ERDOSTEINEMedical-Marketing Platform Edmond Pharma May 1999 Medical-Marketing Platform Index Chronic Bronchitis Erdosteine Profile Market Analysis Marketing Platform Chronic Bronchitis Index Definition Morbidity and mortality Development Pathogenesis Treatment Chronic Bronchitis Chronic bronchitis is a syndrome including: Chronic simple bronchitis (CB) chronic cough mucus hypersecretion Chronic obstructive bronchitis (COB) chronic cough mucus hypersecretion partial peripheral airways obstruction Chronic obstructive pulmonary disease (COPD) chronic cough mucus hypersecretion irreversible or partially reversible peripheral airways obstruction . .Chronic Bronchitis Morbidity and mortality New cases of chronic bronchitis New cases (x 1000 patient-years) 20 15 10 5 0 0–4 Men 5–14 Women 15–24 25–44 45–64 65–74 75+ Age (years) CMR Nijmegen New cases of chronic bronchitis per 1000 patient-years. divided according to age and gender. B: healthy smokers. C: COPD patients who have stopped smoking.Chronic Bronchitis Development Course of lung function FEV1 (%) 100 A B 50 C Disability Death D 5 10 15 20 30 40 50 60 70 80 Age (years) Postma DS Course of lung function. A: healthy non-smokers. . D: COPD patients who smoke. 1989) . proteases. etc) 2 IMPAIRED MUCOCILIARY CLEARANCE 6 DAMAGE TO AIRWAY EPITHELIUM 3 BACTERIAL COLONISATION (eg. etc) 4 PROGRESS to COPD INFLAMMATORY RESPONSE (attraction/activation of granulocytes) 5 INCREASED OXIDATIVE STRESS (consumption of antioxidants) Cole & Wilson “Vicious Circle Hypothesis” The “Vicious Circle Hypothesis” and the development of COPD (modified after Cole and Wilson.Chronic Bronchitis Pathogenesis Vicious Circle Hypothesis and COPD 1 INITIATING FACTORS (eg. increased bacterial adhesion) BACTERIAL PRODUCTS (histamine. smoking. viral infections. Chronic Bronchitis Treatment Goal Prevent disease progression Preserve lung function from further deterioration Management options Preventive measures Smoking cessation Medical treatment Bronchodilators Corticosteroids Antibiotics Mucolytics Pulmonary rehabilitation . Chronic Bronchitis Erdosteine THE FIRST DISEASE MODIFYING AGENT FOR CHRONIC BRONCHITIS Multiple mechanism of action functioning on the four main steps of the pathogenesis of chronic bronchitis Impaired mucociliary clearance Bacterial colonisation Local inflammatory response Oxidative stress Reduction of exacerbation rates Preservation of lung function Slows down disease progression . Erdosteine Profile Index Chemistry Clinical Pharmacology Muco-modulatory activity Antibacterial activity Anti-inflammatory activity Antioxidant activity Clinical Efficacy Tolerability . .Erdosteine Profile Chemistry Two phase pharmacodynamic action Erdosteine chemical structure S CH2 C=O ERDOSTEINE CH2 CH-NH-CO-CH2-S-CH2-COOH COOH HS-CH2-CH2-CH Met I N-thiodiglycolylhomocysteine NH-CO-CH2-S-CH2-COOH COOH COOH HS-CH2-CH2-CH NH2 Met III Homocysteine HS-CH2-CH2-CH NH-COCH3 Met II N-acetylhomocysteine Chemical structure and metabolic pathway of erdosteine. Erdosteine Profile Clinical pharmacology Multifactorial mechanism of action Muco-modulatory activity Antibacterial activity Anti-inflammatory activity Antioxidant activity This multiple mechanism of action allows erdosteine to affect many steps of the vicious circle which characterizes the development of chronic bronchitis . Clinical Pharmacology Muco-modulatory activity Improvement of rheological characteristics of mucus Improvement of mucociliary clearance Reduction of mucus hypersecretion and expectoration volume . 75 1.001 vs baseline).5 1.25 1 Basal Erdosteine Placebo Day 3 Evaluation time Busin S. ( p<0. 