Treatment with A1-PI slows the progression of emphysema in Alpha-1 antitrypsin deficiency

Treatment with an Alpha-1 proteinase inhibitor (A1-PI), a naturally occurring protein that protects lung tissue from breakdown and protects the lung's elasticity, is effective in slowing the progression of emphysema in patients with Alpha-1 antitrypsin deficiency (AATD), a life-threatening genetic disorder, according to a new study presented at the 2013 American Thoracic Society International Conference.

The study showed the efficacy of A1-PIin preventing the loss of lung tissue as measured by computed tomography (CT) scan lung density at full inspiration (TLC), which is a more sensitive measure of disease progression than conventional parameters.This is the first prospective study to demonstrate the efficacy and safety of augmentation therapy in a randomized, placebo-controlled trial using this parameter.

"Our experience of the last quarter century has been that augmentation therapy is associated with better preserved lung function and reduced mortality, " said lead author Kenneth R. Chapman, M.D., director of the Asthma and Airway Centre of the University Health Network, in Toronto. "This randomized, placebo-controlled trial using a sensitive measure of lung density adds the most rigorous evidence to date that augmentation therapy slows the progression of emphysema in patients with Alpha-1 antitrypsin deficiency. The effect of A1-PI seen in this trial was both clinically and statistically significant, finally confirming its benefit in preventing the loss of lung tissue in patients with this potentially debilitating disease."

Chapman added that preliminary data from an extension trial suggest that early treatment with A1-PIshows persistent efficacy in patients with AATD and emphysema. In both the A1-PI and placebo groups who elected to continue treatment withA1-PI 60 mg/kg weekly, the benefit in CT scan lung density decline continued.

AATD is a hereditary condition that can severely affect a patient's lung function. The condition is marked by a low level or absence of A1-PI, a natural protein that protects the lung from breakdown by inhibiting neutrophil elastase, and protects lung elasticity. AATD can lead to emphysema at a young age (<45 years of age), especially among smokers, and progressive loss of lung function that can significantly impact everyday life and life expectancy.

There is no cure for AATD, but there are treatments for the symptoms of the disease, including bronchodilators and inhaled steroids, which help open the airways. Augmentation therapy, which is administered intravenously, has been shown to slow or halt the destruction of lung tissue in AATD.

The current trial, the largest clinical trial of this treatment to date, was a randomized, placebo-controlled, double-blind, multinational, multicenter phase III/IV study comparing the efficacy and safety ofA1-PIwith placebo in 180 subjects with emphysema due to AATD. Patients received A1-PIintravenously 60 mg/kg weekly or matching placebo over two years. The effect ofA1-PI on the progression of emphysema, the primary endpoint of the study, was assessed by the decline of lung density, measured by CT scan. Key secondary endpoints included changes in exercise capacity, symptoms score and rate of pulmonary exacerbations over two years.

There was no difference between groups in baseline characteristics: mean age 53.1 +/- 7.4 year; forced expiratory volume in 1 second (FEV1) 48.9 +/- 11.7%. According to study findings, the annual rate of lung density loss was significantly less in A1-PI-treated patients (-1.45 +/- 0.24 units vs. -2.19 +/-0.25 units; p = 0.017, one sided). Secondary outcome variables and the few adverse reactions reported were not significantly different between groups.

"The augmentation treatment used in the current study is not known to have a role in emphysema caused by tobacco smoking unrelated to alpha-1 antitrypsin deficiency, and our findings apply to a particular type of genetically-related emphysema," said Dr. Chapman. "Furthermore, our findings show preservation, but not restoration, of lung tissue. That is, the treatment slows the damage for people with alpha-1 antitrypsin deficiency but does not repair the damage."

"Although augmentation therapy has been well accepted in the United States, it has been slow to gain acceptance in other countries where augmentation therapy may be unavailable and/or unfunded. Our positive findings may encourage more widespread use of this treatment," said Dr. Chapman.

"With 2013 marking the 50th anniversary of the discovery of Alpha-1 antitrypsin deficiency, we are excited to now have confirmation of the clinical efficacy of this therapy in reducing the loss of lung tissue in Alpha-1 patients who have emphysema, " said Gerry McElvaney, professor of medicine at Royal College of Surgeons of Ireland, and principal investigator of the trial.