Transcript Diapositive 1 - Moodle Lille 2

1
ALLERGEN IMMUNOTHERAPY
Blondeau Eloïse
Boukhalfa Koussayla
Tiquet Laure
Vandaele Anaïs
Stallergenes profile
2
• a European biopharmaceutical company
• 7th largest pharmaceutical company in France.
• specialized in the treatment of severe respiratory
allergies by allergen immunotherapy
• almost 500 000 patients benefit from the
pharmaceutical company’s treatments every year
• Over 1000 people now work at Stallergenes
• Sales in 2011 : 235 M€ ; R&D : 20% of sales
3
RESPIRATORY ALLERGY
A global public health challenge
Respiratory allergy
4
Allergic rhinitis
Rhinitis
Sinusitis
Conjunctivitis
Asthma
“during two or more consecutive days for more than 1 h”
(ARIA 2008)
Respiratory allergy
5
Classified according to symptom duration and severity :
Due to :
Indoor allergens
Outdoor
allergens
Persistent rhinitis
and asthma
Intermittent
rhinitis
Impact on quality of life, sleep, school and work
substancial indirect costs
Allergy diagnostic
6
Consultation with an allergist :
In-depth interview + physical examination
Provisional identification of possible guilty allergen
Skin testing (« Prick-test »)
Sensitization
confirmed
or bordeline
Blood test (specific IgE assay)
Provocation test
or bordeline
Allergy diagnostic
7
Skin Prick Testing
Allergy diagnostic
8
Intra dermal reaction
inspection
palpation
measurement of transverse diameter in mm of induration
Positive > 5 mm
Allergy diagnostic
9
True Test
Respiratory allergy : epidemiology
10
Increasing
prevalence
Western
lifestyle
countries
Very
common
disease
Developing
countries
Tends to be
more
common
Probably
underdiagnosed
Allergic
rhinitis
≈500
million
people
Annual total cost : 2 to 5 billion $ (USA, 2003*)
(direct medical costs, co-morbidities, productivity losses,
OTC medications)
Asthma
≈300
million
people
* ARIA 2008
Allergy treatments
11
EVICTION
• the primary
recommended
solution
• to eradicate all
contacts with the
allergen
• difficulty to put into
practice (formal
identity, pollens)
SYMPTOMACTIC
TREATMENTS
ALLERGENIC
IMMUNOTHERAPY
• prescribed first line
by the general
practitioner
• to reduce the
severity of the
symptoms and
inflammation
• recognised efficacy
• no long-term
benefits (symptoms
return as soon as the
treatment is
stopped)
• no impact on the
natural progression
of the disease.
• the only treatment
that prevent
worsening of the
allergy
• to reduce the body’s
sensitization to the
allergen by
progressively
modulating the
immune response to
the allergen
Allergen-specific immunotherapy :
mechanism
12
Altered T-cell cytokine balance
(shift to Th1)
Induction of regulatory T-cells
Reduction in specific IgE levels
(long term)
Induction of IgG blocking
antibodies
Reduced recruitment of effector
cells (eosinophils, mast cells)
J Clin Invest, 2004
Allergen-specific immunotherapy :
indications
13
Clinically relevant specific IgE
Symptoms of allergic rhinitis,
conjunctivitis and/or asthma
Poor response to
pharmacotherapy/
allergen
avoidance
Adverse effects
of medications
Avoid long-term
medication and
its cost
Coexisting
allergic rhinitis
and asthma
Possible
prevention of
asthma
Reactions to
Hymenoptera
stings
Systemic
reaction :
respiratory,
cardiovascular…
Older than 16
years with
systemic reaction
limited to the
skin
Adapted from J Allergy Clin Immunol., 2007
14
STALLERGENES
A step by step construction
History
15
1962
Creation of
Stallergenes
in Lyon within
the Institut
Mérieux
1980
German market
working with a
distributor
1974
established in
Paris
+ international
operations in
the Benelux
countries and
North Africa
1988
first automated
production chain
for NPP (Named
Patient Product)
Name Patient Product NPP
16
APSI : “Allergène Préparé Spécialement pour un Individu”
NPPs still are not subject in all countries to a specific regulatory framework regarding
pharmaceutical registration.
Automated
distribution lines
Automated
encapsulation
lines
Automated
labelling lines
History
17
1989
Merger of
Stallergenes with the
Allergen Division Institut Pasteur
1993
Acquisition of
Stallergenes by
Wendel Investissement
1992
expansion of
Stallergenes in
Greece, Spain,
Portugal and Turkey
History
18
1994
Launch of Staloral®
(allergen immunotherapy
by sublingual delivery)
Advantages of sublingual route
19
SUBCUTANEOUS ROUTE
SUBLINGUAL ROUTE
Injection
Under the tongue
Administered in a medically controlled
environment (Systemic reactions)
At home
Initiation phase : 13 weeks
Initiation phase : 11 days
Maintenance phase : 3 to 5 years
Maintenance phase : 3 to 5 years
Systemic AE (14 %) : urticaria,
anaphylaxis
Local AE : itching
(Rare systemic AE)
Approved
Not approved by FDA in the USA but
accepted and widely used in Europe
Low dose
Dose of allergen is greater than
subcutaneous immunotherapy
Efficacy of sublingual immunotherapy
20

