Therapies To Treat the Molecular Cause of Cystic Fibrosis Now Approved for Ninety Percent of People with the Disease

Researchers recently found that a combination of three drugs for cystic fibrosis (CF) has substantial benefit in people for whom previous medical treatments did not work. CF, a rare disease resulting in childhood fatality if left untreated, is caused by mutations in the CFTR gene. This gene encodes the CFTR protein, a key cellular channel for chloride ions, (one of the two chemical components of table salt). Everyone receives one version of CFTR from each parent, and if either of those copies is normal that person does not get the disease. But if neither copy produces a functional form of the CFTR protein, he or she will develop CF. There are many disease-causing variants of the CFTR gene known, but by far the most common is one designated Phe508del: 90 percent of people with CF have at least one copy of this variant, and about half received this version of the gene from both parents. Researchers previously developed a medication, ivacaftor, that restores some function to certain disease-causing forms of CFTR, so the protein can act as a channel for chloride. This was life-changing for the small number of people who have these particular variant forms of CFTR. Unfortunately, the Phe508del form not only lacks channel function but is also unstable and is quickly degraded by the cell. In 2018, the U.S. Food and Drug Administration (FDA) approved two different two-drug combinations of ivacaftor, the channel opening drug, along with either of two CFTR stabilizing drugs, tezacaftor or lumacaftor. These combinations made a real clinical difference for people with either two copies of Phe508del or one copy along with a milder CFTR mutation. However, even though they provided some clinical benefit, CFTR function remained too low in people with two copies of Phe508del. Moreover, the existing two-drug combinations were ineffective in people who have one copy of Phe508del plus a “minimally functioning” (MF) CFTR—one that effectively produces either no CFTR protein at all or a form of the protein that does not respond to any of the previously developed medications.

Scientists reasoned that an additional CFTR-stabilizing medicine might be added to one of the approved two-drug combinations to have greater benefit. In 2019, scientists found that such a three-drug combination was significantly more effective than the approved two-drug therapies at improving CFTR function in people with two copies of Phe508del. In a new industry-led clinical trial, with additional support from the NIDDK and others, researchers tested that three-drug combination of tezacaftor, ivacaftor, and a newer medication—elexacaftor—in a study with 403 participants who have one Phe508del variant and one MF variant. The treatment dramatically improved lung function and quality of life while reducing serious CF complications during the 24-week study. The FDA has now approved this triple combination therapy for people ages 12 and over with CF and at least one copy of Phe508del. That the root cause of CF can now be treated in roughly 90 percent of those with the disease is a tremendous achievement, yet further research will be important to develop effective therapies for those whose disease cannot be treated by any of these new methods—and to develop a cure for this life-long disease.