Innovative therapies targeting the root cause of cystic fibrosis (CF) hit the market several years ago, but those treatments were only for a subset of CF patients.  Now, companies like AbbVie and Vertex may have the potential to treat a large majority of the population—up to 90%—according to clinical trial data. In this issue, we’ll explain the science of cystic fibrosis and review the pipeline of hope for this orphan disease.


Cystic fibrosis is a genetic disease caused by one of several possible mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR protein is critical for the production of sweat, digestive fluids, and mucus.

CFTR is classified as a channel protein—a category of proteins that create a channel, or tunnel, across the cell membrane. This specialized gateway allows things to pass through the cell that would otherwise be denied entry or exit. Negatively charged chloride ions use CFTR to exit cells, and if CFTR is not functioning correctly, the chloride ions build up inside of cells, causing the cells to retain water. This buildup affects the fluid balance of tissue, resulting in the characteristically thick mucus seen in the lungs of CF patients, making them vulnerable to fatal lung infections.

CF is an autosomal recessive disorder, meaning if an individual has one functioning copy of the CFTR gene, they will not develop the disease and are termed “carriers.” Two copies of the malfunctioning CFTR gene (one received from each parent) means a CF diagnosis. And while CF is always caused by a mutation in CFTR, many possible mutation combinations have been associated with the disease.

Developing new drugs for CF is an example of the much talked about precision medicine initiative: determining which patient populations will best respond to a particular type of therapy based on their specific mutations.


CFTR mutations can be divided into two classes: those that lessen the quantity of CFTR proteins reaching the cell surface, and those that reduce the functioning of the proteins reaching the cell surface. Drugs that work by assisting CFTR to fold correctly and reach the cell-surface are referred to as CFTR correctors; drugs that enable CFTR to function correctly once it has reached the cell surface are called CFTR potentiators. These two different mechanisms of action are used in combination to fight CF at the cellular level.


In 2012, Vertex Pharmaceuticals (Boston, MA) made headlines by winning FDA approval for Kalydeco, ushering in the first CF drug to treat the underlying cause of the disease. Kalydeco works by binding to the misfolded CFTR protein and increasing its ability to remain open and functional on cellular surfaces—a CFTR potentiator. Although highly effective, it is only a lifesaver for approximately 10% of CF patients. Kalydeco, when used alone, is not helpful to patients whose CFTR is unable to reach the cell surface due to their type of mutation.

When Vertex combined Kalydeco with newly developed lumacaftor, a dynamic duo was born. Coined Orkambi, the combination has the potential to benefit as many as 50% of CF patients. The lumacaftor portion targets the most common mutation (a single amino acid deletion in the CFTR protein) responsible for two-thirds of CF cases. In patients carrying this mutation, the protein is so misfolded it never makes it to the cell surface. Lumacaftor is a CFTR corrector; it works by binding to and stabilizing at least some of the misfolded proteins, improving their ability to travel to the cell surface. Once there, Kalydeco kicks in and improves the function of CFTR. Orkambi was approved in 2015 and is effective in approximately 50% of CF patients.


The next generation of CFTR correctors offer more hope to the CF community, with a giant step forward in drug development. Preclinical testing of next generation CFTR correctors predict efficacy greater than lumacaftor—and these are already in clinical trials.

AbbVie (North Chicago) and Galapagos (Mechelon, Belgium) recently announced a partnership to pursue the clinical development of new CFTR correctors and potentiators. In January 2016, the first duo—GLPG222, a corrector, and GLPG1837, a potentiator—entered Phase I clinical studies. Plans are in the works to move two more candidates—a potentiator called GLPG2451 and the next generation corrector GLPG2737—into clinical testing by the second half of 2016. The testing of double and triple combinations of this batch of potentials are expected to begin in 2017. Preclinical studies indicate that a triple combination could be effective against up to 90% of CF cases!

Vertex is also working on next generation CFTR correctors, with two products in Phase I clinical testing. Plans for a triple-combination drug—using the approved therapies from their prior lineup—are also expected to be up to 90% effective for CF cases.


The direct targeting of the CFTR protein is not the only approach to CF drug discovery currently being entertained in development circles. Vertex is testing an epithelial sodium channel (ENaC) inhibitor (VX-371) in Phase II trials. In CF, ENaC is often up-regulated—meaning a patient makes much more ENaC than those not suffering from the disease. Up-regulation becomes a problem because ENaC reabsorbs sodium ions, which also results in water reabsorption, contributing to the thick mucus that causes the clinical symptoms of CF. By impeding ENaC, sodium ions are balanced which lessens the chances of severe symptoms from manifesting.

Corbus Pharmaceuticals (Norwood, MA) is treating CF as a chronic inflammatory disease. The concept is based upon observations of children with CF, as young as four weeks old, who have elevated levels of inflammatory markers which further drive the progression of the disease. Corbus’ lead compound, Resunab, is an oral anti-inflammatory that works by binding to and activating the CB2 receptor present on a variety of immune cells—think macrophages, T-cells, and B-cells. Activation of the CB2 receptor inhibits the immune function of these cells, potentially resulting in a resolution of the inflammation. Corbus is promoting the drug as a possible treatment for all CF patients, not just those with a particular type of mutation, meaning more avenues of attack.

Spyryx Bioscience (Durham, NC) has identified a tactic based on an observation that links the regulatory protein SPLUNC1 and dehydration which leads to thick mucus, the hallmark of CF. Simply put, SPLUNC1 helps to modulate how much fluid is absorbed into lung cells. Spyryx is currently conducting preclinical testing of an inhalable peptide therapeutic ( a peptide is a short segment of a protein) based on the SPLUNC1 protein that will enhance the absorption of fluid into lung cells, relieving the key symptom of CF.

The leap from managing CF to a bonafide cure has turned into an “all in” battle. With more therapies in the works, the ability to fight CF on all levels is a hopeful step towards shutting down this disease.

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