ERDOSTEINE

Medical-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

0 04 Men 514 Women 1524 2544 4564 6574 75+ Age (years)
CMR Nijmegen

New cases of chronic bronchitis per 1000 patient-years, divided according to age and gender.

Chronic Bronchitis

Development
Course of lung function
FEV1 (%) 100

A B

50
C

Disability

Death

10

15

20

30

40

50

60

70

80 Age (years)
Postma DS

Course of lung function. A: healthy non-smokers; B: healthy smokers; C: COPD patients who have stopped smoking; D: COPD patients who smoke.

Chronic Bronchitis

Pathogenesis
Vicious Circle Hypothesis and COPD
1 INITIATING FACTORS (eg, viral infections, smoking, etc)

IMPAIRED MUCOCILIARY CLEARANCE

DAMAGE TO AIRWAY EPITHELIUM

BACTERIAL COLONISATION (eg, increased bacterial adhesion)

BACTERIAL PRODUCTS (histamine, proteases, 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, 1989)

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

Clinical Pharmacology

Muco-modulatory activity
Improvement of rheological characteristics of mucus
Sputum viscosity
centipoise 2.25 2 1.75 1.5 1.25 1 Basal Erdosteine Placebo Day 3 Evaluation time
Busin S, 1991

End

Mean sputum viscosity before and after treatment with placebo or erdosteine. ( p<0.001 vs baseline).

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

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 2.5 g/ml of erdosteine Met I.

0 1.25 Erdosteine Metabolite III 2.5 5 Concentration (g/ml) Metabolite I N-acetylcysteine Metabolite II
Braga PC et al, 1999

10

Effect of various drugs and drug concentrations on the adhesiveness of S. aureus to human mucosa epithelial cells, as expressed as percentage of the final mean vs control (p0.05).

Clinical Pharmacology

Antibacterial activity
Increase in sputum concentration of antibiotics
Sputum amoxycillin concentrations
g/ml 1.5
*

1
*

0.5

0 0 Group 1 3 First day Group 2 6 0 3 Seventh day 6 hours

Ricevuti G, 1988

Sputum amoxycillin concentrations for amoxycillin plus erdosteine (group 1) or amoxycillin plus placebo (group 2) on days 1 and 7 of treatment. (*p=0.05 for group 1 vs group 2)

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, 1990

Changes in various biochemical properties of sputum after treatment with erdosteine or placebo. (p0.05 vs pretreatment values* and placebo**)

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, oxidative stress is counterbalanced by endogenous antioxidant defence mechanisms (e.g., glutathione: GSH)
In CB the normal oxidant-antioxidant balance is altered Antioxidant therapy is aimed at restoring the normal oxidant-antioxidant balance

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

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, 1998

Mean integral of luminol-dependent chemiluminescence (LDCL SD) of human neutrophils, induced by PMA, associated with erdosteine metabolite l. (*p<0.05 vs control)

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

Erdosteine Profile

Clinical efficacy
55 studies, 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, sputum viscosity, etc.) Spirometric indices (FVC, FEV1, etc.)

Daily dose
300 mg-1200 mg Standard: 600 mg

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, 1995

Comparison of the effects of erdosteine and placebo on efficacy parameters in patients with stable hypersecretory chronic bronchitis. (*p<0.01, **p<0.05, ***p=0.01 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. (*p<0.001 vs placebo)

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 FEV0.5

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<0.05, **p<0.01 vs basal values)

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)

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). (*p<0.02 at days 3-4, **p<0.01 at days 3-4, p<0.01 at days 8-11)

Clinical Efficacy

Paedriatric acute lower respiratory diseases

Efficacy parameter Group 1 (%) Group 2 (%)
Day 31 Day 72 Day 31 Day 72

p value for all patients

Cough

23.8

59.8

20.1

36.6

<0.01 time <0.01 treatment <0.01 time x treatments <0.01 time 0.054 treatment <0.01 time x treatments <0.01 centres 0.987 centres x treatments <0.01 time 0.562 treatments 0.277 time x treatments <0.01 time 0.118 treatments 0.01 time x treatments <0.01 time <0.01 treatments <0.01 time x treatments

Body temperature

3.6

5.6

2.8

4.6

Polypnoea

35.2

49.5

29.2

38.4

Rhonchi

33.3

59.7

24.4

41.1

Rales

17.6

56.3

14.0

31.2

Reductions in various efficacy values/scores after 31 days and 72 days (end of therapy) of treatment with erdosteine (dry syrup) + ampicillin (group 1), or placebo + ampicillin (group 2).

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

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, reference drugs (of which NAC n=218) and placebo.

