Announcement PDF Investor Presentation November | 2015 Invion Limited (ASX:IVX) Clinical-stage life sciences company targeting chronic inflammation Disclaimer The information in this presentation does not constitute personal investment advice. The presentation is not intended to be comprehensive or provide all information required by investors to make an informed decision on any investment in Invion Limited ACN 094 730 417 (Company). In preparing this presentation, the Company did not take into account the investment objectives, financial situation and particular needs of any particular investor. Further advice should be obtained from a professional investment adviser before taking any action on any information dealt with in the presentation. Those acting upon any information without advice do so entirely at their own risk. Whilst this presentation is based on information from sources which are considered reliable, no representation or warranty, express or implied, is made or given by or on behalf of the Company, any of its directors, or any other person about the accuracy, completeness or fairness of the information or opinions contained in this presentation. No responsibility or liability is accepted by any of them for that information or those opinions or for any errors, omissions, misstatements (negligent or otherwise) or for any communication written or otherwise, contained or referred to in this presentation. Accordingly, neither the Company nor any of its directors, officers, employees, advisers, associated persons or subsidiaries are liable for any direct, indirect or consequential loss or damage suffered by any person as a result of relying upon any statement in this presentation or any document supplied with this presentation, or by any future communications in connection with those documents and all of those losses and damages are expressly disclaimed. Any opinions expressed reflect the Company’s position at the date of this presentation and are subject to change. Assets in development Respiratory 1. INV102 (nadolol): beta blocker being targeted to treat chronic inflammatory airway diseases (e.g. asthma and COPD). Oral INV102 is also being studied as an aid to smoking cessation. > 2. Phase 2 completed: • proof of concept in biased ligand activity • clinically efficacious in Smoking reduction and cessation INV104 (zafirlukast): leukotriene receptor antagonist (LTRA) that reduces inflammation, constriction of the airways and the build-up of mucus in the lungs Risk mitigated program including prior clinical proof of concept > Development and manufacturing collaboration with Hovione > Autoimmune 3. INV103 (ala-Cpn10): modified naturally occurring human hypothesised to maintain and restore immune homeostasis > 2 Phase 2 data completed, partnering discussions underway 3 STOP PRESS: Invion successfully completes Phase 2 study of INV102 (nadolol) to aid smoking cessation Data announced 5 October 2015: 4 > Completed Phase 2 trial data demonstrates INV102 treated smokers were more likely to stop smoking completely or dramatically reduce the number of cigarettes smoked > Data demonstrates that INV102 is a safe and effective treatment for patients with chronic bronchitis who are enrolled in smoking cessation programs > Invion is preparing an End of Phase 2 Meeting request to submit to the FDA during Q4 2015 > New data paves the way for INV102 to be developed as a novel inhaled treatment for chronic airway diseases including asthma, COPD and cystic fibrosis Milestone update: achievements in 2015 3 drug assets in 3 phase 2 clinical trials across 4 development programs  Blind-broken interim data from phase 2 smoking cessation trial of INV102 (nadolol)  Pre-IND status for inhaled INV102 (nadolol) as a potential therapy for asthma, COPD & cystic fibrosis  Manufacture of toxicology and clinical supplies and commencement of toxicology studies for inhaled INV102 (nadolol)  Completion of phase 2 clinical trial of INV103 (ala-Cpn10) in lupus patients  Data from phase 2 clinical trial of INV013 (ala-Cpn10) in lupus patients  Selection of formulation and device for inhaled INV104 (zafirlukast)  Commencement of manufacture of toxicology and clinical supplies for INV104 (zafirlukast)  Completion of dosing in phase 2 smoking cessation trial of INV102 (nadolol)  Positive safety and efficacy data from phase 2 oral INV102 (nadolol) study in patients undergoing smoking cessation  Completion of enrolment of NIH-funded phase 2 study of INV102 (nadolol) in asthma patients 5 Smoking cessation Asthma Inhaled INV102 (nadolol) Asthma COPD Cystic Fibrosis Inhaled INV104 (zafirlukast) Asthma INV103 (ala-Cpn10) Lupus (SLE) 6 NIH funded EOP2 ………….. Phase 2 ………….. Phase 1 ………….. Toxicology ………….. Oral INV102 (nadolol) Formulation development and clinical feasibility ………….. Research ………….. Pipeline: 4Q 2014 Phase 3 EOP2 ………….. ………….. Phase 2 Phase 3 Next milestone EOP2 Meeting P3 planning Smoking cessation Asthma Phase 1 ………….. Toxicology ………….. Oral INV102 (nadolol) Formulation development and clinical feasibility ………….. Research ………….. Pipeline: 4Q 2015 NIH funded Inhaled INV102 (nadolol) Enrolment complete, Reporting 2016 Pre-IND status achieved 1Q15 Asthma Tox and clinical supplies manufacture underway COPD Tox studies commenced Cystic Fibrosis Inhaled INV104 (zafirlukast) Asthma partnered with Hovione Commencement of tox studies INV103 (ala-Cpn10) Lupus (SLE) 7 Partnering Targeting chronic inflammatory airway disease INV102 (nadolol) 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 b agonists and ICS are the mainstay treatment of airway disease: e.g. SYMBICORT® and ADVAIR® and DULERA® > However: these drugs have had NO positive impact on death due to chronic airway disease; death is due to increased and abnormal mucus 9 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 10 cells (PMN/EOS) total mucus The critical role of the epithelium in severe airway disease Normal respiratory epithelium Chronic bronchitis 11 Severe asthma Cystic Fibrosis Mucus causes death due to asthma, COPD and cystic fibrosis Mucus plug in bronchus Autopsy slide from 8 year old girl with fatal asthma. Mucus is increased AND abnormal. 