On January 31, 2012 a milestone was reached in the history of cystic fibrosis. The FDA approved Kalydeco (ivacaftor) from Vertex Pharmaceuticals (VRTX), for the treatment of patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene.
Kalydeco is the first drug which treats the underlying cause of the illness instead of the symptoms.
Life expectancy has improved somewhat with conventional products such as inhaled medications that break up mucus, antibiotics that fight infections, and saline solutions that act as expectorants. These products, however, provide only symptomatic relief.
Kalydeco is a pill taken twice daily. It helps the protein made by the CFTR gene function better and as a result, improves lung function. Other negative effects of the disease such as weight loss are also mitigated.
Kalydeco carries a steep price tag: $294,000 per person for a year's supply, making it the 8th most expensive drug in the U.S.
Newer, personalized drugs tend to be hugely expensive, since they address a very small market of people with life-threatening illnesses and probably would not exist without the FDA's orphan-drug designation.
FDA approval was based on two 48-week, placebo-controlled clinical studies involving 213 patients. One trial included patients aged 12 years and older, and another involved patients aged 6 to 11 years. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.
Cystic fibrosis is an inherited, life-threatening disease that clogs airways with thick mucus, inviting bacterial infections and progressively robbing patients of their ability to breathe. The condition affects some 30,000 patients in the U.S. and a total of 70,000 world-wide. CF is the most common fatal genetic disease in the Caucasian population.
There is no cure.
CF patients' median lifespan even now is 37, and many die in their teens.
CF is caused by mutations in a specific gene that encodes for a protein called CFTR, which regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.
The gene was discovered in 1989.
Twenty long and painful years elapsed before a clinically useful drug was developed.
Scientists spent years trying to understand how the gene caused problems. Once they had, they attempted gene replacement, which turned out to be unsuccessful (although doctors are still experimenting with this technique in the UK).
Eventually scientists decided to concentrate on the development of small molecules, with Kalydeco the first success.
The CF gene can have more than 1,000 possible mutations, and G551D causes only 4% of the cases in the U.S.; in other words only about 1,200 people are affected, making the market for the drug small. But for these 1,200 people, Vertex's drug Kalydeco is a godsend.
Each CF mutation occurs in a large gene that encodes a protein (of 1480 amino acids) called the cystic fibrosis transmembrane conductance regulator (CFTR). The protein is responsible for transporting chloride ions through the plasma membrane. Unlike sickle-cell disease, no single mutation is responsible for all cases of cystic fibrosis.
People with cystic fibrosis inherit two mutant genes, one from each parent, but the mutations need not be the same.
However the global cystic fibrosis market would be much larger, if treatment were found for other mutations.
According to market research, the size of the global CF market was $1.1 billion in 2010.
It is estimated that this market will reach $2.5 billion by 2018, at a combined annual growth rate of 10.7%.
Although the global therapeutics market is currently dominated by Novartis (NVS) and Roche (OTCQX:RHHBY), it is believed that companies such as Vertex, privately held PTC Therapeutics, and Cystic Fibrosis Foundation Therapeutics (a non-profit), with their new therapeutic products in the pipeline, will gain a larger share soon.
Kalydeco was approved on January 31, 2012 and the company reported $18.4 million in net product revenues from the drug for the first quarter of 2012 (which in this case consisted of 2 months).
Vertex reported that approximately 600 people have started treatment with Kalydeco since it received FDA approval.
Approval in Europe is expected in the third quarter of 2012.
Now the attention has shifted to the 90% of cystic fibrosis sufferers who have a mutation called F508del, which results in proteins that do not fold into their proper shape and are thus targeted for degradation, reducing the number of channels.
This is a harder problem to fix than that caused by the G551D mutation.
Patients with the G551D mutation have sufficient CFTR proteins on the surface of cells but the proteins are damaged and don't work correctly. Kalydeco is a "potentiator" designed to improve the function of the damaged CFTR proteins.
Patients with the more common F508del mutation have missing or insufficient CFTR proteins on the surface of cells so merely improving the function of these proteins is not enough to reverse the course of the disease. VX-809, another Vertex compound, is therefore designed as a "corrector" drug that increases the amount of CFTR protein on the cell surface.
Reduced chloride content in sweat is a laboratory marker of improved CFTR protein function and is correlated with improved lung function, the most important outcome for CF patients and the endpoint considered by the FDA to approve new drugs.
In 2011 early tests of combination VX-809 with Kalydeco reduced the amount of chloride in sweat - but not by enough. (As reported by Vertex in November 2011 about the results of a first part of a phase 2 trial).
