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Strides in the Treatment of Cystic Fibrosis

It has been over 30 years since the discovery of CFTR—the gene that is mutated in people with cystic fibrosis (CF)—and 7 years since the U.S. Food and Drug Administration (FDA) approved the first drug capable of rescuing CFTR protein function in people with certain CF-causing mutations. This medication, called ivacaftor, is a “potentiator,” meaning it enables certain mutant versions of the CFTR protein to fulfill their critical function as a channel that allows chloride ions to travel in and out of various cells, greatly reducing the burden of the disease. Unfortunately, ivacaftor cannot repair damage caused before treatment begins; and, at least by itself, it is only helpful for the 5 percent or so of people with CF that have a version of the protein (resulting from mutations in the gene such as one designated G551D) that, although inactive without the drug, is stable and reaches the cell surface where it is supposed to reside. However, research has continued to improve functional rescue of various forms of the CFTR protein and thereby continues to improve the health and quality of life for people with CF. For example, the FDA has recently approved the use of “corrector” drugs that help other mutant forms of the CFTR protein reach the cell surface. These can be combined with ivacaftor to improve CFTR function in people who have CF and have one or two copies of ∆F508, the most common disease-causing CFTR mutation. The improvements from these treatment regimens are modest, though clinically meaningful, so work has continued to improve upon this therapeutic approach. In the major recent advances described below, researchers examined whether it might be possible to maximize the clinical value of existing therapies like ivacaftor by starting treatment before birth; tested new, triple drug combinations in clinical trials with participants who have the ∆F508 mutation; and developed new candidate corrector drugs that could potentially raise CFTR channel levels in the majority of people with CF to normal or near-normal levels.

In Utero Treatment May Promote Healthy Development

New research shows that treatment during pregnancy can prevent or reduce developmental complications of CF in an animal model of the disease. While ivacaftor treatment for people with the CFTR-G551D mutation greatly improves patient health and quality of life, CFTR activity appears to be important during embryonic development, even before a baby takes his or her first breath—and thus before treatment begins. For example, infants with CF may be born with intestinal blockages so severe that they are life-threatening. Even in cases where this does not happen, defects in the intestines and pancreas can interfere with proper absorption of nutrients, slowing the baby’s growth. In addition, men with CF are almost invariably infertile, because the vas deferens and epididymis—ducts that carry sperm from the testes—do not develop properly during gestation. Although ivacaftor is FDA- approved for infants as young as 1 year old who have CF and at least one copy of G551D, prevention of these digestive and reproductive consequences of the disease might require treatment to begin earlier potentially even before birth.

To test this hypothesis, researchers utilized a ferret model of CF, which is much more prone to these developmental issues than are mouse or rat CF models. Ferrets born with CFTR-G551D have a very high frequency of serious intestinal blockages; those that survive infancy grow much more slowly than normal due to difficulty absorbing nutrients; and male ferrets with the mutation are sterile. However, the researchers found that if the mothers were treated with ivacaftor during pregnancy, both the digestive system and the male reproductive tract of the offspring developed much more normally. It remains to be determined whether treatment with ivacaftor or other small molecule drugs can safely and effectively promote healthy embryonic and infantile development in people with CF, but these results suggest that such treatments may one day allow much healthier development in children born with the disease and may help advance knowledge about the role of CFTR function during development.

Triple Combination Therapies Show Promise for People with the Most Common CF-causing Mutation

Combinations of recently developed small molecule drugs have shown great promise for significantly improving treatment of people who have CF and have one or two copies of the ∆F508 CFTR mutation. About 90 percent of people with CF have at least one copy of ∆F508, and half have two copies, one from each parent. The effects of the ∆F508 mutation on CFTR function are profound. Not only does the mutation inactivate the chloride channel, it also has two other serious consequences: it interferes with the protein’s biosynthesis, greatly reducing the amount that reaches the cell membrane, where it is needed; and it also renders the protein highly unstable, so that the small amount of CFTR protein that reaches its cellular destination is rapidly degraded. Thus, restoring robust CFTR function in people with ∆F508 will not only require an improvement in the protein’s function, it will also require both an increase in the amount of the mutant protein that cells produce and an improvement in the protein’s stability once it reaches the cell surface. To date, no single medication has been identified that is capable of meeting all of these needs.

Previous research had shown that the corrector drugs lumacaftor and tezacaftor are each capable of stabilizing ∆F508-CFTR during biosynthesis so that a significant amount of the protein reaches the cell surface. That alone is not enough to provide clinical benefit, since the protein remains inactive; but when combined with the potentiator ivacaftor, either corrector can provide a modest but measurable improvement in ∆F508-CFTR function. That was an important achievement, but it remained critical to further increase the amount of the mutant protein on the cell surface in order to improve clinical outcomes. A pharmaceutical company therefore developed new ∆F508-stabilizing drugs that work by different mechanisms from tezacaftor and lumacaftor. They identified two such agents and designated them VX-445 and VX-659. In new research led by the pharmaceutical company but with additional support from the NIDDK, they tested the ability of each of these to supplement tezacaftor-ivacaftor. In lab-cultured human airway cells producing only ∆F508-CFTR or ∆F508-CFTR along with a rarer, minimally functional mutant CFTR protein, both of the tested three-drug combinations significantly increased the net amount of the protein through improved biosynthesis, stability, or both, and increased the flow of chloride ions through the cell membrane compared to the two-drug combinations.

