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Together we innovate …
Strategy Analysis
March 2009
Josselin Courselle
Rebecca Deprez
Julien Maurin
Thomas Patard
1
This is an independent
study performed by
students from the Faculté
des Sciences
Pharmaceutiques of Lille.
The opinions expressed
are our own and not
necessarily those of
Actelion.
2
From ambition …
− 1990 : Roche discovered the first
ENT
DAN
O HELIN
RECEPTOR
TAGONIST
− 1996 : Roche drops clinical trials on
bosentan (liver toxicity).
− 1997: Founding Actelion.
(Allschwil, Switzerland)
JP Clozel
CEO
M Clozel
VP Drug Discovery,
Pharmacology
Preclinical Dev
A Muller
Chairman Board
Former CFO
W Fischli
T Widmann
VP Drug Discovery, Former CEO
Biology
3
… to realization 10 years on
−
−
−
−
−
20 countries worldwide
1949 employees
2000 : IPO Swiss New Market (256Mio CHF)
In the top-15 biopharmaceutical companies
2008 : Entry into the SwissMarketIndex , Best performing stock !
Sales
Marketing
Development
4
3 Marketed products
Zavesca® (miglustat)
Type 1 Gaucher’s disease
Ventavis® (iloprost)
Inhaled prostacyclin
for PAH therapy
Tracleer® (bosentan)
Oral dual endothelin receptor
antagonist « Entan »
For PAH & Digital Ulcers
5
Actelion : A strong communication on
Pulmonary Arterial Hypertension,
Endothelin,« Entans »
PAH_info.com
Endothelin.org
Owns visual and verbal
nomenclature of an entirely new
class of compounds
6
Actelion in Mid-2003
Acquisition
Partnership
Veletri
tezosentan
In-Licencing
Reward
Risk
Generics
Specialty
Pharmaceuticals
Orphan drugs
Hospital drugs
GP products
Actelion :
A Clinical
Developement Company
7
2003-2004: moving upward the
DD pipeline
Sept-2003 :Axovan acquisition
• Phase II clazosentan
• Numerous pre-clinical projects
• Chemistry platform
• GPCR platform
GPCR
Actelion :
A Drug discovery Company
8
2003-2008 : Niche extension PAH &
CardioVascular diseases
Acquisition
PGI2 agonist
Partnership
Pivlaz
In-Licencing
Macitentan
Reward
Clazosentan
Risk
Veletri
tezosentan
Generics
Specialty
Pharmaceuticals
Orphan drugs
Hospital drugs
GP products
9
Acquisition
2003-2008 : Moving towards GP
market
S1P1 Agonist
Orexin
Antagonist
Partnership
CRTH2
Antagonist
In-Licencing
Reward
Risk
Renin
Inhibitor
Generics
Specialty
Pharmaceuticals
Orphan drugs
Hospital drugs
GP products
10
Major therapeutic areas &
Marketed Products
− Pulmonary Arterial Hypertension
−Gaucher’s disease
11
What is PAH?
-Sustained elevation of pulmonary vascular resistance :
>25 mmHg (at rest)
>30 mmHg (while exercising)
right ventricular failure and premature death (median survival 2.8 y)
-Small pulmonary arteries obstruction due to
Vasoconstriction
Thrombosis
Smooth muscle and endothelial cell proliferation
12
WHO functionnal classes
Class I
PAH but without limitation of physical activity.
Class II
Slight limitation of unsual physical activity : dyspnoea or
fatigue, chest pain or near syncope
Comfortable at rest
Class III
Marked limitation of ordinary physical activity.
Comfortable at rest.
Class IV
Inability to carry out any physical activity without
symptoms. Signs of right heart failure.
Dyspnoea and/or fatigue may even be present at rest
mean age of diagnosis: 36
years1
prevalence of 30-50 cases
per million2
1:
Sitbon O et al. Am J Resp Crit Care Med 2008 ; 2: Peacock AJ. BMJ 2003
13
Why does it develop?