12 Smoking cessation, COPD and chronic airway disease: market size and interconnectedness 13 Oral or inhaled nadolol reverses epithelial changes and decreases inflammatory cytokines Control lung tissue Lung tissue of ‘asthmatic’ mice: epithelial cells have been converted to mucusproducing goblet cells. No effect of alprenolol. Lung tissue of ‘asthmatic’ mice treated with INV102 (nadolol) for 28 days: restored epithelium References: 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 14 Mechanism of action of INV102 is unique among drugs: INV102 reverses epithelial changes via inhibition of the beta-arrestin pathway in b2 airway receptors ligand The canonical cAMP-dependent pathway Adenylyl cyclase LABA INV102 Newly discovered pathway ~2000 (R. Lefkowitz) Beta-arrestin Adenylyl cyclase Asthma phenotype 15 ligand Beta-arrestin Restored epithilium INV102: reversing the vicious cycle of airway inflammation INV102 (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 16 cells (PMN/EOS) total mucus INV102: Phase 2 smoking cessation trial design INCLUSION ORAL DOSING 11-15wks WASHOUT 2wks Randomised (IWRS) Controlled Clinical Trial ENDPOINTS Primary Nadolol Treatment (n=78) % Decrease in # of 3-7wks titration & 8wks maintenance cigarettes per day during last 14 days Safety N=155 Failed to quit and chronic cough Change in FEV1, Placebo Control (n=77) exacerbations, titration & maintenance adverse events Trial conducted under Invion-sponsored IND with the the FDA Division of Anesthesia, Analgesia and Addiction Products (DAAAP). Principal Investigator: Mario Castro, MD (Washington University) 17 Phase 2 data strong confirmation of Invion’s strategy Invion hypothesis Proprietary titration scheme safe and enables subjects to reach efficacious doses of drug - no need for rescue medication INV102 therapy will lead to reduction in cigarettes smoked INV102 therapy will lead to complete abstinence in some subjects INV102 (nadolol) inhibits the beta arrestin pathway – a cellular pathway necessary for the activation of mucous metaplasia in the airway 18 Demonstrated in Phase 2 trial 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, 61% on INV102 and 21/59, 36% on placebo) 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 Leveraging the data: upcoming analysis and reporting Ongoing analysis 4Q 2015 Data reported 5 October 2015 > 19 Report on effects of nadolol vs placebo on key biomarkers > ERK1/2 (beta arrestin pathway) > MUC 5AC (abnormal mucus) > 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 > Secondary analysis of responders and biomarker changes - identifying markers that are/are not useful in longer term studies > Dose responses and responders as a function of dose, titration and history Forward strategy: progress on 3 routes to a new class of airway-specific therapy Phase 2 data validates Invion approach for directly treating the airway epithelium even in the face of ongoing insult, such as cigarette smoking 1. 2. Oral INV102 in smoking cessation is Invion’s “short path to market strategy”. > Invion proposing End of Phase 2 meeting to be convened early in 2016 > Phase 3 Program design ready for H2 2016 Inhaled INV102 > 3. 20 Data validates development plan and pathway for inhaled INV102 for asthma, COPD and cystic fibrosis where there is a substantial unmet medical need and commercial opportunity. Finalizing collaboration to design new chemical entity (NCE) that is a biased ligand and inverse agonist at the b2 receptor in the epithelium 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 + ICS (Asthma) > inhaled nadolol + LAMA or LABA (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 21 > IND submission (2016*) > Phase 1 and Phase 2 clinical studies in asthma, COPD and cystic fibrosis (2016-7*) *The information above (and where reflected elsewhere in this presentation) sets out indicative timeframes and assumes: Invion will continue to obtain the full benefit of the available R&D tax incentive for its eligible R&D activities and clinical trials; the studies will proceed based on budgeted costs, assuming normal patient recruitment and clinical trial timelines, and with no material regulatory hurdles; and ordinary R&D expenditure will continue broadly at the same levels as for past financial years INV104 (zafirlukast) Target: a novel inhaled non-steroidal anti-inflammatory treatment for asthma Target: an inhaled reformulation of a successful oral therapeutic for asthma Oral Inhaled Forms Risk of neuropsychiatric/suicide ideation events? Risk of liver toxicity ? Greater efficacy due to higher airway concentrations Potential for once a day dosing ? Potential for expanded exercise induced bronchospasm (EIB) claims ? Rapid onset-of-action for prophylaxis ? Potential claim to reduce use of Steroids/ LABA ? Potential claim for use in children >5 years ? Combination with ICS for anti-inflammatory effect? 