Announcement PDF Invion Limited (ASX:IVX) Clinical-stage life sciences company targeting chronic inflammation Investor Presentation September | 2015 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 II data anticipated 3Q 2015 INV104 (zafirlukast): leukotriene receptor antagonist (LTRA) that reduces inflammation, constriction of the airways and the build-up of mucus in the lungs > Development and manufacturing collaboration announced 3Q 2015 Autoimmune 3. INV103 (ala-Cpn10): modified naturally occurring human hypothesised to maintain and restore immune homeostasis > 3 Phase II data announced 3Q 2015, partnering discussions underway Targeting chronic inflammatory airway disease Oral INV102 (nadolol) Spectrum of airway disease and opportunities Global market size: $34B Exercise Induced Asthma 5 Mild Asthma Moderate Asthma Severe Asthma Chronic Bronchitis $2.4B $1.2B Smoker’s Cough Cystic Fibrosis INV104 (zafirlukast) INV102 (nadolol) Monotherapy + combinations Monotherapy + combinations 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 6 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 7 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 > 8 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 9 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 EOPII / 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 > 10 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 patient phase II smoking cessation study reporting Q315. Leveraging the data: upcoming analysis and reporting > > 11 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 analysis 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 Oral nadolol: 155 patient phase II smoking cessation study reporting Q315. Positive endpoint data Safety Leads to Smoking cessation Biomarkers Oral nadolol program: end of Phase II meeting with FDA / Phase III 12 > Safety of titration doses > No need for rescue medication > Safely delivered to smokers trying to quit + > Report on effects of nadolol vs placebo on key biomarkers IL8, ERK2, MUC5AC. > + Report on smoking cessation rates in nadolol treatment versus placebo = PLUS Inhaled nadolol program: development to proof of concept / Phase II Oral nadolol: 155 patient phase II smoking cessation study reporting Q315. Positive endpoint data Safety > Safety of titration doses > No need for rescue medication > 13 Safely delivered to smokers trying to quit Leads to Smoking cessation Biomarkers + > Report on effects of nadolol vs placebo on key biomarkers IL8, ERK2, MUC5AC. > + Report on smoking cessation rates in nadolol treatment versus placebo Oral nadolol program: end of Phase II meeting with FDA / Phase III Inhaled nadolol program: = PLUS development to proof of concept / Phase II in asthma, COPD Inhaled nadolol program: and cystictofibrosis development proof of concept / Phase II 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 14 inhaled nadolol Safety and 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 Respiratory therapeutics: inhaled program INV102 (nadolol) in asthma, COPD & cystic fibrosis 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 16 > IND submission (2016*) > Phase I and Phase II 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 Inhaled INV102: program status 17 > Collaboration with 3M Drug Delivery systems > Target outcome: proprietary formulation and device using 3M’s proprietary pressurised metered dose inhalation (pMDI) technology > Collaboration encompasses manufacture for toxicology and phase I studies > Formulation and device selected > Toxicology supplies manufactured > Clinical supplies manufactured > Toxicology supplies provided to CRL (Montreal QUE); short-term toxicology ongoing 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. 18 INV104 (zafirlukast) Target: a novel inhaled non-steroidal anti-inflammatory treatment for asthma Target: an inhaled reformulation of a successful oral therapeutic for asthma INV104 (zafirlukast): > Leukotriene-receptor antagonist (LTRA) or “anti-leukotriene” that reduces inflammation, constriction of the airways, and the build-up of mucus in the lungs > Approved worldwide as an oral tablet for asthma (AstraZeneca) > Well established clinical efficacy & safety profile > Inhaled proof of concept using propellants that are now banned (CFCs) > Inhaled formulation indicated as monotherapy for mild persistent asthma and exercise-induced asthma > 20 Indicated to reduce inhaled corticosteroid (ICS) dependency in adults and children > as an alternative as first controller medication in mild persistent and moderate asthma > by addition of low dose ICS treatment rather than doubling ICS > by enabling reduced ICS dose “steroid sparing” in steroid-dependent asthma Inhaled zafirlukast an anti-leukotriene: background and rationale Defined safety profile Defined CMC Airway & nasal secretions are rich in LTC4, D4 and E4 (cysteinyl leukotrienes) Strong scientific rationale 21 Excellent flow characteristics shown in DPI (Turbuhaler) as well as conventional pMDI (1980s-90s) Full toxicology package completed using CFC-based delivery system Single and multiple inhaled forms showed no dose-limiting side effects or blood levels Known tox/ ADME profile > Zeneca (now A/Z) stopped inhaled development in mid 1990s. > Zafirlukast and montelukast have resisted formulation in non-cfc propellant systems. 