− Reduced production of vasodilators
– Prostacyclin
– NO
− Increased production of vasoactive
compounds
– Endothelin (ET)
14
PAH therapy & Actelion portfolio
15
PGI2 pathway : Competitors
Flolan® (epoprostenol: PGI2)
Natural prostacyclin
Remodulin® (treprostinil)
Synthetic analogue
Short half-life
 Intraveinous perfusion
Preferentially given subcutaneously
(small infusion pump)
Low impact on quality of life and
mortality
Pain and discomfort (85% of patients)
75,000 $/year
45,000 $/year
16
Ventavis® (Iloprost) for PAH
PGI2 receptor agonist
2007: CoTherix acquisition
GPCR
17
Ventavis®, freedom from iv prostacyclins
Inhaled formulation of iloprost
↑ stability and ↑ half-life vs natural PGI2
Approved for PAH Class III or IV
Cost: 3100€ / year
The only inhaled PAH therapy on the US market
18
Ventavis®, contributing to growth
− Developed by Schering
− 2004 :Approval & Licenced to CoTherix in US
− 2007 :Acquisition of CoTherix
Bayer Schering Pharma sales in EU & other
countries; Actelion in US
− 2008 : Sales reach CHF 94.6 m
34% increment
19
Ventavis® : Improve access
to treatment
I-neb Adaptative Aerosol Delivery System
Pulmonary drug delivery device
Battery powered
Adaptive Aerosol Delivery (AAD®) technology:
−Constant amount of drug is inhaled
−No waste
Ann Pharmacother. 2005 Jul-Aug;39(7-8):1265-74.
Inhaled iloprost in pulmonary arterial hypertension. Baker SE, Hockman RH.
Prodose AAD
20
Tracleer® (bosentan) for PAH
Mixed ETA/ETB entan
1st in class
GPCR
21
2000: in-licenced from Roche
ET mediated effects in PAH
British Journal of Pharmacology (2008) 153, 1105–1119
22
Bosentan Tracleer®
- 2002 : PAH class III & IV
- 2008 : PAH class II (EARLY)
- 2008 : Digital Ulcers (PAH with connective tissue
diseases like systemic sclerodermia)
- Sales : CHF 1.2 b ; +17%; constant growth
23
Entans competition
ICOS/Encysive/Pfizer
Launched
Myogen/Gilead/GSK
Launched
−Ambrisentan (Letairis® Volibris ® ) 2008 : $112.9 million (US); EU launched
−Sitaxsentan (Thelin ® ) acquired by Pfizer in 2008
Gilead
Updated from Nature Reviews Drug Discovery 986 | 2002 | VOLUME1
Phase III
24
Other PAH competitors in NO
pathway
− Sildenafil (Revatio ® Pfizer) PDE5 inhibitor
(03/2005).
− Riociguat (Bayer Schering Pharma) soluble
guanylate cyclase (sGC) stimulators. Phase III
25
Miglustat (ZavescaTM)
Targeting Genetic disorders
2002: in licenced from OGS / then Celltech
26
Type 1 Gaucher : A bone disease
−
−
−
−
−
Inherited autosomal recessive disorder
Reduced activity of lysosomal ß-glucocerebrosidase
Accumulation of glucosylceramide
Necrosis of bone marrow infiltrated with Gaucher cells
Bone pain, osteonecrosis due to abnormal remodeling
27
Type 1 Gaucher : Treatment
− Enzyme replacement
− Substrate Reduction therapy (inb. Glucosylceramide synthase)
− Chemical chaperone
Glucosylceramide
Substrate
reduction
therapy
glucosylceramide
synthase
3*100 mg/day
~91 881 € /y
Defective
ß-glucocerebrosidase
Ceramide
Chemical
chaperones to
reactivate defective
enzymes
NATURE REVIEWS | MOLECULAR CELL BIOLOGY V5 | JULY 2004 | 554
Enzymereplacement
therapy (ERT)
CEREZYME®
60 IU/kg/2 weeks
~86 140 - 430 700 € /y
Future Lipidol. 2008 June ; 3(3): 273–300.