Wilson et al. (2005)
systemic review of literature in Cochrane, Medline, Embase
library .
22 clinical studies, a total of 979 patients
double-blinded, placebo-controlled, parallel-group studies
Symptoms
SMD = -0.34
(-0.69,-0.15)
p= 0.002
medication
requirements
SMD = -0.43
(-0.63,-0.23)
p= 0.00003
Highly significant reduction in symptoms as
well as definite decrease in medicine intake
for symptoms
BUT sublingual immunotherapy equals the efficacy of
subcutaneous immunotherapy is not clear.
Long-lasting effect of SLIT in children with
asthma due to house dust mite
21
V.Di Rienzo, F.Marcucci, P.Puccinelli, S.Parmiani, F.Frati,
L.Sensi, GW Canonica, G. Passalacqua
Clin Exp Allergy, 2003
35 SLIT +
drugs
60 Children
No More SLIT
Mean
= 8.5 yrs
Asthma/
rhinitis
25 only
drugs
0
5
YEARS
10
Long-lasting effect of SLIT in children with
asthma due to house dust mite
22
0.001
n
No asthma
0.001
40
NS
0.001
0.001
1
1
4
30
2
20
10
The study demonstrates that SLIT is effective in
32efficacy
children and that it31maintains the clinical
31
for 4 to 5 years after discontinuation
24
23
24
SLIT
CTRL
BASELINE
4
SLIT
17
CTRL
END SLIT
3
SLIT
CTRL
10 YEARS
Asthma
Staloral®
23
Sublingual solution with allergenic extracts for ITS
One vial contains 10 mL of a
solution at:
10 ; 100 or 300 IR/Ml of one of
the allergen products.
IR : Index of Reactivity
24
Allergenicity
The allergen extract contains 100 IR/mL
Skin prick-test (Stallerpoint®) : wheal diameter
of 7 mm in 30 patients sensitized
Staloral®
25
Type I allergies for the classification
of Gell and Coombs,
including rhinitis, conjunctivitis,
rhinoconjunctivitis, asthma (minor to
moderate) of seasonal or per-year.
Dose journalière
300
300 IR/ml
200
10 IR/ml
100
100 IR/ml
During 3 years
0
1
3
5
7
9 11 13 15 17 19
INITIATION
MAINTENANCE
ALLERGEN EXTRACTS:
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
ACARIENS: Acarus siro (3.a); Blomia tropicalis (3.a);

POLLENS DE GRAMINEES: Chiendent pied-de-poule (Cynodon dactylon (L.) Pers.) (3.d) ; Dactyle aggloméré (Dactylis
Dermatophagoides farinae (3.d); Dermatophagoides pteronyssinus (3.d);
Glyciphagus domesticus (3.a);Lepidoglyphus destructor (3.b); Tyrophagus putrescentiae(3.a)
glomerata L.) (3.d); Fétuque des prés (Festuca pratensis Hudson.) (3.a), Fléole des prés , (Phleum pratense L.) (3.d); Flouve odorante
(Anthoxanthum odoratum L.) (3.d); Houlque laineuse (Holcus lanatus L.) (3.a); Ivraie vivace (Lolium perenne L.) (3.d), Pâturin des prés (Poa
pratensis L.) (3.d), 5 graminées (pollen de dactyle aggloméré, de fléole des prés, de flouve odorante, d’ivraie vivace, de pâturin des
prés) (3.d) ; Seigle (Secale cereale L.) (3.c).

