Kalydeco: Science at Its Best

I read with a personal interest the approval of Kalydeco (ivacaftor) this week for treatment of the 4% of cystic fibrosis patients carrying the G551D mutation. My first wife Lenore had cystic fibrosis and died at age 26. At that time in 1983 we knew a great deal less about CF than we know now. The introduction of Kalydeco this week brings several key issues in health care to the forefront. Development of drugs to treat disorders with a limited number of patients to use the drug can make the cost to each individual seem crazy expensive. The specific direct targeting of Kalydeco at a specific gene mutation is possibly an indicator of personalized treatments for more common disorders in the future. The whole fast-track process used by the FDA in approval of Kalydeco is an example of their faster approval of some drugs working as promised.

In the years since Lenore’s death CF has been found to be caused by a mutation in the cystic fibrosis trans-membrane conductance regulator  (CFTR) gene that regulates ion transportation (ions like chloride hence the traditional sweat chloride test for CF) and therefore fluid flow within cells. One specific mutation is the G551D mutation (substitution of aspartic acid for glygine at position 551), and the new drug Kalydeco specifically targets the abnormal protein in these specific CF patients. Kalydeco helps the defective protein work more normally, and so reduces the abnormalities in CF patients with this specific mutation.

Unfortunately only about 1 in 25 CF patients have this specific mutation in the CFTR genetic code. The rest have some combination of the other at least 1000 known mutations. The most common CFTR mutation is called F508del (a 3 nucleotide deletion at location 508 leading to a missing phenylalanine amino acid “F”) and about 1 in 30 Caucasians have this specific mutation in the CFTR gene. Kalydeco is not effective in patients who are homozygous for the F508del mutation.  This homozygous F508del mutation is the most common genetic code in CF patients. IN the 4% of CF patients with at least one copy of the G551D mutation Kalydeco has been shown to be effective in reducing CF symptoms, and is an exciting breakthrough.

Patients with the G155D mutation produce a protein that is able to make it to the cell membrane, where Kalydeco allows it to function much more normally.  In patients with the F508del mutation the protein fails to fold in a way that allows it to move to the cell membrane, and so a drug like Kalydeco cannot function.  Scientists are working on possible medications that could allow the migration of the other defective genes to the cell membrane where use in combination with Kalydeco could potentially be effective.

It is exciting not just for the 1200 U.S. patients with this specific type of CF, but also because it is an example of how genetic research, gene analysis in genetic disorders, and great basic science can lead to novel therapy for genetic disorders.

The rapid approval of Kalydeco is a great example of the new expedited FDA approval process for drugs that have the potential to be novel or breakthrough products where there is currently no effective therapy, or the drug is a major advance in therapy.  It took only 3 months for Kalydeco to get FDA approval, even faster than the promised fast-track approval promised for special circumstance drugs.

The catch in this whole process is the incredible anticipated cost of Kalydeco.  In a Wall Street Journal article the estimated annual cost of Kalydeco is reported to be $294,000.  Since the anticipated number of patients eligible to receive this orphan drug is so small, and because of the novel and documented improvements demonstrated in patients using Kalydeco it is expected that insurers will pay for the cost of the medication. If all 1200 eligible patients take Kalydeco the annual cost at this price would be $353 million annually.  Still this price is not Guinness world record. Two more expensive drugs are Soliris for a rare condition parosysmal nocturnal hemoglobinuria at $409K annually and Elaprase for the rare genetic disorder Hunter Syndrome , a polysaccharide storage disorder, at $375K annually. These are examples of orphan drugs with very limited markets where the cost of development is shared by very few patients.

I look forward to seeing more examples of genetic research leading to personalized medications for individuals.

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