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Improved treatment targeting root cause of cystic fibrosis may be on horizon

A clinical trial led by a pharmaceutical company with additional support from other organizations and from an NIDDK-supported Cystic Fibrosis Center that facilitated the conduct of the trial has shown that a combination of two medications provides significant clinical benefit in a subgroup of patients with cystic fibrosis (CF).  CF occurs when people lack a functional copy of the CFTR gene, which encodes a protein required for transporting chloride, one of the two chemical components of salt, in and out of our cells.  People with CF develop severe lung disease, and digestive problems, and commonly develop a form of diabetes once they reach adulthood; these complications significantly diminish both lifespan and quality of life.  People have two copies of this gene, but in people with CF inactivating mutations affect both copies.  While many CFTR mutations are known, the one that is the most common by far is designated Phe508del (also known as F508del or delta F508).  This mutation not only dramatically reduces the amount of CFTR protein that reaches the cell surface where it is needed to function, but also practically eliminates the chloride transporting capability of the small amount of CFTR that does get there.  The combination of these effects means people with two copies of Phe508del—about half of CF patients—have a very severe form of CF.  About another 40 percent of people with CF have one copy of Phe508del paired with one of the rarer CFTR mutations.  A few dozen of these rarer forms of the gene are termed “residual function mutations” as they encode forms of CFTR protein that retain a limited capacity to transport chloride.  People with one copy of a residual-function mutation and one copy of Phe508del typically develop a less severe form of CF than those with two copies of Phe508del.

Using knowledge of the different CFTR mutations, scientists have developed candidate medicines that may help restore sufficient CFTR function to partially alleviate CF symptoms.  Already, a combination of ivacaftor, a compound that facilitates transport of chloride through mutant forms of the CFTR protein, plus lumacaftor, a compound that stabilizes CFTR proteins so they reach the cell surface more easily and in greater amounts, was approved by the U.S. Food and Drug Administration (FDA) in 2015 for use in CF patients with at least one copy of Phe508del.  However, benefits are modest, and some patients experience significant side effects.  The current study tested a combination of ivacaftor and a promising new (not yet FDA-approved) CFTR-stabilizing drug, tezacaftor, in people who have one copy of Phe508del and one copy of a residual-function CFTR mutation.  The study had an unusual design that included two 8-week treatment periods, separated by 8 weeks in which the 248 male and female participants with CF (who were at least 12 years old) did not receive study medications.  Each participant was randomly assigned to receive either combination therapy, ivacaftor alone, or a placebo during the first treatment period, and (after the break) to have one of the other two regimens during the second.  As a result, all of the participants received at least one of the experimental therapies for at least one of the two treatment periods.

The researchers found that the amount of air that participants were able to exhale per second—a standard measure of lung function in people with CF—rose by an average 4.7 percentage points with ivacaftor treatment alone, and 6.8 percentage points with the combined ivacaftor-tezacaftor treatment, compared to a placebo.  (That is, placebo-taking participants able to exhale 50 percent as much as expected for people without CF would be able to exhale an average of 54.7 percent with ivacaftor alone, or 56.8 percent with the combination therapy.)  These improvements may seem small, but they suggest either therapeutic approach could confer clinical benefit.  Indeed, participants—who did not know whether they were taking one of the medication regimens or placebo at any given time—reported significantly better measures of respiratory-related quality of life after taking ivacaftor or ivacaftor-tezacaftor than after taking placebo.  Importantly, there were no differences in the adverse event frequency between placebo and drug treatments.

An important caveat is that the 8-week intervention periods of the study were too short to ascertain definitive effects on long-term clinical outcomes. However, all participants were enrolled in an ongoing follow-on study that should provide greater insights into the longer-term effects of the two treatments.  Moreover, results from a different trial supported entirely by the same pharmaceutical company suggest that the drug combination may also benefit people with two copies of Phe508del.  Together, these studies may form the basis for eventual FDA approval of the tezacaftor-ivacaftor combination to treat the molecular cause of CF in a large proportion of people with the disease.  If results from the two trials are borne out, this treatment approach may one day significantly improve the health and quality of life of many people with CF.