UC Research Helps Advance Treatment of Patients With Rare Lung Disorder

CINCINNATI— Researchers at the University of Cincinnati (UC) and Cincinnati Children’s Hospital Medical Center played a pivotal role in U.S. Food and Drug Administration (FDA) approval of the drug sirolimus for the treatment of lymphangioleiomyomatosis (LAM), a rare lung disorder primarily affecting women.

"FDA approval will enhance access to this effective therapy by increasing prescriber confidence, convincing insurers to cover the cost of the treatment and facilitating approval by other governments around the world,” says Frank McCormack, MD, director of the Division of Pulmonary, Critical Care and Sleep Medicine in the UC College of Medicine.

McCormack was the lead investigator of the clinical trial that enabled the FDA ruling, announced Thursday, May 28. Pfizer Inc., the sponsor of Rapamune, previously filed the supplemental New Drug Application (sNDA) for the use of sirolimus in LAM.

"It is very gratifying to see sirolimus join the ranks as one of only a very few approved drugs for diffuse parenchymal lung disease,” McCormack says. "This approval is a testament to the power of patient advocacy and the importance of academic health centers to patients suffering with diseases too rare to attract financial interest from pharma.”

LAM is a rare but serious lung disease that affects women of childbearing age, causing progressive shortness of breath and recurrent lung collapses, or pneumothoraces. The disease is caused by invasion of the lung by mutant smooth muscle cells, which dissolve healthy lung tissue and replace it with innumerable air-filled holes or cysts.

It is estimated that LAM affects 5 women per million worldwide. The cost of sirolimus is about $6,000 per year at 2 milligrams per day, says McCormack.

LAM is typically diagnosed in patients around the age of 35, and results in breathlessness with daily activities within a decade in most patients. Median survival in LAM has been variably reported as 10 to 30 years. Until recently, treatment options have been limited to unproven anti-hormonal strategies and supportive care, with lung transplantation reserved as a last resort for advanced cases, explains McCormack.

Rapamune was previously approved to prevent the rejection of transplanted organs. McCormack, who has studied interstitial lung disease for more than 20 years, led the Multicenter International LAM Efficacy of Sirolimus, or MILES trial.

The study found that sirolimus stabilized lung function and improved quality of life and measures of functional performance in LAM patients. The results were published in the April 28, 2011, issue of the New England Journal of Medicine.

Funding for the study was provided by the National Institutes of Health Office of Rare Disease Research, the FDA, the LAM Foundation, the Tuberous Sclerosis Alliance and the Japanese and Canadian Ministries of Health, explains McCormack.

Sirolimus is not cure for LAM, but it does halt he disease’s progression, explains McCormack.

During the MILES trial the most common side effects of the drug included mucositis, diarrhea, nausea, hypercholesterolemia, acneiform rash and swelling in the lower extremities.

McCormack says the LAM Foundation’s support was a critical component of the MILES trial.

Founded by Sue Byrnes, the mother of a Cincinnati LAM patient, the foundation began organizing and educating LAM patients about the importance of trials in the mid-1990s. The organization developed an $11 million dollar research portfolio that provided the groundwork for clinical trials, and nurtured a research community that could effectively compete for NIH funding, explains McCormack.

"When basic research in fruit flies and human lung tissues revealed the obvious promise of sirolimus in LAM in the early 2000s, the LAM patient and research communities launched a trial that no pharmaceutical company would have considered financially advisable at the time given the rarity of the illness,” McCormack says.

"Physician scientists at 13 academic health centers around the world volunteered their time and conducted the trial on shoestring budget,” says McCormack.

The trial would not have been possible without the longstanding collaboration of Bruce Trapnell, MD, a pulmonologist at Cincinnati Children’s and a professor in the UC Department of Pediatrics, says McCormack. Trapnell was the principal investigator of Rare Lung Disease Consortium, which provided critical infrastructure for the trial, he says.
 
Byrnes called the FDA’s approval a "historic milestone” and astounding news for women with LAM.

"My heartfelt gratitude goes to the selfless women with LAM who participated in the MILES trial and to the foundation’s scientific director Dr. Frank McCormack for his extraordinary commitment,” says Byrnes. "No one knows better than I the overwhelming challenges he encountered along the way and the countless hours he spent to bring us to this place.”

Pfizer donated sirolimus as part of the MILES trial, and provided funding for trial visits in a grant to McCormack. The drug company did not have a role in the trial’s design or conduct, reports McCormack.

To learn more about LAM and ongoing research, visit www.thelamfoundation.org.