23 Singulair Prevention Only Form FDA pre-IND established framework for reformulation of zafirlukast Agreement reached with FDA on: > > > 24 chemistry manufacturing and controls (GMP) > active pharmaceutical ingredient (API) with drug master file (DMF) > formulation: dry powder inhaler (DPI) approved for development toxicology and bioanalytical assay (GLP) to support 4 weeks’ dosing > 2 species for 28 days: naso-pulmonary exposure > 1 species for 6 months IND submission and clinical program > phase 1: single rising dose study for safety (paradoxical bronchoconstriction) and pharmacokinetics > phase 1: multiple dose safety study for safety (paradoxical bronchoconstriction) and pharmacokinetics > phase 2: challenges to reprise previous studies: cold air, exercise and allergen [cat and ragweed]; steady state dosing for signs and symptoms of asthma [diary card] and attenuation of response to exercise and/or allergen About Hovione and the XCaps inhaler > International company with over 50 years’ experience in the development and compliant manufacture of active pharmaceutical ingredients and drug product intermediates > With four FDA inspected sites in the U.S., China, Ireland, and Portugal, the company focuses on the most demanding customers, in the most regulated markets > In the inhalation area, Hovione is the only independent company offering such a broad range of services. POWDAIR® is a patent protected device filed and granted in over 40 countries, including US (US 8677992) and EU (EP 2546460). POWDAIR® device is simple, reusable and low-cost. This DPI is indicated for applications where a chronic or a medium term acute capsule based delivery of an API is needed. 25 Targeting chronic inflammation caused by autoimmune disease INV103 (ala-Cpn10) INV103 (ala-Cpn10): background and rationale > > > > Minimally modified form of naturally occurring protein Maintains heptameric structure and function Intracellular function: prevent protein misfolding Extracellular function: Cpn10 proposed as a founding member of the Resolution Associated Molecular Pattern (RAMPs) family (Shields et al, Clin Exp Immunol, 2011, 165: 292-300) a critical component of prevention of autoimmunity > Significant clinical data base > 250 patients > demonstrated anti-inflammatory and immunoregulatory activity in multiple indications including RA, psoriasis > Strong pre-clinical data in lupus animal model (3 studies) > 27 reduced renal and circulating levels of key pro-inflammatory mediators (TNF-α, IL-6 and MCP-1) reduced CD4+ T cells and auto-reactive T cells and increased the number of activated DC (critical in the establishment of self tolerance) > Toxicology support through 3 months’ dosing > Intellectual Property position: composition of matter protection in all major markets (US 2026) INV103 (ala-Cpn10): phase 2 lupus data 28 > Three sets of data were reviewed from subjects who received twice-weekly doses of 10, 30 or 100mg of ala-Cpn10, or placebo > INV103 (ala-Cpn10) well tolerated at 3 and 10 times previous highest dose > 10mg iv twice weekly showed no effect on stimulated peripheral blood mononuclear cells (PBMC) production of 3 key cytokines (IL-1Beta, IL-6 and TNF-alpha) at 1 month of dosing > In contrast, 30mg and 100mg iv twice weekly showed reduced response to stimulation by LPS after 1 month of dosing > These data reflect relevant activity at the target cell type in patients with a target (autoimmune) disease > Extending these findings will require a partner. Data is now being provided to pharma groups with a view to partnering the program Milestone update: achievements in 2015 3 drug assets in 3 phase 2 clinical trials across 4 development programs  Blind-broken interim data from phase 2 smoking cessation trial of INV102 (nadolol)  Pre-IND status for inhaled INV102 (nadolol) as a potential therapy for asthma, COPD & cystic fibrosis  Manufacture of toxicology and clinical supplies and commencement of toxicology studies for inhaled INV102 (nadolol)  Completion of phase 2 clinical trial of INV103 (ala-Cpn10) in lupus patients  Data from phase 2 clinical trial of INV013 (ala-Cpn10) in lupus patients  Selection of formulation and device for inhaled INV104 (zafirlukast)  Commencement of manufacture of toxicology and clinical supplies for INV104 (zafirlukast)  Completion of dosing in phase 2 smoking cessation trial of INV102 (nadolol)  Positive safety and efficacy data from phase 2 oral INV102 (nadolol) study in patients undergoing smoking cessation  Completion of enrolment of NIH-funded phase 2 study of INV102 (nadolol) in asthma patients 29 Corporate snapshot 30 Sector Life Sciences (Biotechnology) Principal activities Clinical-stage pharmaceutical drug development Pipeline 3 drug assets, multiple clinical and pre-clinical programs Operations Australia & USA ASX code IVX Share price (2-Nov-15) $0.012 Shares on issue ~894 M Options on issue ~115M Market cap (2-Nov-15) $10.7M Cash at bank (30-Sep-15) $0.5M R&D tax rebate received (9-Oct-15) $2.4M Dr Greg Collier Managing Director and CEO Invion Limited c/- McCullough Robertson Lawyers, Level 11, 66 Eagle Street Brisbane, QLD, 4000 Australia P: +61 7 3295 0500 E: greg.collier@inviongroup.com W: www.inviongroup.com