1991 End Mean sputum viscosity before and after treatment with placebo or erdosteine.Clinical Pharmacology Muco-modulatory activity Improvement of rheological characteristics of mucus Sputum viscosity centipoise 2. .25 2 1. .Clinical Pharmacology Muco-modulatory activity Improvement of mucociliary clearance Mucociliary transport MCT (mm/min) 13 11 9 7 5 3 0 Placebo 1 2 3 4 5 6 7 8 Normal range days Erdosteine 300 mg Olivieri D et al. 1991 Mean value ( SD) of mucociliary transport before and after treatment with placebo ( n=8) or erdosteine 300 mg ( n=8) tid for 8 days by oral route. Shaded area represents the normal values ± SD in healthy non-smokers. Clinical Pharmacology Muco-modulatory activity Reduction of mucus hypersecretion and expectoration volume Expectoration volume ml 30 25 20 15 10 5 0 Basal Erdosteine Placebo Day 3 Evaluation time End Busin S et al. 1991 Mean expectoration volume before and after treatment with placebo or erdosteine. . (p<0.001 vs baseline). Clinical Pharmacology Antibacterial activity Inhibition of bacterial adhesion Increase in sputum concentration of antibiotics . 5 5 Concentration (g/ml) Metabolite I N-acetylcysteine Metabolite II Braga PC et al.05).5 g/ml of erdosteine Met I. as expressed as percentage of the final mean vs control (p0. 1999 10 Effect of various drugs and drug concentrations on the adhesiveness of S. aureus to 2. . 0 1.Clinical Pharmacology Antibacterial activity Inhibition of bacterial adhesion Inhibition of adhesiveness in Staphylococcus aureus % Change 30 * * * A 20 10 B Scanning electron micrographs showing bacterial adhesion to epithelial buccal cells before (A) and after (B) the exposure of S. aureus to human mucosa epithelial cells.25 Erdosteine Metabolite III 2. 05 for group 1 vs group 2) . 1988 Sputum amoxycillin concentrations for amoxycillin plus erdosteine (group 1) or amoxycillin plus placebo (group 2) on days 1 and 7 of treatment.5 * 1 * 0.Clinical Pharmacology Antibacterial activity Increase in sputum concentration of antibiotics Sputum amoxycillin concentrations g/ml 1. (*p=0.5 * 0 0 Group 1 3 First day Group 2 6 0 3 Seventh day 6 hours Ricevuti G. (p0.05 vs pretreatment values* and placebo**) . 1990 Changes in various biochemical properties of sputum after treatment with erdosteine or placebo.Clinical Pharmacology Anti-inflammatory activity Biochemical properties of sputum % Change 80 60 40 */** 20 0 -20 -40 Total proteins DNA * */** ** Albumin IgG Total IgA Lysozyme Lactoferrin Lactoferrin/ albumin Lysozyme/ albumin Total IgA/albumin Erdosteine Placebo Marchioni CF et al. glutathione: GSH) In CB the normal oxidant-antioxidant balance is altered Antioxidant therapy is aimed at restoring the normal oxidant-antioxidant balance . oxidative stress is counterbalanced by endogenous antioxidant defence mechanisms (e.Clinical Pharmacology Antioxidant activity Inflammation in CB causes an increase in activated phagocytic cells which release a variety of oxidants (reactive oxigen-derived species: ROS) associated with direct toxicity to lung structures In normal condition.g.. Clinical Pharmacology Antioxidant activity Because of the presence of SH groups. erdosteine exerts a high antioxidant activity Direct scavenging capacity on free radicals Stimulation of the endogenous antioxidant system (GSH) Erdosteine antioxidant activity has been widely demonstrated Decrease in ROS production Increase of GSH in plasma and bronchoalveolar lavage (BAL) fluid Protection against smoke-induced 1-antitrypsin inactivation . induced by PMA. 1998 Mean integral of luminol-dependent chemiluminescence (LDCL ± SD) of human neutrophils.Clinical Pharmacology Antioxidant activity Decrease in ROS production Free radical scavenging measured by chemiluminescence (LDCL) Integral of LDCL (x 109 counts) 6 4 * 2 * 0 Control 10 30 100 Metabolite l (mol/L) 300 * 1000 Miyake K et al. associated with erdosteine metabolite l.05 vs control) . (*p<0. Clinical Pharmacology Antioxidant activity Increase of GSH levels in plasma and BAL GSH levels in plasma and BAL % Change 90 80 70 60 50 40 30 20 10 0 Plasma GSH Erdosteine NAC BAL GSH Mitrea M et al, 1998 Percentage increase (vs basal) of GSH levels in plasma and BAL after treatment with either erdosteine or NAC. Clinical Pharmacology Antioxidant activity Protection against smoke-induced 1-antitrypsin inactivation The protective threshold of active 1-antitrypsin % Subjects with 1 -AT > 1.3 M 100 80 60 40 20 0 Pretreatment Non-smokers Erdosteine Placebo