Actelion

ACTELION LTD
DELIVERING ON OUR STRATEGY

Company Presentation
February 2016
Copyright 2016 Actelion Pharmaceuticals Ltd
The following information contains certain forward-looking statements, relating to the

companys business, which can be identified by the use of forward-looking terminology such
as estimates, believes, expects, may, are expected to, will, will continue, should,
would be, seeks, pending or anticipates or similar expressions, or by discussions of
strategy, plans or intentions. Such statements include descriptions of the companys
investment and research and development programs and anticipated expenditures in
connection therewith, descriptions of new products expected to be introduced by the company
and anticipated customer demand for such products and products in the companys existing
portfolio. Such statements reflect the current views of the company with respect to future
events and are subject to certain risks, uncertainties and assumptions. Many factors could
cause the actual results, performance or achievements of the company to be materially
different from any future results, performances or achievements that may be expressed or
implied by such forward-looking statements. Should one or more of these risks or uncertainties
materialize, or should underlying assumptions prove incorrect, actual results may vary
materially from those described herein as anticipated, believed, estimated or expected.
2016 Actelion Pharmaceuticals Ltd
February 2016
Company presentation
TABLE OF CONTENTS
Actelion at a Glance
Actelion Today
Strategy for Value Creation
Sustain & Grow the PAH Franchise
Build Additional Specialty Franchises
Optimize Profitability
Management & Board
February 2016
ACTELION
AT A GLANCE
February 2016
ACTELION PHARMACEUTICALS LTD

ACTELION IS A FULLY INTEGRATED BIOPHARMACEUTICAL
COMPANY WITH INNOVATION AT ITS CORE
Leader in the
science and medicine of
pulmonary arterial hypertension
(PAH)
Actelion Center, Allschwil
FOUNDED IN 1997 IN ALLSCHWIL, SWITZERLAND

Total employees (December 15)
Drug Discovery
Clinical Development
Marketing & Sales
Support Functions
2,547
371
422
1,425
329
Global reach with more than 30 affiliates worldwide

7 Products on the Market:
Opsumit, Tracleer, Uptravi, Veletri, Ventavis, Valchlor,
Zavesca
2015 Sales: CHF 2.042 Billion
Core earnings: CHF 814 million
Over 65000 Patients currently treated with an Actelion
medication
Extensive Research & Development portfolio
February 2016
STAGES OF COMPANY DEVELOPMENT

2020
2014
2007
2001
1997
Build pipeline
and commercial
Company formed,
infrastructure
development
& approval of
Tracleer
February 2016
Commercial
leverage
and prepare for
Tracleer LOE
Opsumit, Uptravi
and development of
new franchises
PAH, Life Cycle

Management
and New
Franchises
ACTELION TODAY
February 2016
ACTELION TODAY
A UNIQUE COMPANY
1 Based on innovation
2 Fully integrated and global
3 Highly profitable
4 Comprehensive infrastructure
5 Unencumbered assets
February 2016
ACTELION TODAY
A UNIQUE COMPANY
Searching only for innovative products
In-house research infrastructure from

discovery to clinical development
With a broad pipeline of interesting

projects on novel targets
3 Highly profitable
February 2016
ACTELION TODAY
FULLY INTEGRATED AND GLOBAL
A UNIQUE COMPANY
From Research to Commercialization
More than 30 operative affiliates worldwide
Product availability in >60 markets
3 Highly profitable
Commercial Operations
R&D Centers
10
February 2016
ACTELION TODAY
A UNIQUE COMPANY
CORE EARNINGS
3 Highly profitable
11
February 2016
900
800
700
600
500
400
300
200
100
0
2009
2010
2011
2012
2013
2014
2015
ACTELION TODAY
A UNIQUE COMPANY
Swiss company
One discovery center in Switzerland
3 Highly profitable
Full global development capabilities
Fully established infrastructure from

process to buildings
Focus on quality
12
February 2016
ACTELION TODAY
A UNIQUE COMPANY
Full rights to all products*
Strong balance sheet and financing capacity
No major alliances for own products
3 Highly profitable
*Cooperation with Nippon Shinyaku in

