• Lower Respiratory Infections
• Pulmonary Clinical Trials
• Chronic Obstructive Pulmonary Disease

Results from the Treatment of Emphysema with a Selective Retinoid Agonist (TESRA; NCT00413205) study showed that emphysema patients had a mixed response to treatment with the retinoid agonist palovarotene. Treatment with palovarotene failed to meet the primary endpoint of improving lung function (FEV₁) in the overall analysis. However, the subset of patients with lower lobe emphysema had a significant reduction in the rate of decline in lung function.

A post hoc analysis in the lower lung suggested that palovarotene was associated with less worsening over time in most outcomes in patients with lower lung emphysema predominance. “These findings are very much post hoc and preliminary and require confirmation using a more detailed analysis of emphysema progression in different parts of the lung. However, the observations from this hypothesis-generating study do suggest that they need to be tested again but in a group of patients identified beforehand as having predominant lower lung emphysema,” said Paul W. Jones, MD, PhD, St. George's University of London, London, United Kingdom.

TESRA was a Phase 2, double-blind, randomized, placebo-controlled, multicenter trial that involved investigators at 69 centers in 12 countries. Palovarotene is an oral retinoid agonist that is selective for the gamma receptor, which is thought to play a key role in alveolar formation. In preclinical models of emphysema, the drug reduced inflammation, promoted structural repair, and improved lung function.

TESRA involved ex-smokers who had computed tomography-documented emphysema, baseline postbronchodilator FEV₁ <70% of predicted, and baseline TL_CO <70% of predicted. They were randomized 2:1 to palovarotene 5 mg/day or placebo, both in addition to optimized therapy for chronic obstructive pulmonary disease (COPD). Treatment and follow-up continued for 2 years. The primary outcome was the change in FEV₁ after 2 years.

When the trial ended, patients in the palovarotene arm had a 4.5-ml improvement in FEV₁ compared with the placebo group, a difference that failed to achieve statistical significance (p=0.86).

Four regions of interest had been identified in the lungs: upper quartile, upper half, lower half, and lowest quartile. Patients in the placebo arm had greater loss of lung function in the lower half and lowest quartile, compared with the upper half and upper quartile. A post hoc analysis of these regions of interest showed that in patients who were treated with placebo, the change in FEV₁ in the lower half of the lung averaged −56.7 ml at 12 months and −124.4 ml at 24 months and −56.2 ml at 12 months and −174.7 ml at 24 months in the lower quartile. In contrast, the rate of loss of FEV₁ in patients who were treated with paloverotene was less: lower half −33.0 ml and −40.9 ml at 12 and 24 months; lowest quartile: −56.2 ml and −46.0 ml at 12 and 24 months. A similar response pattern emerged with respect to DL_CO, 6-minute walk distance, and quality of life.

In addition to optimal COPD therapy, in patients with lower lung emphysema, palovarotene significantly reduced the decline in DL_CO and FEV₁, which may be suggestive of a disease-modifying effect.

• © 2011 MD Conference Express