POLLENS D’ARBRES : Aulne glutineux (Alnus glutinosa (L.) Gaertn.) (3.d) ; Bouleau blanc (Betula pendula Roth.) (3.d); Charme
(Carpinus betulus L.) (3.a) ; Châtaignier (Castanea sativa Mill.) (3.a) ; Chêne pédonculé (Quercus robur L.) (3.a) ; Cyprès d’Italie
(Cupressus sempervirens L.) (3.c) ; Frêne élevé (Fraxinus excelsior L.)(3.b); Génévrier de Ashe (Juniperus ashei Buchholz) (3.c); Hêtre
(Fagus sylvatica L.) (3.a); Marronnier d'inde (Aesculus hippocastanum L.) (3.a); Mimosa (Acacia dealbata link..) (3.a); Noisetier (Corylus
avellana L.) (3.d); Olivier (Olea europaea L.) (3.c) ; Peuplier blanc (Populus alba L.) (3.a) ; Platane hybride (Platanus hispanica x Mill ex
Munchh..) (3.a) ; Robinier faux-acacia (Robinia pseudoacacia L.) (3.a) ; Saule marsault (Salix caprea L.) (3.a) ; Sureau noir (Sambucus
nigra L.) (3.a) ; Tilleul à petites feuilles (Tilia cordata Mill.) (3.a) ; Troène (Ligustrum vulgare L.) (3.a)

POLLENS D’HERBACEES : Ambroisie à feuilles d'armoise

MOISISSURES : Alternaria alternata (3.c) ; Botrytis cinerea (3.a) ; Pleospora herbarum (3.a)

PHANERES : phanères de chat (3.c) ; phanères de cheval (3.b) : phanères de chien (3.b) ; phanères de cobaye (3.a) ; phanères de
(Ambrosia artemisiifolia L.) (3.d) ; Amarante réfléchie (Amaranthus
retroflexus L.) (3.a); Armoise commune (Artemisia vulgaris L.) (3.b); Chénopode blanc Chenopodium album L.) (3.a); Colza (Brassica napus
L.) (3.a); Marguerite (Chrysanthemum leucanthemum L.) (3.a); Ortie dioïque (Urtica dioïca L.) (3.a); Pariétaire de Judée (Parietaria
judaica L.) (3.c) ; Pariétaire officinale (Parietaria officinalis L.) (3.c); Pissenlit (Taraxacum officinale Web.) (3.a) ; Plantain lancéolé
(Plantago lanceolata L.) (3.a); Solidage du canada (Solidago Canadensis L.) (3.a); Soude salsovie (Salsola kaliL.) (3.a)
hamster (3.a) ; phanères de lapin (3.a).

