Cystic fibrosis developments and pipeline drugs

Cystic fibrosis treatment has changed greatly in the past decade. Newer cystic fibrosis drugs called CFTR modulators have improved lung function and quality of life for many patients, and a number of these therapies are now on the market in the US.^1,2,3

However, these drugs do not work for all patients. Multiple experimental CF therapeutics are in preclinical or clinical studies, including drugs that could potentially be helpful for patients with few other options. These include antisense oligonucleotides, protein amplifiers, and read-through agents.^1,2,4

Cystic fibrosis causes and consequences

Cystic fibrosis is caused by a wide range of mutations in the CFTR gene, which encodes an ion channel protein called the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is responsible for transporting chloride and bicarbonate across the cell membranes of epithelial cells.¹

In cystic fibrosis, the lack of fully functional CFTR leads to dysregulated water balance on epithelial surfaces, the buildup of thickened mucus, and in turn, chronic inflammation and high susceptibility to infections. The lungs are the most affected, and most morbidity and mortality are the result of patients’ progressive lung damage. The pancreas, sweat glands, and intestine are also affected, and some patients develop complications relating to these organs

Over 1700 disease-causing mutations are known, and these are grouped into five or six categories.^1, The specific mutation a patient has affects their disease severity and manifestations. The most common type of cystic fibrosis-causing mutation in CFTR leads to a misfolded protein, which is more susceptible to degradation and does not function as well at the cell membrane.¹

Earlier cystic fibrosis treatments

In the 1950s and earlier, most cystic fibrosis patients died in early childhood. The development of more effective physical therapy for clearing the airways, antibiotics, nutritional therapy, bronchodilators, and symptomatic treatments extended many patients’ lives into their 20s, 30s, and 40s.³ Dornase alfa (sold as Pulmozyme and used since the 1990s) is a cystic fibrosis-specific mucolytic used to help clear the thickened mucus from patients’ lungs.⁵These became the mainstay of cystic fibrosis treatments before the rise of CFTR modulators.

How do current CFTR-modulating cystic fibrosis drugs work?

CFTR modulators are now extending life expectancy even further for many patients. For patients who have some CFTR proteins, even if it is abnormal or present only at low levels, CFTR modulators can often help. CFTR correctors, like lumacaftor, tezacaftor, and several newer molecules, can help these abnormal proteins function better, in turn improving patients’ lung function.¹