Japan for macitentan and selexipag
13
February 2016
STRATEGY FOR VALUE

CREATION
SUSTAIN AND
GROW THE PAH
FRANCHISE
BUILD ADDITIONAL
SPECIALTY
FRANCHISES
OPTIMIZE PROFITABILITY
14
February 2016
STRATEGIC PRINCIPLES
FOUR GOALS FOR ACTELION
Drive innovation forward
Maximize the value of innovation
Pursue top quality science, internally

and externally, balanced with medical
need and commercial potential
Leverage our global presence
Insist on the highest quality in all we do
Expand innovative commercial

capabilities to new customers and
regions. Manage alliances putting the
product first
15
February 2016
Develop projects ourselves and seek

partners or out-license when necessary to
maximize value
Quality is crucial and needs to be

ingrained across all functions
2015
STRONG PERFORMANCE CONTINUES
Operational Highlights
Strong, sustained Opsumit launch trajectory across

markets
Uptravi Approved and launched in the US, EU filing
resulted in positive CHMP opinion
Pipeline Advancing late-stage assets
Pipeline Significant progress in discovery and earlystage development
16
February 2016
2015
KEY FINANCIAL HIGHLIGHTS
Core EPS
PRODUCT SALES
CHF 6.16
>CHF 2
BILLION
CASH RETURNED
TO SHAREHOLDERS
CORE EARNINGS
>CHF 800
MILLION
17
February 2016
ALMOST
CHF 1
BILLION
STRATEGY FOR VALUE

CREATION
SUSTAIN AND
GROW THE PAH
FRANCHISE
BUILD ADDITIONAL
SPECIALTY
FRANCHISES
18
February 2016
PULMONARY ARTERIAL HYPERTENSION

A LIFE-THREATENING AND OFTEN MISUNDERSTOOD CONDITION
Disease of the blood vessels carrying blood from the heart to the lungs
- the pulmonary arteries

When PAH develops, blood circulating through these vessels becomes
restricted, and the right side of the heart is put under increasing strain to pump
blood through the lungs
Normal artery
19
Artery showing
vasoconstriction
February 2016
Diseased artery showing tissue

thickening and fibrosis
CLINICAL SEVERITY OF PAH

CLASSIFIED BY WORLD HEALTH ORGANIZATION (WHO)
This system grades PAH severity according to the functional status of the patient
FUNCTIONAL
CLASS
SYMPTOMATIC PROFILE
Patients with pulmonary hypertension but without resulting limitation of physical activity.
Ordinary physical activity does not cause dyspnoea or fatigue, chest pain, or near
syncope.
II
Patients with pulmonary hypertension resulting in slight limitation of physical activity.

They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or
fatigue, chest pain, or near syncope.
III
Patients with pulmonary hypertension resulting in marked limitation of physical activity.

They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or
fatigue, chest pain, or near syncope.
IV
Patients with pulmonary hypertension with inability to carry out any physical activity
without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or
fatigue may even be present at rest. Discomfort is increased by any physical activity.
20
February 2016
TREATMENT PATHWAYS IN PAH
ENDOTHELIN RECEPTOR
ANTAGONISTS (ERA)
PHOSPHODIESTERASE-5INHIBITORS (PDE-5i)
PROSTACYCLIN
RECEPTOR AGONISTS
IP
RECEPTOR
AGONIST
21
February 2016
PGI2
ANALOGUES
SIGNIFICANT PROGRESS IN THE FIELD OF PAH
PAH targeted therapies

Multiple approved
1st
1st
PGI2
1990
INCREASING DISEASE
AWARENESS
PRECLINICAL/
CLINICAL RESEARCH
22
Oral PDE-5i
2000
IMPROVEMENT IN SYMPTOMS,
MEASURED BY 6MWD
ERA:
PDE-5i:
PGI2:
Oral ERA
1st
NATIONAL
NETWORKS
endothelin receptor antagonist

phosphodiesterase-5 inhibitor
prostacyclin
February 2016
2010
DISEASE WORSENING, MEASURED BY

TIME TO CLINICAL WORSENING
REFERENCE
CENTERS
PATIENT
ASSOCIATIONS
DISEASE
REGISTRIES
therapies in 2010
CONTROLLED
CLINICAL TRIALS
EVIDENCE-BASED
GUIDELINES
PROCEEDINGS FROM
3RD WORLD
CONGRESS 2003
ESC 2004
GUIDELINES
DISEASE PROGRESSION OVER YEARS,

MEASURED BY MORBIDITY/MORTALITY
SCREENING
HIGH-RISK GROUPS
PROCEEDINGS FROM
4TH WORLD
CONGRESS 2008
ESC/ERS 2009
GUIDELINES
ORAL THERAPIES IN PAH

