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Vertex’ Newly Approved Cystic Fibrosis Drug Illustrates Hopes and Challenges of Treating Rare Diseases


By Olivier Morteau 

February 1, 2012 | As expected, Vertex Pharmaceuticals has received FDA approval for Kalydeco (ivacaftor, VX-770), a drug that treats a minority of cystic fibrosis (CF) patients with a specific mutation in the CFTR gene. 

Last December, FDA decided to grant priority review for Kalydeco, targeting April 2012 for its approval. Kalydeco becomes the first drug ever to treat the underlying cause of CF by improving the activity of the defective CFTR protein. However, it only targets a specific mutation of the CFTR gene, G551D, present in a small percentage of patients.  

The Kalydeco approval raises new hopes for CF patients, the most common recessively inherited genetic disorder among people of European descent, affecting about 30,000 people in the United States and 70,000 worldwide. The gene was co-discovered by NIH director Francis Collins in 1989, but a cure has proven elusive – although life expectancy of CF patients has roughly doubled due to improvements in antibiotic treatment, but remains below 40 years of age.  

The CFTR gene produces a protein located in the membrane of cells lining the airways and other organs that pumps chloride ions. In CF patients, the pump malfunctions, preventing chloride secretion. This results in a sticky, abnormal mucus that clogs the lungs and pancreas, and proves an ideal breeding ground for the dangerous Pseudomonas aeruginosa bacteria.  

In a Phase 3 trial in young CF patients, published in November in The New England Journal of Medicine, Kalydeco improved pulmonary function by more than 10% within two weeks, and the effect was sustained after a year. The drug also reduced helped patients gain weight and decreased the telltale concentration of sweat chloride. The drug also showed an excellent safety profile, with a similar incidence of adverse events with the drug and with the placebo. 

More than 1,700 mutations have been identified in CF patients. The most common, F508del, occurs in 70% of patients, whereas the G551D substitution only occurs in 4% of patients.  

The common F508del mutation impairs the intracellular processing of CFTR and hinders its delivery to the cell surface. By contrast, the G551D mutation does not interfere with CFTR delivery to the membrane, but rather impairs the protein’s channel function.  

Kalydeco was discovered via high-throughput screening (HTS) of 228,000 chemically diverse compounds using a cell-based membrane potential assay based on fluorescence resonance energy transfer (FRET). (In FRET, energy is transferred from a donor fluorescent molecule in an excited state to a nearby acceptor fluorescent molecule.) HTS selection of CFTR potentiators was followed by lead optimization using analog synthesis, i.e. synthesis of compound variants that displayed increased efficacy, in vitro selectivity, and pharmacokinetic profile. 

Vertex is also developing VX-809, a CFTR corrector designed to help the protein reach the cell surface, and is conducting a Phase II clinical trial to assess the safety and efficacy of a Kalydeco/VX-809 combination therapy in patients with the F508del mutation. 

Cost of Care 

The Kalydeco story invites a more general debate on the future of personalized medicine and the treatment of rare diseases. Francis Collins estimates that 6,000 of the 7,000 known human diseases worldwide are rare diseases, and that almost 25 million Americans suffer from rare diseases.  

As the highly respected biopharma communications expert Adriana Jenkins emphasized in a poignant article (‘A Dying Wish,’ Forbes, Feb 28, 2011), shortly before her death from cancer, a major challenge of personalized medicine will be how to make drugs affordable to niche patient populations, given the small market size and the expectations from drug companies to recover their long-term, costly investments.  

The 1983 Orphan Drug Act allows FDA to offer drug companies incentives including fast-track review and market exclusivity for several years after approval. In addition, the CF Foundation has invested $75 million in the Vertex CF drug program. Nevertheless, Kalydeco will be an expensive medication, with a current annual estimate of $294,000 per patient. Analysts forecast a potential $500 million in annual sales for Vertex. The company announced it would provide the drug free of charge for households with a yearly income of $150,000 or less. For the others, Vertex would cover up to 30% of the drug’s list price. 

In her Forbes commentary, Jenkins described how Herceptin increased her own life expectancy following diagnosis with HER2+ breast cancer. One way to make personalized medicine drugs affordable for these patients, Jenkins suggested, would be to give similar incentives to companies as those provided by the Orphan Drug Act. 

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