Biotech Changes The Game

The FDA approval of Vertex Pharmaceutical’s (Boston, MA) Orkambi last week further shifted the paradigm of treating cystic fibrosis (CF) for up to half of its sufferers—moving from a management of symptoms approach to targeting the underlying cause. Until very recently, the only strategy against CF involved reducing the risk of lung infections by taking mucus thinning medications and antibiotics—and rarely, late stage bilateral lung transplants. CF is an orphan disease affecting around 70,000 people globally and is prevalent in America, Europe and Australia.

This WEEKLY will discuss how Vertex’s two game-changers—Kalydeco and Orkambi—target the root of the disease, and find out what’s next in line to take on Cystic Fibrosis.

Cystic Fibrosis Explained

CF is a genetic disease caused by one of several possible mutations in the gene encoding the “cystic fibrosis transmembrane conductance regulator” (CTFR) protein. The CTFR protein is critical for the production of sweat, digestive fluids and mucus. CTFR 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 will otherwise be denied entry or exit. Negatively charged chloride ions use CTFR to exit cells, and if CTFR is not functioning correctly, the chloride ions build up inside of cells. The buildup affects the fluid balance of tissue, resulting in the characteristically thick mucus seen in the lungs of CF patients, making them vulnerable to potentially fatal lung infections.

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

The mutations can be divided into two classes: those that lessen the quantity of CTFR 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 CFTR potentiators.

To The Market: Kalydeco & Orkambi

In 2012, Vertex Pharmaceuticals won 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 CTFR 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—by itself— is not helpful to patients whose mutation causes CTFR to not reach the cell surface.

When Vertex combined Kalydeco with newly developed lumacaftor, a dynamic duo was born. Coined Orkambi, the potential to benefit as many as 50% of CF patients widened the eyes of the industry. The lumacaftor portion targets the most common mutation (a single amino acid deletion in the CTFR 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 CTFR, potentially bringing positive outcomes for a big part of the CF community. 


Corbus Pharmaceuticals (Norwood, MA) is about to take a swing at Vertex’s market share thanks to their current contender, Resonab, in Phase II clinical trials. Rather than targeting the CFTR protein directly, Corbus is treating CF as a chronic inflammatory disease. This is based on the observation that children as young as four weeks old with CF have elevated levels of inflammatory markers, which further drives disease progression.

Resonab is an oral anti-inflammatory—it works by binding to and activating the CB2 receptor, which is 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, 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.

On The Horizon: Spyryx Biosciences

Spyryx Bioscience (Durham, NC) is taking a different approach to treating CF—a tactic which might also benefit the entire patient population. Their efforts are based on an observation of the link between the regulatory protein SPLUNC1 and the dehydration leading to thick mucus—the hallmark of CF. SPLUNC1 helps to modulate how much fluid is absorbed into lung cells. Spyryx is currently conducting preclinical testing of inhalable peptide therapeutics (short segments of proteins) based on the SPLUNC1 protein that will enhance the absorption of fluid into lung cells, relieving the key symptoms of CF.

The leap from simply managing CF to attacking its roots shows the amazing potential of drug development. With even more therapies in the pipeline, the ability to fight CF on all levels is the path towards shutting out the disease.

Share This