To explain the many challenges involved in turning scientific discoveries into treatments and cures, I often say, “Research is not a 100-yard dash, it’s a marathon.” Perhaps there is no better example of this than cystic fibrosis (CF). Back in 1989, I co-led the team that identified the cystic fibrosis transmembrane conductance regulator (CFTR) gene—the gene responsible for this life-shortening, inherited disease that affects some 70,000 people worldwide . Yet, it has taken more than 25 years of additional basic, translational, and clinical research to reach the point where we are today: seeing the emergence of precise combination drug therapy that may help about half of all people with CF.
CF is a recessive disease—that is, affected individuals have a misspelling of both copies of CFTR, one inherited from each parent; the parents are asymptomatic carriers. The first major advance in designer drug treatment for CF came in 2012, when the Food and Drug Administration (FDA) approved ivacaftor (Kalydeco™), the first drug to target specifically CF’s underlying molecular cause . Exciting news, but the rub was that ivacaftor was expected to help only about 4 percent of CF patients—those who carry a copy of the relatively rare G551D mutation (that means a normal glycine at position 551 in the 1480 amino acid protein has been changed to aspartic acid) in CFTR. What could be done for the roughly 50 percent of CF patients who carry two copies of the far more common F508del mutation (that means a phenylalanine at position 508 is missing)? New findings show one answer may be to team ivacaftor with an experimental drug called lumacaftor.
Reporting in The New England Journal of Medicine, the TRAFFIC and TRANSPORT Study Groups—a large international team that includes researchers funded by the Cystic Fibrosis Foundation and NIH—recently presented results of two Phase III clinical trials of lumacaftor-ivacaftor therapy . The trials involved more than 1,100 CF patients, age 12 and older, all of whom have two copies of the F508del mutation.
Over the 24-week study period, researchers found that patients randomly assigned to receive lumacaftor-ivacaftor therapy fared significantly better than a matched control group assigned to placebos. For example, compared to the controls, CF patients receiving lumacaftor-ivacaftor therapy were more likely to show significant improvements in lung function and less likely to develop lung infections. In addition, members of the combination therapy group required fewer hospital visits and fewer treatments with IV antibiotics, plus some began to gain weight—a challenge for many people with CF.
Lumacaftor-ivacaftor therapy also appears relatively safe: no deaths were reported during the study. Based on these and other scientific data, an expert advisory panel recently recommended the FDA approve the drug combination, which has been named Orkambi™ by its developer, Vertex Pharmaceuticals Inc., Boston .
So, how does this new drug duo work? Each drug targets a specific way in which mutations can disrupt the CFTR protein’s normal function, which is to sit in the membrane of epithelial cells and act as a gated channel that allows chloride ions to pass in and out of the cell. If this function is disrupted, water and salt equilibrium is upset, and thick mucus can clog the lungs and obstruct the pancreas, leading to life-threatening lung infections and malnutrition.
The common F508del mutation causes the CFTR protein to be so badly misfolded that it gets hung up in the processing system within the cell, failing to reach the cell’s membrane. On the other hand, the rarer G551D mutation allows the CFTR protein to reach its destination properly and form a gated channel—but these channels don’t open and close properly.
In patients with F508del mutations, lumacaftor works to assist the folding process and ferry the CFTR protein to the place it belongs in the cell membrane. There, the protein has the potential to form gated channels, but ivacaftor provides an extra boost by improving the ability of those channels to open and close (which happens to be the same mechanism by which the drug helps CF patients with G551D).
While this is a major advance, it must be noted that the lumacaftor-ivacaftor combination treatment doesn’t work as well for CF patients with F508del as ivacaftor alone does for those with G551D. Efforts are under way to find other drugs that do a better job of correcting the folding problems of the F508del mutation, and one of those next generation compounds already appears promising in early clinical trials.
Meanwhile, lumacaftor-ivacaftor trials are ongoing, evaluating whether the early benefits of the drug combo will hold up over the longer term. Other trials are testing the safety and efficacy of the drugs in CF patients under the age of 12—with the goal of finding ways to protect the children’s lungs, pancreas, and other organs early on before they are weakened and damaged.
To reap the full benefit of the new targeted treatments, researchers emphasize that all CF patients (just like those participating in the TRAFFIC and TRANSPORT clinical trials) will need to continue the standard interventions recommended by their physicians, such as inhaled medications, antibiotics, nutritional measures, and chest physical therapy. Indeed, the potential for positive synergies between new and existing approaches to healthcare is something to keep in mind as we move forward with the Precision Medicine Initiative and efforts to develop targeted ways of helping folks with a great many other diseases.
 Identification of the cystic fibrosis gene: chromosome walking and jumping. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Science.1989 Sep 8;245(4922):1059-65.
 FDA approves Kalydeco to treat rare form of cystic fibrosis. U.S. Food and Drug Administration (FDA). January 31, 2012.
 Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. Wainwright, CE, Elborn, JS, Ramsey, BW, Marigowda, G, Huang, X, Cipolli, M, Colombo, C, Davies, JC, De Boeck, K, Flume, PA, Konstan, MW, McColley, SA, McCoy, K, McKone, EF, Munck, A, Ratjen, F, Rowe, SM, Waltz, D, Boyle, MP. N Engl J Med. 2015 May 17. [Epub ahead of print]
 Cystic fibrosis drug wins approval of FDA advisory panel. The New York Times. May 12, 2015.
What Is Cystic Fibrosis? (National Heart, Lung, and Blood Institute/NIH)
A Study of Lumacaftor in Combination With Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older Who Are Homozygous for the F508del-CFTR Mutation (TRANSPORT). Clinicaltrials.gov. March 4, 2013.
NIH Support: National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases