Announcement PDF INV102 (nadolol) A new approach to the treatment of chronic airway disease Treating the airway: background and rationale > Existing drugs do an excellent job in opening constricted airways: bronchodilators include b-adrenergic and anti-muscarinic drug classes > Existing drugs do an excellent job in decreasing inflammatory cells in the airway: inhaled corticosteroid (ICS) and anti-IL5 monoclonal antibody drug classes > Fixed combinations of beta agonists and ICS are the mainstay treatment of airway disease: e.g. Symbicort® and ADVAIR® > However: these drugs have had NO positive impact on death due to chronic airway disease; death is due to increased abnormal mucus and inflammation 2 Nadolol franchise: market size, relevance and interconnectedness Chronic Obstructive Pulmonary Disease (COPD) is an umbrella term used to describe chronic lung diseases that cause limitations in lung airflow. 3 The “vicious cycle” of chronic inflammatory airway disease Inflammation from: - cigarette smoke - chronic infection (C.F.) - allergen, O3 (asthma) Increased IL-8 and betaarrestin pathway activity + Increased goblet cell production/ loss of ciliated epithelial cells Changes in basal cell populations Normal Histology mucin clearance Increased damage from abnormal mucins inflammatory cells / infection Increased recruitment of inflammatory Mucous metaplasia found in COPD, asthma and CF 4 cells (PMN/EOS) total mucus Nadolol has unique properties that could treat airway disease > In cell experiments, INV102 (nadolol): > > In animal experiments, nadolol: > > > > Blocks (prevents) or reduces (treats) the increase in goblet cells caused by inflammation Blocks the b-arrestin pathway in airway b2 receptors Reduces markers of airway inflammation (IL-5) and abnormal mucus production (MUC5AC) In human studies, orally administered nadolol > 5 Blocks the b-arrestin pathway on airway epithelial cell b2 receptors (Lefkowitz) Decreases biomarkers of inflammation (IL-8) and b-arrestin pathway activation (ERK2) > Decreases airway hyper-responsiveness, a hallmark of asthma > Can be safely administered by titration to minimize risk of cardiovascular side effects Nadolol could reverse the “vicious cycle” of airway inflammation Shown in clinical trial Nadolol DECREASED IL-8 and betaarrestin pathway activity + DECREASED Mucous metaplasia found in COPD, asthma and CF goblet cell production/ loss of ciliated epithelial cells Restoration of ciliated epithelial cells mucin clearance DECREASED damage from abnormal mucins inflammatory cells / infection DECREASED recruitment of inflammatory Normal Histology 6 cells (PMN/EOS) total mucus Oral nadolol program: progress and active clinical trials and results Clinical benefits  the only drug targeted to address the unmet medical need of mucous metaplasia in the airway  targeted as an add-on to existing therapies to make them safer and more effective by reducing mucous production  targeted to assist lung healing and aid smoking cessation in patients trying to quit Development strategy  proof of concept  identify speed to market commercial strategy (smoking cessation)  identify wider use and IP opportunity (inhaled nadolol)  phase II trials in mild asthma and smoking cessation > safety and biomarker data from phase II trials underpins inhaled drug program > endpoint in smoking cessation trial leads to EOPIII / Phase III Development program  pharmacology is based on biased ligand and inverse agonist activity at beta receptor in airway  chemistry and manufacturing, including titration dose development  toxicology and metabolism profile  IND status  2 x proof of concept studies in patients with mild asthma (Hanania)  phase II in mild asthma (NIH sponsored, ongoing) & Phase II in smoking cessations (reports Q3 2015)  interim data shows clinical relevant changes in biomarkers of inflammation > 7 Final data to characterize airway epithelial response through biochemical markers; design next oral and inhaled studies; and create new intellectual property based on correlations of safety and efficacy with biochemical marker profiles. Oral nadolol: 155 patients phase II smoking cessation study reporting Q315. Leveraging the data: upcoming analysis and reporting > > 8 Third quarter planned analyses and reporting Fourth Quarter Biomarkers Combined data Report on effects of nadolol vs placebo on key biomarkers > IL-8 (neutrophil attraction) > ERK2 (beta arrestin pathway) > MUC 5AC (abnormal mucus) Secondary analysis of responders and biomarker changes - identifying markers that are/are not useful in longer term studies Smoking cessation > Report on smoking cessation rates in nadolol treatment versus placebo > Secondary analyis is on reduction versus cessation rates > > Correlation of smoking cessation/ reduction data with baseline biomarkers > Correlation of smoking cessation/ reduction data with biomarker changes > New IP prosecution Dose responses and responders as a function of dose, titration and history Nadolol franchise: progressively de-risked oral nadolol Data from current phase II trials in asthma and smoking cessation will support the development of oral nadolol as an aid to smoking cessation. Next steps: EOPII / PHIII 9 inhaled nadolol Biomarker data from oral phase II programs will support the development of inhaled nadolol to target direct treatment of the airway epithelium. Inhaled nadolol is targeted to treat COPD, asthma and cystic fibrosis. Next steps: IND and commencement of phase 1 studies Inhaled nadolol program: progress and clinical development strategy Clinical benefits  once daily dosing directly to the site of injury at 1/100 of the oral dose to mitigate systemic side effects  targeted for long term use in COPD, severe asthma and cystic fibrosis as an add-on to existing therapies to make them safer and more effective by reducing mucous production an enabling lung healing > Medium-term development: combination therapies > inhaled nadolol + LABA + ICS (Asthma) > inhaled nadolol + LAMA + ICS (COPD) > inhaled nadolol + antibiotics (CF) Status of collaboration with 3M Drug Delivery systems for proprietary formulation and device using 3M’s pressurised metered dose inhalation (pMDI) technology  Formulation and device selected  Toxicology supplies manufactured  Clinical supplies manufactured  Toxicology supplies provided to CRL (Montreal QUE); toxicology studies have commenced Development program  Pre-IND status with FDA  Commencement of toxicology studies 10 > IND submission (2016) > Phase I and Phase II clinical studies in asthma, COPD and cystic fibrosis (2016-7) Nguyen LP., et.al., 2011. Complementary anti-inflammatory effects of a β-blocker and a corticosteroid in an asthma model. Arch Pharmacol. 2011: Oct 2; Nguyen, LP, et al. (2008). Am J Respir Cell Mol Biol 38:256-262