palovarotene and Emphysema

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.

Topics: Animals; Clinical Trials as Topic; Dose-Response Relationship, Drug; Emphysema; Humans; Pulmonary Alveoli; Pyrazoles; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Signal Transduction; Smoking; Stilbenes

Palovarotene is an oral γ-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 α(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 α(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 end-point; 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 placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). 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 α(1)-antitrypsin deficiency.

Topics: Adult; Aged; Animals; Double-Blind Method; Emphysema; Female; Forced Expiratory Volume; Gases; Genotype; Humans; Inflammation; Least-Squares Analysis; Male; Middle Aged; Placebos; Pyrazoles; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Smoking; Stilbenes; Tomography, X-Ray Computed

Emphysema is characterized by the destruction of alveolar wall and enlargement of alveolar airspaces, resulting in a reduction of the total lung gas exchange area, loss of lung elastic recoil and hyperinflation. The REPAIR study (Retinoid treatment of Emphysema in Patients on the Alpha-1 International Registry) is the first proof-of-concept study of a new potential disease-modifying drug, Palovarotene©, an orally active, gamma selective retinoid agonist in patients with emphysema secondary to alpha-1-antitrypsin deficiency (AATD) as a model population for the general smoke-induced emphysema population. This article describes the study design as well as the effectiveness of the quality control that was implemented on the key efficacy endpoints, based on data derived from the placebo-treated subjects. In this multicentre, multinational study the implementation of standardized procedures included: careful site selection, use of trained staff, regular monitoring and machine calibration, use of biological controls and regular feedback to sites by an independent quality control centre. All of these procedures resulted in high-quality measurements of lung density, spirometry, static lung volumes and gas transfer. It was also confirmed that CT lung density was the most sensitive endpoint followed by TLco, FEV(1) and RV measured by body box.

Topics: Administration, Oral; alpha 1-Antitrypsin Deficiency; Double-Blind Method; Emphysema; Female; Humans; Male; Middle Aged; Pulmonary Emphysema; Pyrazoles; Quality Control; Receptors, Retinoic Acid; Research Design; Respiratory Function Tests; Retinoic Acid Receptor gamma; Stilbenes