Post-treatment Vagliasindi M et al, 1989 * Percentage of individuals with lung levels of 1 -antitrypsin above the protective threshold of 1.3 M. (*p<0.05 vs pretreatment and placebo) Clinical Pharmacology Summary Erdosteine may help in the prevention of disease progression since it acts on the key pathogenetic factors of CB Vicious circle hypothesis and COPD IMPAIRED MUCOCILIARY CLEARANCE DAMAGE TO AIRWAY EPITHELIUM BACTERIAL COLONISATION (eg, increased bacterial adhesion) BACTERIAL PRODUCTS (histamine, proteases, etc) PROGRESS to COPD INFLAMMATORY RESPONSE (attraction/activation of granulocytes) INCREASED OXIDATIVE STRESS (consumption of antioxidants) Site of action of erdosteine Cole & Wilson “Vicious Circle Hypothesis” ) Spirometric indices (FVC. etc.Erdosteine Profile Clinical efficacy 55 studies.) Daily dose 300 mg-1200 mg Standard: 600 mg . etc. sputum viscosity. FEV1. more than 1600 CB patients Disease conditions Stable COB Exacerbations of COB Paedriatric acute lower respiratory diseases Comparative studies vs NAC and ambroxol Synergism with antibiotic therapy Endpoints Symptom improvement (exacerbation rates. 05. (*p<0. **p<0.Clinical Efficacy Stable COB Effect of erdosteine on clinical parameters vs placebo Cough frequency 0 Cough severity Chest discomfort Dyspnoea Global efficacy index -5 -10 -15 -20 -25 -30 -35 *** * ** % Reduction Erdosteine Placebo Ghiringhelli G. ***p=0.01. 1995 Comparison of the effects of erdosteine and placebo on efficacy parameters in patients with stable hypersecretory chronic bronchitis.01 vs placebo) . Clinical Efficacy COB: Prevention of seasonal exacerbations Exacerbations of chronic bronchitis % Patients 50 40 30 20 * * 10 0 No relapse Erdosteine 1 relapse Placebo * * 2 relapses >3 relapses Fioretti M et al. 1991 Percentage of patients with exacerbations of chronic bronchitis after 6 months of treatment with erdosteine or placebo.001 vs placebo) . (*p<0. Clinical Efficacy Acute exacerbations in CB COMPARISON WITH AMBROXOL Erdosteine vs ambroxol: spirometric parameters % Change 35 30 25 20 15 * * ** * * * 10 5 0 -5 Day 3 Day 7 FVC Erdosteine Day 3 Day 7 FEV0.05.01 vs basal values) . (*p<0.5 Ambroxol Day 3 Day 7 PEF Day 3 Day 7 MMFR Fumagalli G. 1988 Changes in various spirometric parameters during and after treatment with erdosteine or ambroxol. **p<0. Clinical Efficacy Acute exacerbations in CB COMPARISON WITH NAC Erdosteine vs NAC (ml/3h) 20 10 Sputum volume (cPs) 150 130 Sputum viscosity 0 Basal 4 * 6 Days * Final 110 90 70 (n/3h) 40 30 20 10 0 Frequency of cough 50 * 6 Days Final Basal 4 * 6 Days Final Basal 4 Erdosteine N-acetylcysteine Zanasi A et al. 1991 Changes in various clinical parameters during and after treatment with erdosteine or N-acetylcysteine. (*p<0.01 between groups) . (*p<0.01 at days 8-11) .Clinical Efficacy Synergism with antibiotic therapy Clinical parameters % Patients improved 45 40 35 *† *† ** † ** † ** † ** † 30 25 20 15 10 5 0 Sputum appearance Group 1 Sputum viscosity Group 2 Expectoration difficulty Catarrh at Cough quality auscultation and frequency Dyspnoea intensity Marchioni CF. 1995 Various clinical efficacy parameters after treatment with amoxycillin plus erdosteine (group 1) or amoxycillin plus placebo (group 2).02 at days 3-4. **p<0.01 at days 3-4. † p<0. 2 49. .054 treatment <0.1 36. or placebo + ampicillin (group 2).2 38.1 Rales 17.8 59.6 5.4 41.01 time 0.01 time <0.562 treatments 0.6 2.6 <0.118 treatments 0.01 time x treatments Body temperature 3.277 time x treatments <0.987 centres x treatments <0.01 treatments <0.01 time x treatments <0.3 59.3 14.8 20.01 time x treatments <0.6 Polypnoea 35.5 29.01 centres 0.8 4.4 Rhonchi 33.01 time 0.0 31.7 24.Clinical Efficacy Paedriatric acute lower respiratory diseases Efficacy parameter Group 1 (%) Group 2 (%) Day 3±1 Day 7±2 Day 3±1 Day 7±2 p value for all patients Cough 23.6 56.01 treatment <0.01 time x treatments <0.01 time <0.01 time 0.2 Reductions in various efficacy values/scores after 3±1 days and 7±2 days (end of therapy) of treatment with erdosteine (dry syrup) + ampicillin (group 1). Clinical Efficacy Summary (I) Stable COB Significant improvements of symptoms and of clinical/spirometric parameters Significant reductions in the number of 2-mimetics inhalations Reacutization of COB Less severe symptoms Reduced absence from work Reduction of relapse rates Paediatric acute lower respiratory infections Synergistic activity with antibiotics Early symptoms improvement . Clinical Efficacy Summary (II) Comparison with ambroxol Faster and more consistent reduction of cough More favourable evolution of spirometric parameters Overall superior therapeutic profile Comparison with NAC Faster onset of symptoms improvement More favourable evolution of spirometric parameters Better GI tolerability and compliance Overall superior therapeutic profile Synergism with antibiotic therapy Faster and better recovery from exacerbations . High GI tolerability. reference drugs (of which NAC n=218) and placebo. safe co-medication . good patient’s compliance Free of drug interactions.Erdosteine Profile Tolerability Excellent safety profile evaluated in more than 1500 patients at daily doses up to 1200 mg Frequency of adverse reactions % Frequency 20 15 10 5 0 GI reactions CV reactions Cutaneous-mucosal reactions General reactions Final total Erdosteine (n=1520) Reference drugs (n=303) Placebo (n=656) Frequency of adverse reactions with erdosteine. Market Analysis Index Market definition Market size and trend Competitive profile . Market Analysis Market definition IMS Diagnosis 490 Bronchitis (not specified acute/chronic) 491 Chronic bronchitis 492 Emphysema 496 Chronic airways obstruction ENT (different categories) Goals of therapy Preserve lung function Reduction of exacerbation rates Improvement of quality of life Target patient Middle age smoking people (40+) Elderly people . Market Analysis Market definition Prescriber GPs (80%) Lung specialists ENT specialists Therapeutic approach Different from asthma Bronchodilators Corticosteroids Antibiotics Mucolytics Treatment characteristics Co-medication Acute/Chronic treatment . 4 96.8 2.6 USD million 2034 212 - % growth +34 = - Europe Germany France Italy Spain Belgium Netherlands 51.8 1052 - +5 - Africa/Asia/Australasia Latin America 26.1 20.7 35.4 14.Market Analysis Market size and trend Country Worldwide North America USA Canada % 100 10.6 535 235 +4 +12 .4 3.3 11.8 2.2 6. Market Analysis Competitive profile Comparison of mucolytic agents by pharmacological activities vs erdosteine Compound NAC SCC (S-carbocysteine) Mucolytic + + + + + + Antioxidant + +/? ? ? Antiinflammatory +/- Antibacterial +/- Ambroxol Bromhexin Guaiacol Sobrerol Erdosteine + + + + . Marketing Platform Index SWOT analysis Target audience Features and benefits Product positioning Key claims . Marketing Platform SWOT analysis STRENGTHS WEAKNESSES OPPORTUNITIES TREATHS . SWOT Analysis Strengths Multifactorial mechanism of action which counteracts disease progression at different levels Two-phase pharmacodynamics: bid administration Antibacterial activity in contrast to NAC Placebo-like tolerability Reduced GI side-effects compared to NAC Synergism with antibiotics More effective than NAC and ambroxol Full range of pharmaceutical forms Patent protection – the only drug in this class . international brand .SWOT Analysis Weaknesses Possible perception as ‘another mucolytic agent’ No strong. under-treatment of CB/COPD: stretchable market Trend to prolong treatment and prevent exacerbations in CB patients . different from ‘old fashion’ mucolytics High and growing incidence of CB/COPD: large market in expansion Under-diagnosis.SWOT Analysis Opportunities Need for new treatment options. SWOT Analysis Threats Established ‘mucolytic’ market Strong competition with low priced alternatives Skeptical medical attitude towards mucolytics . Marketing Platform Target audience Lung specialists/Pneumologists ENTs Paediatricians GPs . ameliorating symptoms. reducing exacerbation rates and improving lung function .Marketing Platform Features and benefits Features Multifactorial mechanism of