Entering the era of highly effective modulator therapies

Abstract

Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer‐term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual‐agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA‐based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF.

Clinical course and risk factors for severe COVID-19 among Italian patients with cystic fibrosis: a study within the Italian Cystic Fibrosis Society

“…CFTR modulators are oral drugs which improve CFTR function (potentiators) or facilitate its trafficking toward the cell membrane (correctors). Some of them proved to be highly effective in improving the clinical manifestations of the disease, while others showed only slight/moderate effects [ 21 ]. The potential role of CFTR modulators in preventing hospitalization in CF patients with COVID-19 was also evaluated in a study based on a research network of Health Care Organizations in the USA, which found a reduced risk, although not statistically significant (OR 0.57, 95% CI 0.30–1.08), among 68 patients with CF treated with CFTR modulators as compared with 353 untreated patients [ 22 ].…”

Combining Ivacaftor and Intensive Antibiotics Achieves Limited Clearance of Cystic Fibrosis Infections

“…The genetic disease cystic fibrosis (CF) has been transformed by drugs that act on the basic CF defect, impaired anion conductance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel ( 1 ). Studies of ivacaftor, the first highly effective drug of this kind (called CFTR modulators), showed that treatment improved subjects’ lung and digestive function and nutritional status and reduced pulmonary exacerbations ( 2 ).…”

Low diversity and instability of the sinus microbiota over time in adults with cystic fibrosis

“…More work is needed in a larger cohort to understand the causes and consequences of sinus microbial community instability in adults with CF CRS, and how community structure relates to the inflammatory environment of the sinuses. Furthermore, the CF community has entered the era of highly effective modulator therapy (HEMT), in which widespread use of HEMT is changing CF disease in unprecedented ways that will require complementary changes in how CF is managed for many people 50 . Initiation of HEMT early in life may delay respiratory disease progression and it is possible that management of sinus disease could offer an additional opportunity to prevent or delay LRT disease, as well as to relieve the symptomatic quality of life burden for people with CF.…”