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.
There will be ongoing analysis of the clinical data generated from this trial to examine which patients responded to INV102 therapy and if this correlated with any of the several biomarkers measured in the sputum samples collected. The aim of the further analysis will be to determine if the company can generate further IP around predicting patient response to INV102, and also determining the best patient groups to be selected for Phase 3 trials. The study was conducted on 155 patients at multiple US trial sites, including Washington University. All patients had tried to quit smoking multiple times but were defeated by chronic “smoker’s cough” resulting from the build-up of mucus in the lungs following the last cigarette. The trial was designed to evaluate the efficacy of INV102 in improving rates of smoking cessation over a 10-12 week treatment period.
Invion’s phase II clinical trial investigating the use of INV102 in patients with mild asthma known as ‘NIMA’ (for ‘nadolol in mild asthma’) commenced in January 2015, and is operating under an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). The US National Institutes of Health (NIH) is funding the clinical trial with a non-dilutive funding contribution in excess of USD$4 million. The study of approximately 60 patients is being conducted in partnership with Baylor University (Texas), Duke University (North Carolina), and Washington University (St Louis). In September 2014, the Company provided an update on blinded interim data from the trial. Evaluation of data from the first 21 patients to have completed the study showed that patients (n=19) had tolerated titration to their highest dose without severe adverse events; that patients had shown no pattern of cardiovascular or respiratory effects during the four hours of observation required after each titration dose; that during initial titration and through the three months of stable daily dosing, patients demonstrated no requirement to increase rescue medication usage; and that no pattern of adverse events had emerged – a significant finding given that nadolol is currently contraindicated in patients with asthma due to risks associated with worsening bronchospasm.
The trial is expected to complete enrolment in 2015.
The feasibility studies for inhaled nadolol are being conducted under a collaboration with 3M Drug Delivery Systems. The collaboration encompasses manufacture for toxicology and phase I studies. In the period under review, the program has progressed with formulation and device being selected, the manufacture of supplies for toxicology and clinical studies, and the commencement of toxicology studies.