action which acts on the vicious circle characterizing the development of CB Benefits Stops/slows the disease progression. reducing exacerbation rates and improving lung function More prolonged availability of free thiol groups for a more sustained efficacy compared to other drugs . ameliorating symptoms.Marketing Platform Features and benefits Features Multifactorial mechanism of action which acts on the vicious circle characterising the development of CB Unique two-phase pharmacodynamic profile: 2 active metabolites with different half-lives Benefits Stops/slows the disease progression. Marketing Platform Features and benefits Features Multifactorial mechanism of action which acts on the vicious circle characterising the development of CB Unique two-phase pharmacodynamic profile: 2 active metabolites with different half-lives Anti-adhesive activity which inhibits bacterial colonisation Benefits Stops/slows the disease progression. ameliorating symptoms. reducing exacerbation rates and improving lung function More prolonged availability of free thiol groups for a more sustained efficacy compared to other drugs Antibacterial activity which helps in recovering from CB exacerbations better and faster . Marketing Platform Features and benefits Features Multifactorial mechanism of action which acts on the vicious circle characterising the development of CB Unique two-phase pharmacodynamic profile: 2 active metabolites with different half-lives Anti-adhesive activity which inhibits bacterial colonisation Synergistic activity with antibiotic therapy Benefits Stops/slows the disease progression. ameliorating symptoms. reducing exacerbation rates and improving lung function More prolonged availability of free thiol groups for a more sustained efficacy compared to other drugs Antibacterial activity which helps in recovering from CB exacerbations better and faster Improves the direct activity of antibiotics without adding side effects . Marketing Platform Features and benefits Features Decreasing ROS production and increasing GSH levels Benefits Adding powerful antioxidant activity to the mucomodulatory effect . Marketing Platform Features and benefits Features Decreasing ROS production and increasing GSH levels Strong conclusions from comparative clinical trials Benefits Adding powerful antioxidant activity to the mucomodulatory effect More effective (more rapid. in more patients) than ambroxol and NAC . released only after absorption Benefits Adding powerful antioxidant activity to the mucomodulatory effect More effective (more rapid.Marketing Platform Features and benefits Features Decreasing ROS production and increasing GSH levels Strong conclusions from comparative clinical trials Chemically blocked thiol groups. in more patients) than ambroxol and NAC No unpleasant odour. no reflux. no GI side effects (in contrast to NAC) . no reflux. released only after absorption Placebo-like side effect profile Benefits Adding powerful antioxidant activity to the mucomodulatory effect More effective (more rapid. no GI side effects (in contrast to NAC) Very well tolerated therapy.Marketing Platform Features and benefits Features Decreasing ROS production and increasing GSH levels Strong conclusions from comparative clinical trials Chemically blocked thiol groups. in more patients) than ambroxol and NAC No unpleasant odour. even at the long term . released only after absorption Placebo-like side effect profile Full range of pharmaceutical form Benefits Adding powerful antioxidant activity to the mucomodulatory effect More effective (more rapid. even at the long term Patient compliance .Marketing Platform Features and benefits Features Decreasing ROS production and increasing GSH levels Strong conclusions from comparative clinical trials Chemically blocked thiol groups. in more patients) than ambroxol and NAC No unpleasant odour. no reflux. no GI side effects (in contrast to NAC) Very well tolerated therapy. is able to slow disease progression and to preserve lung function Product definition The first disease modifying