INV102 (nadolol) – targeted to reverse the cycle of airway inflammation
INV102 (nadolol) is a beta adrenergic biased ligand (beta blocker) targeted to reverse mucous metaplasia in the airway epithelium treat chronic inflammatory airway diseases. INV102 is hypothesised to work via the inhibition of a cellular pathway (the beta arrestin pathway) that causes cells lining the lungs to change from normal to mucus-producing cells. This mechanism is completely different from drugs presently approved and indicated either for smoking cessation or the treatment of chronic respiratory disease.
Pre-clinical studies in murine models of asthma demonstrated that chronic treatment with INV102 (nadolol) resulted in healing of the airway epithelium. Two proof-of-concept phase IIa clinical trials in mild asthmatics demonstrated that 9 -10 weeks of treatment produced a dose-dependent decrease in airway hyper-responsiveness that achieved clinically significant improvement. These findings led the US National Institutes of Health (NIH) to fund a six-month phase IIb study in asthma which initiated in January 2013.
In October 2015, Invion released Phase 2 data from its Phase 2 randomised, double blinded, placebo controlled study of INV102 in smoking cessation. Summary data shows smokers administered INV102 were more likely to stop smoking completely, or dramatically reduce the number of cigarettes smoked. In addition, INV102 reduced key biomarkers MUC5AC and ERK1 in collected sputum samples – supporting Invion’s hypothesis that INV102 has a novel mechanism of action directly targeting epithelial cells lining the airway:
- INV102 was safe and well tolerated, and Invion’s proprietary titration scheme enabled patients to reach efficacious doses
- Trial subjects treated with INV102 were more likely to achieve abstinence at the conclusion of dosing (12/62, 19.3%) compared to those administered placebo (7/59, 11%)
- More patients treated with INV102 achieved a >70% reduction in cigarettes smoked compared with placebo treated patients (38/62 on INV102 and 21/59 on placebo)
- Two key markers of the beta arrestin pathway – ERK1 and MUC5AC – which are necessary for the activation of mucous metaplasia in the airway, showed the most robust changes. MUC5AC levels were reduced by 82% in INV102 treated patients, compared to 54% in placebo subjects. ERK1 levels were reduced by 47% for INV102 compared with 27% for placebo.
The feasibility studies for inhaled nadolol were conducted under a collaboration with 3M Drug Delivery Systems. The collaboration encompassed manufacture for toxicology and phase I studies.