NATURE REVIEWS | CANCER V4 | AUGUST 2004 | 604
28
Miglustat sales
+20%
29
Niemann-Pick type C disease
−
−
−
−
−
Very rare
Reduced activity of lysosomal sphingomyelinase
Accumulation of sphingomyelin
Severe SNC disabilities
Zavesca® Approved in 2008 as a sphingomyeline
synthase inhibitor
Substrate
reduction
therapy
30
Broad Clinical Portfolio
31
Life cycle management &
current drug families
Miglustat
Iloprost & other PGI2r agonists
Entans
32
Zavesca® in Cystic Fibrosis
− Autosomal recessive genetic disorder
− Progressive lung & pancreas dysfunction
− Caused by defected CFTR chloride channel
−Norez C., Noel S., Wilke M., Bijvelds M., Jorna H., Melin P., DeJonge H. and Becq F. Rescue of functional delF508-CFTR
channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat. FEBS Lett. 508, 2081-86; 2006.
33
Zavesca® in Cystic Fibrosis
Chemical
chaperones to
reactivate defective
enzymes
− Acts as a chemical chaperone of the
CFTR (del508)
− Phase IIa results expected Q2-2009
−Norez C., Noel S., Wilke M., Bijvelds M., Jorna H., Melin P., DeJonge H. and Becq F. Rescue of functional delF508-CFTR
channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat. FEBS Lett. 508, 2081-86; 2006.
−Antigny et al, Cell Calcium, 43, 175-183 2008
34
PGI2 agonists :Improve patient
access to treatment
Q2 2009 – PROWESS 15
New device to ↓ inhalation time and ↑ patient compliance
Study design: 64 patients, crossover study
35
PGI2 agonists : New combinations ?
2006 :phase II/III STEP
Efficacy and added benefit of using Ventavis® in
patients with PAH already undergoing treatment with
bosentan, or sildenafil
Mc Laughlin et al., AJRCCM, 2006
Ghofrani et al., JACC, 2003
36
Improve patient access to treatment :
PGI2 agonists in a pill ?
GPCR
− Discovered by Nippon Shinyaku
− 2008: Actelion outside Japan &
co-development & commercialization in Japan
− First-in-class , Non-prostanoid PGI2 receptor agonist
− Pro-drug offers protection to gastro-intestinal tract
37
ACT-293987: current status
Results of phase I
Good safety profile
Linear PK after single oral dose
Half-life supports twice-a-day oral dosing
No accumulation after multiple dosing
2008 : A phase IIa study in PAH
Objective: evaluate acute hemodynamic
effects and tolerability of up-titration to 800μg
bid
Results are expected in Q3 2009
−Kuwano et al (2008). J Pharmacol Exp Ther 326: 691-699.
38
Bosentan : Extension of Indications
2002
Chronic Thrombo Embolic
Pulmonary Hypertension
2007
2008
+ Sildenafil
39
Bosentan in IPF (Idiopathic
Pulmonary Fibrosis ) Ph.III
− Orphan disease
− Easily diagnosed (unlike PAH)
− Death in 3-years
− Bosentan normalizes cells with fibers
− Results expected in Q2-2009
− If Bosentan goes in IPF, Fast track status
and double revenue in 2 years
King T.E. et al. High-resolution computed tomography (HRCT) features
correlate with response to bosentan in idiopathic pulmonary fibrosis
(IPF): the BUILD 1 study [abstract]. Am J Respir Crit Care Med.
175:A567; 2007.
40
Macitentan in PAH Ph.III
− 100 times more potent than bosentan
− Mixte ETA/ETB
− Directed towards tissues to avoid
vascular effects
− SERAPHIN study
− Expected results in 2009
US5,292,740
Tracleer Patent Extension till Nov-2015 (US) 2017 (EU)
41
Clazosentan in cerebral vasospasm.
