Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor

Abstract

Palovarotene is an oral c-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement.REPAIR (Retinoid treatment of Emphysema in Patients on the a 1 -antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg?day -1 palovarotene given for 1 year to 262 patients with severe a 1 -antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary endpoint; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebocorrected difference of lung density was -0.45 HU at week 28 (p50.64) and -0.25 HU at week 52 (p50.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene.Palovarotene 5 mg?day -1 over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe a 1 -antitrypsin deficiency.

Update on alpha-1 antitrypsin deficiency: New therapies

“…Retinoic acid abrogates elastase-induced emphysema in rats [69] and so was evaluated in man [70]. 133 and 129 individuals with severe α 1 -antitrypsin deficiency were randomised to placebo or 5 mg/day palovarotene (an oral γ- …”

Emerging therapeutic strategies in COPD

“…Retinoic acid is known to increase alveolar septation during lung development. A clinical trial with palovarotene failed to show significant benefit on lung density in moderate-to-severe emphysema patients with a1 antitrypsin deficiency [70].…”

Regulation of Retinoic Acid Receptor Beta by Interleukin-15 in the Lung during Cigarette Smoking and Influenza Virus Infection

“…Given the beneficial effects of RA in animal models of emphysema, the therapeutic potential of RA and RARg agonist were evaluated in human patients with emphysema that were mostly focused on patients with a 1 -antitrypsin deficiencies (57,58). Unfortunately, both of these trials failed to show significance of the benefit on the primary outcomes of lung function and density.…”