November 4, 2011 | 8:27 am

Ivacaftor – a Breakthrough in Cystic Fibrosis Treatment

Posted by Albert Fuchs, M.D.

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One of the implicit themes we were taught in medical school is that an understanding of the basic science of a disease informs and guides treatment of patients. The general philosophy that we absorbed was that an understanding of the molecular or cellular defects in a disease would explain the abnormal organ physiology which would explain the patient’s abnormal signs and symptoms. This understanding of the abnormality at a molecular or cellular level would also help discover medications that corrected or ameliorated this abnormality. Just as physics forms the foundation of chemistry which leads to organic chemistry and then to cell biology, we were led to believe that understanding physiology would form a foundation for understanding medicine.

It turns out that this beautiful philosophy is usually wrong.

One reason is that we don’t understand human physiology in nearly enough detail to understand all the mechanisms that malfunction in any disease, or to predict the effects of any treatment. A single mammalian cell is more complex than the most complicated systems engineered by people, and our understanding of the molecular mechanisms that allow cells, tissues, organs and people to function is incomplete. Just to take one example, everything we knew about how estrogen works suggested it should prevent strokes and heart attacks. It doesn’t.

Another reason that medicine is disconnected from basic science is that understanding the molecular basis of a disease frequently gets us no closer to finding a treatment. The best-known example of this is sickle cell anemia, a disease in which the abnormal gene is known, the abnormal hemoglobin molecule produced by this gene is known, the abnormal way this hemoglobin folds is known, the way this abnormal folding disrupts red blood cells is known, and the way the abnormal sickle-shaped red blood cells make people sick is known. And we are still frustratingly far from a treatment directed at the basic defect.

So medicine is usually a deeply pragmatic practice, largely separated from the basic sciences. We know what works because of trials in which medications are actually tried on patients (and first on animals), not from our understanding of molecules, cells or organs. And those medications are usually found serendipitously, not by design. The basic sciences may give us a vocabulary and an intellectual framework, but they rarely give us an actual treatment.

This week, we have a very happy exception.

Cystic fibrosis is the most common fatal genetic disorder in whites, affecting 30,000 people in the US. The gene responsible for it was discovered in 1989. In healthy people, this gene codes for an ion channel – a protein on the cell surface that controls the flow of charged atoms, like chloride and iodide, into and out of cells. In people with cystic fibrosis this protein malfunctions or is absent.

This inability of cells to pump ions where they’re supposed to go leads to an inability to secrete water (which follows the ions). This leads to many of the clinical manifestations of cystic fibrosis. Airway secretions are too dry because airway linings cannot secrete enough fluid. This creates thick mucus that is difficult to cough up, obstructs airways, and predisposes to lung infections. Pancreatic secretions are also too thick, destroying the pancreas.

Patients frequently lose weight because of recurrent infections and because of malnutrition caused by pancreatic failure. They develop progressive decrease of their lung function and eventually succumb to respiratory failure or infection. Forty years ago the median survival age was 11. Now, with better treatment of infections and drugs aimed and loosening secretions, median survival is 37.

Ivacaftor is a medicine that was designed specifically to treat cystic fibrosis. It is a molecule that was designed to keep dysfunctional ion channels open. That means it is only useful for the 4% of cystic fibrosis patients with the specific mutation that causes ion channels to be present, but not working. This week The New England Journal of Medicine published a study testing the effects of ivacaftor in cystic fibrosis patients with this specific mutation.

167 patients were randomized to ivacaftor or to placebo. The differences between the two groups were striking. The ivacaftor group gained weight, had improvement in lung function, and had fewer respiratory exacerbations. The benefits started within two weeks of treatment and persisted for the duration of the trial. And the trial found no serious side-effects.

It’s hard to overstate the significance of this development. For newborns with this specific mutation, ivacaftor may completely reverse their disease. There is reason to hope that if the disease is treated prior to permanent lung and pancreas damage, people will live entirely normal lives apart from taking a pill twice a day. Obviously, more work must be done to substantiate this, as well as to find similar treatments for the cystic fibrosis patients with other mutations.

This is a breathtaking improvement in the care of a disease that was recently a death sentence, and it is a beautiful demonstration that understanding a disease at the molecular level can actually lead to an effective treatment.

Learn more:
Cystic fibrosis drug ivacaftor offers patients new hope (LA Times)
A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation (New England Journal of Medicine article)
Therapy for Cystic Fibrosis — The End of the Beginning? (New England Journal of Medicine editorial)

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