Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema

Curr Opin Investig Drugs. 2009 Nov;10(11):1243-50.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Dose-Response Relationship, Drug
  • Emphysema / drug therapy*
  • Emphysema / etiology
  • Emphysema / physiopathology
  • Humans
  • Pulmonary Alveoli / pathology
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Receptors, Retinoic Acid / agonists*
  • Signal Transduction
  • Smoking / adverse effects
  • Stilbenes / adverse effects
  • Stilbenes / pharmacology*
  • Stilbenes / therapeutic use

Substances

  • Pyrazoles
  • Receptors, Retinoic Acid
  • Stilbenes
  • retinoic acid receptor gamma
  • Palovarotene