved cystic fibrosis treatment is Science Breakthrough of the Year. https://www.charite.de/en/service/press_reports/artikel/detail/improved_cystic_fibrosis_treatment_is_science_breakthrough_of_the_year/. Published Nov. 7, 2022. Accessed Nov. 16, 2022.

Middleton PG, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1908639.