INSECTES : blatte germanique (3.b) ; moustique (3.b)
Process of standardization of Staloral300.
27
Sieving
Drying
Storage
Process of standardization of Staloral300.
28
Extraction
Purification
Process of standardization of Staloral300.
29
Ajustement of
dosage of the
allergen
Standardization in
IR
History
30
1999
Purchase of Bayer
Pharma’s Allergy
division
the world’s number 2
company in its
market.
1995
Creation of a
subsidiary in
Germany and
purchase of a
laboratory in
Belgium
1997
Creation of a
subsidiary in Italy and
in Central Europe
(Czech Republic and
Slovakia);
Establishment in Antony
(Paris area)
1999
Opening of a
subsidiary in
Spain.
History
31
2000
Pursuit of
international
development in
South Africa,
Australia, New
Zealand and
Poland.
2003
The Stalair
program
2001
Stallergenes
enters the Middle
East markets
2007
Development of a
first product
candidate as part
of the Enhanced
Allergens
program
Development of recombinant allergens
32
produced by genetic engineering
complex
biological
extracts
products that
are purer and
have better
features
The Stalair programm
33
Phase I
Oralair®
Actair®
Stalair® rBet v1
Ragweed pollen
Japanese cedar
pollen
Phase II
Phase III
•Sublingual grass pollen immunotherapy tablets
•Marketed in Germany , Europe, Australia, Russia…
•Dust mite immunotherapy tablet
•Phase III adult (Europe). Current phase III study in children
•Recombinant birch pollen allergen
•Phase IIb/III clinical trial
•aimed primarily at the US market
•early stage of development
•aimed primarily at the Japanese market
•early stage of development
Approved
Oralair®
34
Phase IIb/III : Optimal dose of SLIT with a 5–grass
pollen tablet for seasonal allergic rhinitis
35
628 adults
(18-45 years)
With seasonal
grass pollen–
related
allergic rhinitis
10 % of
asthma
Optimal dose, efficacy, and safety of once-daily SLIT with a 5–grass pollen tablet for seasonal allergic
rhinitis, Alain Didier and al, Rhinitis, sinusitis, and upper airway disease, 2007 .
RTSS : Rhinoconjunctivitis
Total Symptom Score
36
Sneezing
Watery eyes
Rhinorrhea
RTSS
Ocular
pruritus
Nasal
congestion
Nasal
pruritus
Results of the study
37
RTSS
300-IR / 500-IR
≠ Placebo
P = 0.0001
Improvement
(Mean)
300-IR : 37.0 %
500-IR : 35.3 %
The 300-IR/500-IR doses both demonstrated
significant efficacy compared with placebo
The risk-benefit ratio favors the use of 300-IR
tablets for clinical practice
History
38
2008
24/01/08 : market authorization in
Germany for Oralair®
5-grass-pollen SLIT tablets in pediatric
allergic rhinoconjunctivitis
39
278 children
of 5-17 years
With seasonal
grass pollen–
related
allergic rhinitis
21.4 % of
asthma
Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic
rhinoconjunctivitis, Ulrich Wahn and al, Rhinitis, sinusitis, and upper airway disease, 2008.
Results of the study
40
RTSS
Improvement
300-IR ≠ Placebo
Mean : 28.0 %
P = 0.001
Median : 39.3 %
5-grass-pollen SLIT tablets (300 IR) reduce
RTSS in children and adolescents with grass
pollen–related rhinoconjunctivitis
History
41
2009
19/01/09 : paediatric marketing authorization
in Germany for Oralair®.
27/11/09 : European approval for the Oralair®
tablet in Europe
2010
19/04/10 : positive resultats of the phase III
« Oralair » in USA
Partnership-Oralair
42
Partnership of development
and marketing in Canada
(2007)
Partnership of marketing in
Russia and CEI (2009)
Oralair®
43
ORALAIR 100 IR & 300 IR sublingual tablets
Initiation treatment
ORALAIR 300 IR sublingual tablets
Continuation treatment
Oralair®
44
THERAPEUTIC INDICATIONS :
Treatment of grass pollen allergic rhinitis
•with or without conjunctivitis
•in adults, adolescents and children above the age of 5
•with clinically relevant symptoms,
•confirmed by a positive cutaneous test
and/or
•a positive titre of the specific IgE to the grass pollen.
Pharmacotherapeutic group: Allergen extracts, grass pollen.
ATC code: V01AA02
Actair®
45
THERAPEUTIC INDICATION :
allergic rhinitis to dust mites
Phase IIb/III : Safety and Efficacy Study of SLIT
in House Dust Mite Allergic Rhinitis
46
Placebo
486 adults
(18-50 years)
House dust
mite-related
allergic rhinitis
300 IR
500 IR
12 months
The results are positive but not published
Pediatric Phase III : Study of SLIT in House
Dust Mite Allergic Rhinitis
47
Placebo
471 children
(5-17 years)
House dust
mite-related
allergic rhinitis
300 IR
36 months
About 1 year after the start the committee of experts (DSMB)
recommanded termination of the study
The study is terminated in 04/07/2011
Actair®
48
History
49
September
2010
an exclusive partnership with Shionogi
The agreement signed in Japan
50
the tablet against Japanese cedar pollen
Actair® (immunotherapy tablet against dust mites)
This agreement is financially satisfactory:
€ 24 million upfront,
€ 46 million of development milestones plus royalties on sales
History
51
November
2010
Transfer of the 47% shareholding held by
Wendel Group in Stallergenes SA to Ares Life
Sciences I SARL
Ares Life Sciences :
a new majority shareholder
52
10/11/2010 :
Wendel transfers its 47%
shareholding to Ares Life
Sciences (a 300 million € benefit
for Wendel)
Ares
manages its
own funds
origins in the
pharmaceutical
industry and in
biology
Public offering by
Ares Life Sciences
(march 2011)
significant
financial
resources
Goal = international expansion, particularly in USA
Invaluable
support and
experience
Leadership transition : a consequence ?
53



Albert SAPORTA
Chairman and chief
executive officer
(since 1999)
Non executive
chairman
(01/2012)
Managing director
(since 2002)
Leaves the
company
(10/2011)
Former Executive
Vice-President of the
Merck-Serono Group
Managing director
(10/2011)
Louis CHAMPION
Roberto GRADNIK
History
54
January
2011
Stallergenes opens a new raw material
production unit in Amilly (Loiret).
A new raw material
production unit situated in Amilly
an investment of
€ 6 million
55
dedicated to the harvest and treatment of grass pollens
(Oralair®, allergic immunotherapy treatments)
The area of cultivation
will reach150 hectares
in the next few years,
allowing Stallergenes to
produce
half of its grass pollen
requirements.
importance of
quality assurance
and
standardisation
an extension
of its
dustmite
production
activities ?
World's leading producer of
grass pollens and house
dust mites
Development in the United States
56