High GI tolerability, good patients compliance Free of drug interactions, safe co-medication

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

Market Analysis

Market size and trend

Country Worldwide North America
USA Canada

% 100 10.4
96.4 3.6

USD million 2034 212

-

% growth +34 =
-

Europe
Germany France Italy Spain Belgium Netherlands

51.7
35.1 20.4 14.2 6.8 2.8 2.8

1052
-

+5
-

Africa/Asia/Australasia Latin America

26.3 11.6

535 235

+4 +12

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

SWOT Analysis

Weaknesses
Possible perception as another mucolytic agent No strong, international brand

SWOT Analysis

Opportunities
Need for new treatment options, different from old fashion mucolytics High and growing incidence of CB/COPD: large market in expansion Under-diagnosis, under-treatment of CB/COPD: stretchable market Trend to prolong treatment and prevent exacerbations in CB patients

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

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, 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 characterising the development of CB Unique two-phase pharmacodynamic profile: 2 active metabolites with different half-lives

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

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

Marketing Platform

Features and benefits

Features
Decreasing ROS production and increasing GSH levels Strong conclusions from comparative clinical trials Chemically blocked thiol groups, released only after absorption

Benefits
Adding powerful antioxidant activity to the mucomodulatory effect More effective (more rapid, in more patients) than ambroxol and NAC No unpleasant odour, no reflux, no GI side effects (in contrast to NAC)

Marketing Platform

Features and benefits

Features
Decreasing ROS production and increasing GSH levels Strong conclusions from comparative clinical trials Chemically blocked thiol groups, released only after absorption Placebo-like side effect profile

Benefits
Adding powerful antioxidant activity to the mucomodulatory effect More effective (more rapid, in more patients) than ambroxol and NAC No unpleasant odour, no reflux, no GI side effects (in contrast to NAC)

Very well tolerated therapy, even at the long term

Marketing Platform

Features and benefits

Features
Decreasing ROS production and increasing GSH levels Strong conclusions from comparative clinical trials Chemically blocked thiol groups, 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, in more patients) than ambroxol and NAC No unpleasant odour, no reflux, no GI side effects (in contrast to NAC)

Very well tolerated therapy, even at the long term

Patient compliance

Marketing Platform

Product positioning
Positioning statement

Erdosteine is the first disease modifying agent in chronic bronchitis which, besides improving symptoms, is able to slow disease progression and to preserve lung function
Product definition

The first disease modifying agent in chronic bronchitis

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, good patient compliance

Key Claims

Multifactorial mechanism of action

Rationale
By acting on the key pathogenetic factors of CB, erdosteine breaks the vicious circle characteristic of the development of the disease. Erdosteine improves the mucociliary clearance of the airways and directly inhibits bacterial colonisation. Erdosteine tends to reduce local inflammation while stimulating physiological antioxidant mechanisms. Through these multiple mechanisms, erdosteine prevents the progression from milder disease forms to more severe conditions.

Key messages

Acting at the core of CB Slowing Chronic Bronchitis progression

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. Met II is released more slowly than Met I. This unique two-phase pharmacodynamics allows a more prolonged availability of erdosteine and consequently a sustained activity and control of CB.

Key messages

Full control of Chronic Bronchitis

Sustained control of Chronic Bronchitis

Key Claims

Dual antibacterial activity

Rationale
In contrast to other mucolytics (i.e., NAC), erdosteine inhibits bacterial adhesion and increases antibiotic concentrations in the sputum. This double action of erdosteine results in a better and faster pathogen clearance, and consequent better and faster recovery from exacerbations in chronic bronchitis.

Key messages

Fast recovery from CB exacerbations

Fast recovery, fewer exacerbations in CB

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, ranging from milder forms, such as chronic obstructive bronchitis, to more severe pathologies, such as chronic obstructive pulmonary disease. Overall, results from clinical studies, performed in strict adherence with international standards on clinical research, indicate that orally administered erdosteine is a new, effective treatment for chronic bronchitis.

Key messages

Stopping disease progression in CB

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

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. In comparison with other mucolytics, erdosteine has shown to preserve lung function, as evaluated through an improvement of some spirometric parameters, such as FEV1 and FVC.

Key messages

Saving lung function in CB

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 has shown placebo-like tolerability, also confirmed over the long-term. In addition, erdosteine is devoid of drug interaction, allowing safe co-medication. Finally, erdosteine is a pro-drug with two blocked thiol groups. This means that erdosteine does not have an unpleasant smell and does not cause reflux phenomena after ingestion. The absence of these problems enhances patient compliance with erdosteine.

Key messages

Sustained control without problems in CB Improving the CB patients quality of life