While Kalydeco nearly halves the chloride content of sweat in people with G551D, the combination therapy cut it by only 13% in those with F508del.
Some have suggested the dose used was not high enough. A larger dose is now being tested in a clinical trial, with results expected later in 2012.
If the data are positive, Vertex is expected to move the Kalydeco-VX-809 combination into phase 3 studies.
There are many other approaches; all in all more than 30 new drugs are in trials for the treatment of cystic fibrosis.
PTC Therapeutics, based in South Plainfield, New Jersey, is developing ataluren or PTC124.
People with cystic fibrosis have what is called a nonsense mutation.
Nonsense mutations create a premature stop signal in the messenger RNA. This premature stop signal causes the ribosome to halt translation before a functioning protein is generated, creating a shortened, non-functioning protein.
The resulting protein cannot be expressed in its entirety and is no longer functional.
Ataluren overrides the premature stop signal, enabling the synthesis of a functioning protein. Ataluren does not alter the patient's genetic code or introduce genetic materials into the body.
PTC124 has shown promise in animal models of cystic fibrosis and phase 3 clinical trials are now being conducted on humans.
In April 2012 PTC published data from the phase 2 study in the European Respiratory Journal. The three-month data showed that treatment with ataluren resulted in statistically significant improvements in chloride channel activity and lung function, and a reduction of CF-related coughing.
Pharmaxis, an Australian company, markets Bronchitol, a remedy created in an Australian laboratory and manufactured in Sydney.
Bronchitol is a dry powder form of mannitol (an osmotic agent) that is inhaled and helps rehydrate CF secretions, thereby improving airway clearance.
Bronchitol, after completing two large multinational Phase 3 trials (NCT00446680 and NCT00630812), was approved for the treatment of CF in Australia and Europe. It has been submitted for FDA approval.
Because of mannitol's osmotic properties, it promotes the movement of fluid from the intracellular into the extracellular space. In emergency care, mannitol is used in the treatment of closed head injuries to decrease cerebral edema and intracranial pressure, and in the promotion of urinary excretion of toxic substances.
Arikace is a liposomal amikacin that can be inhaled by Cystic Fibrosis patients with Pseudomonas aeruginosa lung infections.
Pseudomonas aeruginosa is a Gram-negative bacterium commonly found in soil and ground water. It rarely affects healthy people. An opportunistic pathogen, P. aeruginosa is more likely to infect those patients already very sick and can cause a wide range of infections, particularly among immunocompromised people (HIV or cancer patients) and persons with severe burns, diabetes mellitus, or cystic fibrosis.
This phase 3 trial compares 560 mg of Arikace to TOBI, a commercially available tobramycin solution that patients inhale twice daily.
Arikace is administered once daily via the new eFlow Nebulizer System made by PARI Pharma GmbH.
eFlow Technology produces aerosols with a very high density of an active drug, a precisely defined droplet size, and a high proportion of respirable droplets delivered in the shortest possible period of time.
About 300 patients will participate in the trial. The primary endpoint is a change in pulmonary function (FEV-1) measured after three 28 day on-treatment and three 28 day off-treatment cycles (about six months).
Gilead (GILD) also has a compound, GS9411, that works by blocking sodium absorption. Excessive sodium absorption from the airway is thought to contribute to airway dehydration.
A Phase 1 trial has been completed (trial NCT00800579 and others).
Also, the gene therapy approach mentioned above still has some proponents. Several institutions in the United Kingdom, working with Genzyme, now part of Sanofi (SNY) are trying to use gene replacement therapy to help the cell to express normal CFTR. They expect to receive backing from the British government for their next clinical trial.
According to its website, the Cystic Fibrosis Foundation in Bethesda, Maryland, a non-profit charity, has actively supported the development of new drugs. It has invested $75 million in Kalydeco and will receive royalties from drug sales. It also supports numerous other drug development projects.
In November 2011 the foundation signed a research agreement with Genzyme for the discovery of new drugs to treat patients with F508del, the most common mutation.
The effort will focus on identifying compounds known as "correctors," which may help the malfunctioning CFTR protein to operate correctly. Researchers will screen different compounds using compound libraries of both Genzyme and its parent company, Sanofi.
The foundation also co-sponsors a project with Pfizer in New York. Pfizer (PFE) recently bought FoldRx, a firm based in Cambridge that develops therapies for misfolded proteins. The foundation hopes that more sophisticated chemical screens, such as testing drugs in cells cultured from patients with cystic fibrosis rather than in rat cells, as was done originally, may yield greater success.