The researchers also reported clinical trial results of these triple combination therapies in men and women with CF who had at least one copy of ∆F508-CFTR. The two 4-week trials involved similar numbers of participants—122 for VX-445 and 117 for VX-659—and yielded very similar results. The resulting triple combination therapies significantly boosted CFTR function, based on improvements in measures of respiratory function and quality of life, among other tests. For example, in people with two copies of ∆F508 CFTR who had been taking a combination of tezacaftor and ivacaftor at the beginning of the trial, a measure of respiratory function improved 9.7 percent with the addition of VX-659, and 11 percent when VX-445 was the third added drug. People with one copy of ∆F508-CFTR and one copy of a different minimally functioning CF mutation—none of whom had been taking tezacaftor-ivacaftor to begin with—had an average improvement of 13.3 percent or 13.8 percent in the same test when they began taking the VX-659 or VX-445 triple combination therapies, respectively. Although these improvements may appear small, their expected health benefit is potentially significant. Importantly, neither of the three-drug combinations appears to have caused serious side effects. Based in part on these results, the FDA approved the VX-445-tezacaftor-ivacaftor triple combination for treating CF in people ages 12 and over with at least one copy of the ∆F508- CFTR variant. Further research will be needed to determine the long-term impact of this therapy on patient health, but the findings described here suggest it will provide a significant improvement in health for the majority of people with CF.

Improving Combination Therapy for Cystic Fibrosis

Researchers have developed new candidate medications that correct distinct structural defects of ∆F508-CFTR, the most common CF-causing mutation, an approach that could potentially lead to improved therapies for the great majority of people with the disease. Like many proteins, CFTR contains multiple functional elements, called “domains.” Two such CFTR domains bind to a key, channel-activating cofactor called a nucleotide, so these structural elements are referred to as nucleotide-binding domains 1 and 2 (NBD1 and NBD2). Two other structural elements are the parts of the protein that cross the cell membrane (where CFTR must be located to allow the flow of chloride ions) and are thus called membrane spanning domains 1 and 2 (MSD1 and MSD2). The ∆F508-CFTR mutation, while located in NBD1, not only destabilizes that key structural element, it also destabilizes NBD2 and the interactions of both NBDs with the MSDs. The two FDA-approved CFTR-corrector drugs, lumacaftor and tezacaftor, both work by similar means, stabilizing the interactions of NBD1 with MSD1 and MSD2. The researchers considered the possibility that restoring full or nearly full function of ∆F508-CFTR would also require stabilizing the NBDs themselves, as w ll as the interactions of NBD2 with the MSDs.

The scientists screened 600,000 different chemical compounds in human cell lines and employed a variety of techniques to identify new CFTR correctors that would act on different parts of the protein than do the existing FDA-approved agents. For example, they determined which of them allowed more of the protein to accumulate in the cell membrane of cells expressing ΔF508-CFTR that were already being treated with lumacaftor: the idea is that if the candidate drug works by a different mechanism from lumacaftor, the actions of the two together would be expected to yield significantly greater stabilization of CFTR than will either medicine by itself. They followed up with tests to determine which of the key domains of CFTR these compounds bound to, in order to separate them into groups that act on distinct portions of the protein. With such approaches, they provisionally assigned them into three classes: I, compounds like lumacaftor that stabilize the interactions of NBD1 with the MSDs; II, compounds that stabilize NBD2 or its interactions with the MSDs; and III, compounds that specifically stabilize NBD1.

While each of these compounds on its own stabilized ΔF508-CFTR just a little bit, when they combined correctors of different classes the researchers observed a synergistic increase in stability of the mutant protein. For example, if a class I and a class II corrector each improved stability by 5 percent on its own, combining them together yielded substantially more than 10 percent improvement. And indeed, by treating cells simultaneously with all three classes of corrector, the scientists were able to make ∆F508- CFTR roughly as stable as normal, healthy forms of CFTR. Importantly, even without addition of a potentiator like ivacaftor, these new triple corrector combinations also yielded near-normal CFTR function in cultured cells, and restored chloride channel function in mice that have ∆F508-CFTR in place of their normal CFTR gene. Further, the triple correctors also appeared to be effective in treating a variety of other, rarer CF-causing mutations. Clinical trials would be needed to determine whether any of these combinations is safe and effective in people with CF. If one or more of them is, it could lead to a dramatic improvement in health for people with the disease.

Sun X, Yi Y, Yan Z,…Engelhardt JF. In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis. Sci Transl Med 11: pii: eaau7531, 2019.

Davies JC, Moskowitz SM, Brown C,…Rowe SM. VX16-659-101 Study Group. VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 379: 1599-1611, 2018.

Keating D, Marigowda G, Burr L,Taylor-Cousar JL. VX16-445-001 Study Group. VX-445-tezacaftor-ivacaftor in patients with cystic and one or two Phe508del alleles. N Engl J Med 379: 1612-1620, 2018.

Veit G, Xu H, Dreano E,…Lukacs GL. Structure-guided combination therapy to potently improve the f CFTRs. Nat Med 24: 1732-1742, 2018.

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