Ph.III
− Cerebral vasospasm occurs after
subarachnoid hemorrhage from
a ruptured aneurysm
− 10-15% die or permanent disability
− ETA antagonist designed for parenteral use
− Used as prevention of rebleeding of coiled or
clipped aneurysms
J Neurosurg 103:9–17, 2005
Ro 61-1790, VML 588, and AXV-034343
CONCIOUS
42
Tezosentan VeletriTM
in post cardiac surgery
− 2001 VERITAS study for Acute Heart Failure
does not meet primary efficacy objective.
− 2004 VERITAS study being stopped for
futility.
− 2008 in cardiac bypass separation was
lower than expected.
43
New therapeutic areas
Autoimmune disorders
Asthma
Sleep disorders
44
GPCR
ACT-S1P1 agonist
for autoimmune diseases
(S1P = Sphingosine-1-phosphate)
45
Sphingosine-1-phosphate receptor
& S1P
− S1P :
− Bioactive lipid
− Released by platelets, mast and other cells.
− Regulate migration of lymphocytes
− S1P receptors :
− GPCRs ; 5 subtypes
− Agonists lock lymphocyte
migration and prevent lymphocyte
recruitment to sites of inflammation
46
Autoimmune Diseases
− Diseases that involve
migration of pathogenic
lymphocytes from lymph
node to tissues
Psoriasis
Multiple sclerosis
Rheumatoid Arthritis
47
ACT-S1P1 receptor agonist
− First-in-class since selective S1P1
− once-a-day oral dosing
− Competitor : FTY520 (Novartis) Phase III (not selective)
OH
OH
NH2
− Program initiated in 2004
− 2006 Partnership with Roche
− 2008 Phase II in Psoriasis
Kappos L. et al. N Engl J Med 355(11):1124-40; 2006
48
GPCR
CRTH2 antagonists
for allergic airway inflammation
49
CRTH2 receptor
GPCR
Chemoattractant Receptor – homologous
molecule expressed on Th2 lymphocytes
− Cognate receptor for PGD2
− Role in Th2-dependent allergic
inflammation
− Involved in patients suffering from asthma
Novel oral treatment for allergic airway
disease
50
Mode of action
Allergen
Mast cell
PGD2
CRTH2
Migration
Local activation
Cytokine release
Amplification of symptoms
Allergen induces release of PGD2
Th2 cells
51
Mode of action
Mast cell
PGD2
Receptor antagonist
CRTH2
↓ recruitment
activation
amplification
symptoms
Th2 cells
CRTH2 receptor antagonist prevents recruitment and stops the process
52
GPCR
Current status CRTH2 antagonists
Preclinical
− inhibits secretion of proinflammatory cytokines by Th2
cells
− inhibits migration of eosinophils
Clinical data
− Well tolerated in healthy volunteers
− Phase IIa double-blind, placebo controlled, crossover
study (proof of mechanism) in asthma completed
− Phase IIb in asthma initiated in 2009
53
Almorexant for sleep disorders
Oral orexin receptor antagonist
GPCR
54
Almorexant
− Orexins = A pair of highly excitatory neuropeptide
hormones
− First-in-class orexin receptor antagonist
− Treatment for insomnia or jetlag
− The only compound in Phase III
Hoever P, et al.SLEEP 2008 22nd Annual
Meeting of the Associated Professional Sleep
Societies, LLC (APSS) June 7-12, 2008
55
Almorexant and Sleep cycle
56
The Sleep-Wake Switch:
Wakefulness
Orexin
VLPO = ventrolateral preoptic area
Orexin
Circadian “alerting” signal
Saper CB et al. Hypothalamic regulation of sleep and circadian
rhythms. Nature 2005;437:1257-1263.
57
Key data for Almorexant
− Partnership with GSK and the two companies
sharing profit.