agent in chronic bronchitis . besides improving symptoms.Marketing Platform Product positioning Positioning statement Erdosteine is the first disease modifying agent in chronic bronchitis which. good patient compliance .Marketing Platform Key Claims Multifactorial mechanism of action Prolonged bioavailability Dual antibacterial activity Clinically proven efficacy Fast improvement of CB symptoms Preservation of lung function Placebo-like tolerability. Through these multiple mechanisms. Erdosteine improves the mucociliary clearance of the airways and directly inhibits bacterial colonisation. Erdosteine tends to reduce local inflammation while stimulating physiological antioxidant mechanisms. erdosteine prevents the progression from milder disease forms to more severe conditions. erdosteine breaks the vicious circle characteristic of the development of the disease. Key messages Acting at the core of CB Slowing Chronic Bronchitis progression .Key Claims Multifactorial mechanism of action Rationale By acting on the key pathogenetic factors of CB. Met II is released more slowly than Met I. Key messages Full control of Chronic Bronchitis Sustained control of Chronic Bronchitis . This unique two-phase pharmacodynamics allows a more prolonged availability of erdosteine and consequently a sustained activity and control of CB.Key Claims Prolonged bioavailability Rationale Erdosteine is inactive and only after metabolisation in the intestine is it transformed into two active metabolites. Met I and II. .Key Claims Dual antibacterial activity Rationale In contrast to other mucolytics (i. NAC). fewer exacerbations in CB . erdosteine inhibits bacterial adhesion and increases antibiotic concentrations in the sputum. Key messages Fast recovery from CB exacerbations Fast recovery. This double action of erdosteine results in a better and faster pathogen clearance. and consequent better and faster recovery from exacerbations in chronic bronchitis.e. Key messages Stopping disease progression in CB . effective treatment for chronic bronchitis. results from clinical studies. such as chronic obstructive pulmonary disease. such as chronic obstructive bronchitis. performed in strict adherence with international standards on clinical research. ranging from milder forms.Key Claims Clinically proven efficacy Rationale The efficacy of erdosteine has been evaluated in 55 controlled studies involving more than 1600 CB patients with a wide range of disease conditions. indicate that orally administered erdosteine is a new. Overall. to more severe pathologies. Key Claims Fast improvement of CB symptoms Rationale The direct comparison of erdosteine and the ‘gold standard’ NAC in the treatment of acute exacerbations in CB patients shows that erdosteine acts faster and better than NAC. in terms of both symptom improvement and lung function capacity. Key messages Expanding the boundaries of CB treatment A new level of controlling CB progression . In comparison with other mucolytics. as evaluated through an improvement of some spirometric parameters. erdosteine has shown to preserve lung function. such as FEV1 and FVC.Key Claims Preservation of lung function Rationale Many airways diseases such as asthma and CB develop into severe conditions which result in the deterioration of lung function. Key messages Saving lung function in CB . Erdosteine has shown placebo-like tolerability. allowing safe co-medication. Key messages Sustained control without problems in CB Improving the CB patient’s quality of life . In addition.Key Claims Placebo-like tolerability for good patient compliance Rationale Tolerability of erdosteine has been evaluated in more than 1500 patients at doses ranging from 600 mg/day to 1200 mg/day. erdosteine is devoid of drug interaction. The absence of these problems enhances patient compliance with erdosteine. erdosteine is a pro-drug with two blocked thiol groups. Finally. also confirmed over the long-term. This means that erdosteine does not have an unpleasant smell and does not cause reflux phenomena after ingestion.