title: Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema.
abstract: Emphysema is characterized by the destruction of alveoli and alveolar ducts within the lungs. Retinoid signaling is believed to play a role in alveologenesis, with the retinoic acid receptor gamma thought to be required for alveolar formation. Based on this hypothesis, Roche Holding AG is developing palovarotene (R-667, RO-3300074), a selective retinoic acid receptor gamma agonist for the treatment of emphysema. In small animal studies, palovarotene was claimed to reverse the structural, functional and inflammatory features of cigarette smoke-induced emphysema. Phase I clinical trials of palovarotene in patients with emphysema demonstrated that the drug is well tolerated, with improvements observed in markers of emphysema progression. Unlike all-trans retinoic acid, the pharmacokinetic profile of palovarotene appears to be dose-proportional. At the time of publication, a phase II, placebo-controlled trial was ongoing, and was expected to report prospective measurements of exercise, gas transfer and lung densitometry endpoints. The development of a selective retinoic acid receptor gamma agonist for the treatment of emphysema represents the first of a new class of small-molecule regenerative therapies that may prove useful for the treatment of destructive or age-related lung disease.
authors.affiliation: Royal Brompton Hospital, Biomedical Research Unit, Department of Respiratory Medicine, and National Heart and Lung Institute, Imperial College, Fulham Road, London, SW3 6NP, UK. m.hind@imperial.ac.uk
authors.forename: Matthew
authors.initials: M
authors.lastname: Hind
authors.forename: Sian
authors.initials: S
authors.lastname: Stinchcombe
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004646:Emphysema / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D011650:Pulmonary Alveoli / Q000473:pathology; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects; D013267:Stilbenes / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000097768:Retinoic Acid Receptor gamma
chemical_list: D011720:Pyrazoles; D018168:Receptors, Retinoic Acid; D013267:Stilbenes; D000097768:Retinoic Acid Receptor gamma; C546535:Palovarotene