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| |  Retinoid Receptor Agonist Lacks Efficacy in Selected Emphysema Patients: Presented at ERS By Evelyn Harvey VIENNA, Austria -- September 16, 2009 -- A trial of palovarotene, a novel retinoid receptor agonist, in patients with alpha-1 antitrypsin deficiency (AATD) emphysema has produced disappointing results -- with some indication of decreased total lung capacity but no significant improvements in lung function, researchers reported at the 19th Annual Congress of the European Respiratory Society (ERS). Presenter Jan Stolk, MD, PhD, Leiden University Medical Center, Leiden, the Netherlands explained here on September 14 that retinoid receptor agonists have been developed in rat models of emphysema and were shown significantly to restore elastin content, alveolar structure, and lung function. The Retinoid Treatment of Emphysema in Patients on the Alpha-1 Antitrypsin International Registry (REPAIR) study recruited 262 patients with AATD emphysema confirmed by computed tomography. AATD subjects were chosen due to the rapid progression of emphysema at a relatively young age and subsequent lack of comorbidities. In the treatment group, 129 subjects received palovarotene 5 mg/day for 1 year, while placebo was given to 133 control patients. Baseline characteristics, including medication profiles, were similar between groups. Measurements of lung density adjusted to the 15th percentile, the test of lung function for carbon monoxide (Tlco) and forced expiratory volume in 1 second (FEV1) were found to be the most reproducible measures of efficacy. The results for lung density, the primary efficacy parameter, were not significant, with a difference of only 0.3 Hounsfield units (HU) observed in the 110 completers of palovarotene treatment relative to the 117 placebo completers. Lung density declined overall in both groups. No significant differences in Tlco and FEV1 data were seen with palovarotene compared with placebo. A difference in total lung capacity of 83 mL was seen between placebo and palovarotene subjects after 1 year (P = .07). Palovarotene was well tolerated, and no clinically relevant changes were observed in laboratory parameters. A higher rate of mucocutaneous adverse events was observed in the palovarotene-treated patients (81% vs 46% in the placebo group), which led to a higher rate of withdrawal in the treated group. These effects were mild and reversible, however. "Palovarotene probably has pharmacological effects due the concordant effects on efficacy parameters," Dr. Stolk concluded. "However, 1 year of palovarotene treatment may not be sufficient for clinically relevant benefits, and a clear phenotype of responders has yet to be identified." It is also possible that the ongoing damage to the lungs occurring in the AAT-deficient emphysema patients masked the restorative effects of palovarotene seen in the animal model, where emphysema was transiently induced, Dr. Stolz hypothesised. Further trials including concomitant augmentation therapy may therefore be indicated. A 2-year trial of palovarotene treatment in 492 patients with smoke-induced emphysema is in progress. Funding for this study was provided by F. Hoffmann-La Roche Ltd. [Presentation title: Repair (Retinoid Treatment of Emphysema in Patients on the Alpha-1 Antitrypsin International Registry) Study Results. Abstract 1633]
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