A drug developed to fight cancer is showing early promise as a treatment for pulmonary hypertension, researchers from the University of Chicago Medical Center report May 19 at the American Thoracic Society International Conference in Toronto, Canada.
In the first human trial of sorafenib (Nexavar) as a treatment for pulmonary hypertension, eight out of the first nine patients increased their ability to exercise. Six out of nine had significant improvements in right ventricular ejection fraction, the ability of the heart to pump blood to the lungs. Four had a significant decrease in pulmonary artery pressures.
"This is not a disease where we are used to seeing people who have been stable on the strongest medications we have suddenly get better," said study author Mardi Gomberg-Maitland, MD, MSc, assistant professor of medicine at the University of Chicago. "We have drugs that may slow progression of the disease but nothing that can stop or reverse the process."
"To see these improvements in such a short time," she said, "is quite promising. Although evaluation of this drug is at a very early stage, and this study focused on safety and tolerability, we are genuinely excited about the results."
Pulmonary hypertension and cancer share certain features. Both diseases involve abnormal cellular growth. In pulmonary hypertension, these abnormal cells line the blood vessels leading from the heart to the lungs. These abnormal cells release signals that stimulate the growth of small new blood vessels. This enables the renegade cells to grow even faster, which thickens the vessel walls and reduces blood flow.
As the arteries close off, pressures within them build up. This requires the heart to pump harder to force blood through the narrowed tubes to the lungs. Eventually the heart can no longer keep up and damage to the overworked muscle begins to accumulate. Sorafenib appears to interfere with that harmful process.
The drug was originally evaluated at the University of Chicago as a treatment for kidney cancer. Gomberg-Maitland - who is married to a member of the sorafenib-cancer team - recognized with her husband that its effects also might slow the growth and thickening of the pulmonary artery walls. In an important preclinical trial, she and colleagues demonstrated that sorafenib was effective in reducing pulmonary hypertension in a rat model. With these encouraging results, they organized this trial.
The trial enrolled patients with pulmonary hypertension who had stable disease. Patients in the study continued to take their standard medications, primarily prostacyclin, in combination with sildenafil. They also took sorafenib for 16 weeks, but at doses lower than those given to cancer patients.
"All patients had some improvement," Gomberg-Maitland said. "Some had dramatic improvement."
Most patients in the trial increased their exercise capacity, as measured by time on a treadmill or a six-minute walk test. They had an eight-percent improvement, on average, in right ventricular ejection fraction, as measured by three-dimensional echocardiography. Four patients had significant improvements in the ability of the heart to pump blood to the lungs, as measured by cardiac catheterization.
For Martha Wheeler, 50, of Indianapolis, Indiana, the change in her lifestyle meant more than the study's quantifiable endpoints. Diagnosed 13 years ago, she hadn't been able to play with her granddaughter, ride a bicycle or walk for more than a minute or two. Now she can do all three, including walk three-quarters of a mile. "I can do more than that," she said, "if I push myself."