200mcg demonstrated 12 hour protection from allergen. Once daily dosing achievable at <1000mcg/day Established efficacy & defined dose for inhalation FDA pre-IND established framework for reformulation of zafirlukast Agreement reached with FDA on: > > > 22 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 I: single rising dose study for safety (paradoxical bronchoconstriction) and pharmacokinetics > phase I: multiple dose safety study for safety (paradoxical bronchoconstriction) and pharmacokinetics > phase II: 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 Inhaled Product Rationale Oral 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 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 Inhaled Form Hovione CMC collaboration mitigates major risk of inhaled zafirlukast development Formulation & device partner, Hovione > Invion will collaborate with Hovione to develop the proprietary novel technology – a dry powder formulation of zafirlukast and the accompanying inhalational delivery device > under the terms of the agreement, Hovione will provide chemistry and manufacturing services to develop and optimise the dry powder inhalation formulation which will be delivered using its proprietary device technology known as the XCaps inhaler system > Hovione device is ideally suited for fixed combination with ICS, bronchodilators, or INV102 (nadolol). > IP protection provided under licence via Hovione formulation and device, Invion retains commercialisation rights CMC solution complements existing and planned toxicology and clinical packages > previously completed using CFC-based device > 24 Clinical proof of concept based on inhalational challenge studies; previously completed using CFC-based device 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. XCaps is a patent protected device filed and granted in over 40 countries, including US (US 8677992) and EU (EP 2546460). XCaps device is simple, reusable and lowcost. This DPI is indicated for applications where a chronic or a medium term acute capsule based delivery of an API is needed. 25 Expected placement of inhaled zafirlukast in treatment regimes > As many as 334 million people have asthma which occurs in people of all ages. Wheeze is the most common symptom and the burden of disability is high. > In 2007 the U.S. spent over $56 billion on asthma care, of which nearly $27 billion was spent on pediatric asthma. Inhaled zafirlukast 26 > targeted for use as a controller/ preventer with few or no side effects for the full range of asthma therapy > especially useful in LTD4-driven asthma including aspirin sensitivity and in children > indicated as steroid sparing > inhaler will facilitate substitution for inhaled corticosteroids (ICS) > for many patients, inhaled product alone (monotherapy) will be effective Inhaled zafirlukast program: progress and clinical development strategy Clinical benefits  FDA approved as an oral asthma therapy  Proof of concept previously conducted using inhaled drug  Non-steroidal  Higher local concentrations without systemic exposure (decreased risk of generic duplication) Status of collaboration with Hovione for proprietary formulation and device using Hovione’s patented XCaps inhaler system  Formulation and device selected  Program of works for manufacture of toxicology and clinical supplies > Formulation complete for toxicology (non GMP) (3Q2015) > Manufacture of toxicology supplies (4Q2015-1Q2016*) > Clinical materials manufactured to support IND and Phase 1 (2Q-3Q 2016*) Development program  Pre-IND status with FDA  Formulation and device collaboration 27 > Commencement of toxicology studies (4Q2015*) > IND submission (3Q2016*) > Phase I and Phase II clinical studies in (3Q2016 – 2Q2017*) *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 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) > 29 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 II lupus data 30 > 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 Asthma NIH funded Smoking cessation Phase I ………….. Oral INV102 (nadolol) Formulation development and clinical feasibility ………….. Research ………….. Pipeline Phase II Next milestone Completion of enrolment 2H15, Reporting 2016 Phase II data 3Q15 Inhaled INV102 (nadolol) Pre-IND status achieved 1Q15 Asthma Tox and clinical supplies manufacture underway COPD Tox studies commenced 1H15 Cystic Fibrosis Inhaled INV104 (zafirlukast) Asthma partnered with Hovione Manufacture of tox supplies 4Q15 INV103 (ala-Cpn10) Lupus (SLE) 31 Partnering Program targets: 12-18 months Oral INV102 (nadolol) > advanced into Phase III as an adjunct to smoking cessation in patients with chronic cough and/or chronic bronchitis > IP based on combination of nadolol safety and efficacy with diagnostics from smoking cessation study Inhaled INV102 (nadolol) > proprietary formulation in PMDI (CMC) > completion of toxicology program in 2 species to support POC (Tox) > completion of robust Phase I program to support phase II in 3 indications Inhaled INV104 (zafirlukast) 32 > proprietary formulation and device > completion of toxicology 28 days, 2 species with Charles River Labs > phase I studies showing safety of inhaled zafirlukast > plans for repeat of Phase II studies which had previously provided POC (1994) *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 Board and Management with proven track record > Chairman of Board of Directors, Mr Brett Heading > > Managing Director & CEO, Dr Greg Collier > > Senior biotechnology director and executive with 20+ years experience in research, research management, advisory. Formerly COO and CFO, ChemGenex Pharmaceuticals. Warren Brown, B Eng, Non-executive Director > 33 25 year veteran of the pharmaceutical industry, Graduated from the University of Chicago, board certified in internal medicine, pulmonary and critical care medicine. Senior executive roles at AZ & GSK. 5 FDAapproved drugs, including “first in class” and for the beta blocker carvedilol (Coreg®). James Campbell, PhD MBA, Non- executive Director > > 20 year career in pharmaceutical research, development and commercialisation, former CEO ChemGenex Pharmaceuticals, 150 peer reviewed publications, 33 patents, Roche Award for Excellence Executive VP R&D and CMO, Dr Mitchell Glass > > Senior partner of law firm McCullough Robertson, 27 years as a company director. Former Chairman, ChemGenex Pharmaceuticals (sold to Cephalon $230M); former Director, Peplin Biotech Limited. Experienced in corporate strategy and project management. Background in consulting engineering and contract negotiation. Corporate snapshot 34 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 (4-Sep-15) $0.014 Shares on issue ~894 M Options on issue ~115M Market cap (4-Sep-15) $12.5M Cash at bank (30-Jun-15) $2.285M Placement completed with US institutional investor (1-Sep-15) $1M 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 Investor Presentation September | 2015