The VO61.08 trial conducted with Oralair® :
positive
May 2011 : subsidiary in US (Boston)
Stallergenes is preparing for a pre-BLA in
the context of a BLA (Biological License
Application) with the FDA.
Marketing of 3 products : Oralair ®, Actair ®, Ragweed pollen tablet
An international presence
57
Market focused in Europe (mainly in
Germany, France, Spain and Italy
Sales of Stallergenes :
96% in Europe
Market and competitors
58
Current Market of 750 M€
Market in 2022 : 3.5 B€
60% of the world market is
shared by Stallergenes and
ALK-Abello
Just three pure players :
Stallergenes , ALK-Abello and
Allergy Therapeutics
ALK-Abello is yet in USA
AMM of GRAZAX (ALK-Abello)
in France
Great performance in a difficult context
59
Capturing market share thanks to Oralair®
Great performance in a difficult context
60
European market trends : 3% decrease in S1 2011
• German rebate
• Regulatory pressure in the Netherlands
• Very low pollen season in 2010
• Economical crisis in southern Europe (Spain, Italy, Greece)
Stallergenes : 4% increase of market share
• Lesser presence in Germany and Netherlands
• Oralair success : resisting better than competition in
Germany + increasing global sales in other countries
Products
61
Information and services
62
MEETINGS
with doctors in their
surgeries to international scientific
conventions.
VARIED MEANS OF
COMMUNICATION:
telephone
assistance, teaching
materials, training,
postgraduate
teaching programmes
AN INTERACTIVE WEB
SITE
with a
reserved area for
healthcare professionals
and a medical
document database
Information and services
63
AN INTERACTIVE WEB
SITE
An area dedicated to the
general public and
patients
APSI
- deferred payment systems,
-a voice server to follow
on a daily basis the preparation
of their treatment,
-the sending of SMS
to notify them of the shipment
date of their treatment.
64
FINANCIAL ANALYSIS
Evolution of turnover (Sales)
65
250,000,000
225,000,000
9%
200,000,000
12%
Chiffres d'affaires
175,000,000
13%
150,000,000
16%
125,000,000
16%
100,000,000
2006
2007
2008
2009
2010
2011
R&D investment
66
R&D investment :170 million in 7
years (since 2004)
Investments carried out in France, in collaboration with competent public scientific organisations
:CNRS, INSERM, CEA, the Institut Pasteur, INRA, CEMAGEF
Gross Margin
67
255,000,000
205,000,000
77,64% CA
155,000,000
Chiffres d'affaires
Marge brute
105,000,000
55,000,000
5,000,000
2006
2007
2008
2009
2010
Net Income
68
250,000,000
200,000,000
150,000,000
Chiffres d'affaires
Résultat net
100,000,000
50,000,000
14,2%CA
2006
2007
2008
2009
2010
EBITDA
69
250,000,000
200,000,000
150,000,000
Chiffres d'affaires
EBITDA
100,000,000
50,000,000
2006
2007
2008
2009
2010
ROTA (%) – Economic returns
70
R.E
Actifs
Resultat
=
EBIT
Total Net Assets
120
100
80
60
40
48.09
35.86
32.98
30.47
32.92
2006
2007
2008
2009
20
0
2010
EBIT
ROTA (%)
Total capitaux investis
ROE (%) – Financial returns
71
Capitaux
propres
R.F
=
Resultat
RNC
Capitaux propres
140
120
100
80
RNC
ROE
CP
60
40
34.67
27.7
24.09
23
21.61
23.55
2006
2007
2008
2009
2010
20
0
2005
Share Price
72
AMMORALAIR
Allemagne
PIII +
ACTAIR
UE
Supply of
Ares
59 €/share
Arret de
PIII
ACTAIR
SWOT
73
STRENGHT
•Stalair® : 5 major allergens in the
world
•Satisfactory clinical data
•Leading producer of pollen & dust
mite
•Global extension
•Development contract with Japan
•Potential disease modifying
WEAKNESS
•Laboratory without experience for
the process approval and
administrative procedures
•ALK already present in the US
•Depending on the pollen season
•High cost treatment
SWOT
74
OPPORTUNITIES
•Growing awareness of allergic
rhinitis
•Sublingual IT still lacking from many
countries
•Limited competition
•Generic products excluded from this
market
•High-technology for the extraction
of natural products
THREAT
•Reduction in health spending by the
States
•Slow approval procedures
•Increased administrative costs
related to the process of approvals
Trophies of Stallergenes
75
BFM
AWARDS
2009
Trophée des
industriels
2010
76
THANKS FOR
YOUR ATTENTION !