− GSK finances 40% of development cost
− Clinical trial end of phase III
− Results in Q3 2009
58
Almorexant partnership
− Actelion received an up front payment of CHF 150
million
− About CHF 3 billions for all milestones
Possibilities for Actelion to develop another research
program
59
Why Almorexant could be a
blockbuster ?
− 25-30% of western populations suffer from
insomnia1
− In US direct health effects of insomnia cost
at least 15 billion USD2
- Up to 2-3 billion USD market/year3
− 7 of the 10 best pharma were at the door
after 1 week3
1:WHO
2:Hublin, C., Kaprio, J., Partinen, M. & Koskenvuo, M.
Insufficient sleep — a population-based study in adults.
Sleep 24, 392–400 (2001)
3: Reuters
60
Summary of Expectations for 2009
Healthcare Conference
27th Annual Healthcare Conference
J.P. Morgan is pleased to announce the 27th Annual Healthcare Conference, January 12-15, 2009 in San Francisco
61
Our Opinion About Actelion
Financial Analysis
SWOT
Would we join Actelion?
62
Financial data
IPO: about CHF 250 m
Market capitalization as of IPO: CHF 1 Billion
2008: CHF 7,4 Billion
Major shareholders as per 31-12-2008
−Management and Directors > 5%
−BB Biotech > 5%
−Fidelity Management and Research > 5%
−Rudolf Maag > 5%
−Actelion Ltd > 3%
−Barclays PLC > 3%
−MFS Investment Management > 3%
−Credit Suisse > 3%
63
Operating Income
CHF millions
400
300
200
371.4
268.2
100
85.6
152.3
142.6
0
2004
2005
2006
2007
2008
64
Cash EBIT
600
CHF millions
FX impact
500
400
300
200
100
471.4
476.8
2007
2008
320.4
105
178.6
0
2004
2005
2006
65
Key financial results
− Strong financial performance
– Cash ↑
– 2-digit growth
− Financial independance
− Strong performance of all marketed products
Healthcare Conference
27th Annual Healthcare Conference
January 12-15, 2009 in San Francisco
66
Progression of revenues
1473.5
Company report 2007 & 2008
67
Tracleer in total net revenues
2007
2008
− Tracleer is 90% revenue
− Sales will progress in 2009 (new indications)
− Competitors
68
Actelion: Inside Analysis
Strengths
Weaknesses
−Important partnerships
−Only one blockbuster (2015 US
−Cash
2017 EU)
−Efficient technological platforms
−Lack of diversification the
−Clinical expertise
«Entans » company
−Independence of research
−First-in-class
−Rapid development
−First-in-class
−Blockbuster: Tracleer®
−Possible blockbuster: Almorexant®
69
Actelion : Outside analysis
Opportunities
Threats
−New partnerships
−Sildenafil (Revatio®)
−New candidates (cash)
−Sitaxsentan (Thelin®)
−Actelion buyout (?)
−Actelion buyout
70
Would we join Actelion?
− In R&D (309 + 495 employees):
–
–
–
–
Good technical platforms;
25 active projects in drug discovery
10 compounds in clinical development
R&D expenses growth:
71
Would we join Actelion?
− In Sales & Marketing (852 employees):
– Sales in GP products will be done in Partnership
Ex for Almorexant :
• In key markets, Actelion books sales.
• In emerging markets GSK books sales.
– Still a lot to do in specialists areas
• Creating and shape a long-term PAH franchise and
Digital Ulcer market
• Build the IPF market
– Markets in Latin America, Middle East and Asia
− In Regulatory affairs
72
Some job offers
73
PGI2
PGI2agonist
agonist
Macitentan
Macitentan
S1P1 Agonist
Pivlaz
Pivlaz
Clazosentan
Clazosentan
Generics
CRTH2
Antagonist
Renin
Inhibitor
First in class products
Therapeutic niches
Nevertheless:
1 blockbuster
A Rich pipeline
Good perspectives
Orexin
Antagonist
Specialty
Pharmaceuticals
Orphan drugs
Hospital drugs
GP products
74
Thank you for your attention
75