UCSF Researchers Drive Major Progress in Lung Disease

Idiopathic Pulmonary Fibrosis Drug Trials Hailed as ‘Major Breakthrough for Patients’; Statins Shown Ineffective in COPD, Acute Respiratory Distress Syndrome

By Pete Farley on May 18, 2014

Researchers from UC San Francisco played major roles in five significant multicenter studies of lung disease published May 18, 2014 in The New England Journal of Medicine (NEJM).

In one set of trials, three different drugs were tested in separate studies for their effectiveness in idiopathic pulmonary fibrosis (IPF), a progressive scarring disease of the lungs primarily affecting the elderly. The disease has a 3-year survival rate of about 50 percent, a worse prognosis than that for many cancers. Two new therapies, pirfendone and nintedanib, were found to significantly slow the rate of disease progression in patients with mild to moderate IPF, and one, pirfenidone, was shown to reduce the risk of death by 68 percent in patients who received the drug for 52 weeks.

Two additional trials assessed the effectiveness of statin drugs in acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). Neither statin was found to provide benefit for patients with these conditions.

The findings of all five studies are being reported at the annual meeting of the American Thoracic Society, being held this year in San Diego, Calif., from May 16 to May 21.

The pirfenidone trial was led by Talmadge E. King, Jr., MD, professor and chair of UCSF’s Department of Medicine, in his role as member of a research consortium known as the ASCEND Study Group. Though this drug, manufactured by Brisbane, Calif.-based InterMune, has been approved for IPF in other countries, it has not yet received approval from the U.S. Food and Drug Administration (FDA).

Harold R. Collard, MD, associate professor of medicine and director of UCSF’s Interstitial Lung Disease Program, was the co-lead investigator and senior author of the research on nintedanibin patients with IPF. The work was conducted by a research group known as the INPULSIS Trial Investigators.

King and Collard were also steering committee members for a study of a compound known as acetylcysteine, conducted by the Idiopathic Pulmonary Fibrosis Clinical Research Network. That trial showed no significant difference in disease progression between patients taking the drug and those receiving placebo.

Pirfenidone and nintedanib are quite likely the first effective treatments for IPF, and the trials of these two drugs were hailed in an accompanying NEJM editorial as “a major breakthrough for patients.” The success of pirfenidone and nintedanib, and the failure of acetylcysteine, suggests that “idiopathic pulmonary fibrosis is a disease perpetuated by aberrant wound healing, rather than primarily by chronic inflammation,” writes editorial author Gary M. Hunninghake, MD, MPH, of Brigham and Women’s Hospital in Boston, and this knowledge should help guide the development of future treatments.

In a fourth trial published in this week’s NEJM, UCSF’s Michael A. Matthay, MD, professor of medicine and anesthesia, Kathleen D. Liu, MD, PhD, associate professor of medicine, and Carolyn Calfee, MD, associate professor of medicine, took part in a study of the effectiveness of rosuvastatin (trade name Crestor) in ARDS. The trial, conducted by The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, failed to find any benefit from this treatment for ARDS patients.

Finally, in a study of the effectiveness of simvastatin (trade name Zocor) in COPD, Stephen C. Lazarus, MD, professor of medicine, Prescott G. Woodruff, MD, associate professor of medicine, and members the COPD Clinical Research Network and the Canadian Institutes of Health Research did not establish any clinical benefit for the drug in COPD.

Though the findings of both statin trials were negative, these results are important, said an NEJM editorial entitled “Statin Strikeout.” Both drugs, which have been approved by the FDA to reduce inflammatory responses in other conditions, have been given to patients on the theory that inflammatory mechanisms underlie both ARDS and COPD. Although the theory behind these “off-label” uses was reasonable, and clinical observations seemed to back up that theory, write Jeffrey M. Drazen, MD, and Annetine C. Gelijns, PhD, of the Icahn School of Medicine at Mt. Sinai in New York, double-blind trials were essential to establish whether these drugs really are effective in these lung diseases.