RANDOMIZED CONTROLLED TRIALS
Drug
Study
Duration
Primary endpoint
No. of
patients
Study-3511,2
12 weeks
6-MWD
32
BREATHE-13
16 weeks
6-MWD
213
EARLY4
24 weeks
PVR, 6-MWD
185
Sildenafil
SUPER-15
12 weeks
6-MWD
277
Tadalafil
PHIRST6
16 weeks
6-MWD
405
ARIES-17,8
12 weeks
6-MWD
202
ARIES-27,9
12 weeks
6-MWD
192
AMBITION10
78.6 weeks
Clinical failure
610
Macitentan
SERAPHIN11
103.9 weeks
Morbidity/Mortality
742
Selexipag
GRIPHON12
76.4 weeks
Morbidity/Mortality
1,156
Bosentan
Ambrisentan
Short-term
fixed
treatment
period trial
design
1. Channick RN, et al. Lancet 2001. 2. Badesch D, et al. Curr Ther Res 2002.
3. Rubin LJ, et al. N Engl J Med 2002. 4. Gali N, et al. Lancet 2008.
5. Gali N, et al. N Engl J Med 2005. 6. Gali N, et al. Circulation 2009.
7. Gali N, et al. Circulation 2008. 8. Oudiz R, et al. Chest 2006.
9. Oudiz RJ, et al. J Am Coll Cardiol 2009. 10. Gali N, et al. Eur Respir J 2014.
11. Pulido, et al. N Engl J Med 2013. 12. Sitbon O et al. N Engl J Med 2015.
23
February 2016
EVOLUTION OF THE TREATMENT GUIDELINES

FROM RANDOMISED CONTROLLED TRIALS TO EVIDENCE-BASED
GUIDELINES
A wealth of data concerning PAH management has emerged in recent years
Not only from RCTs, but also clinical practice, including disease registries
This has led to published management guidelines1, updated

recommendations2, and approval of multiple therapies
1. Gali N, et al. Eur Heart J 2009. 2. Gali N, et al. J Am Coll Cardiol 2013.
24
February 2016
TRACLEER: OUR FIRST

SUCCESS
25
February 2016
TRACLEER: FIRST ORAL PRODUCT IN PAH

THE FIRST DECADE OF SHAPING PAH TREATMENT
Tracleer (bosentan) is an orally available

endothelin receptor antagonist (ERA) approved
for the treatment of PAH in over 60 countries, including
the United States in November 2001, the European Union
in May 2002 and Japan in April 2005
26
February 2016
TRANSITION TO OPSUMIT
RESILIENCE vs. GENERICS
CHF million
- 6% in Units
-11% at CER(1)
~ 7,000
DU patients
(+9%)
1,418
1,212
~ 39,000
PAH patients
(-9%)
FY 2014
(1) Excluding
27
FY 2015
impact of prior-year US rebate reversals
February 2016
ACTELIONS PAH PORTFOLIO
28
February 2016
ACTELIONS PAH FRANCHISE
29
February 2016
TRANSFORMING OUR PAH PORTFOLIO

MOVING TO OUTCOME-BASED THERAPY
30
February 2016
UNIQUELY POSITIONED TO BUILD & SERVE PAH

COVERING CONTINUUM OF CARE WITH OUTCOME-BASED MEDICINES
FC II
FC III
+/- PDE-5 inhibitor
31
February 2016
FC IV
ENGINE OF
TRANSFORMATION
32
February 2016
OPSUMIT
ENGINE OF TRANSFORMATION
Opsumit (macitentan) is an orally available

endothelin receptor antagonist (ERA) approved
for the treatment of PAH in over 35 countries,
including the United States in October 2013, the European
Union in December 2013 and Japan in March 2015
33
February 2016
OPSUMIT: A LANDMARK IN PAH
The effect of macitentan to reduce combined morbidity/mortality events
34
a multi-center, event driven long-term, placebo controlled study
average duration of exposure approximately 2 years,
in 742 patients
with symptomatic PAH
WHO functional class (FC) II-III
who were randomized to placebo (n=250), 3mg macitentan (n=250),

or 10mg macitentan (n=242) once daily
Patients were treated with Opsumit monotherapy or in combination with

phosphodiesterase-5 inhibitors or inhaled prostanoids
February 2016
STRONG LAUNCH DYNAMICS

SUSTAINED
Strong launch trajectory sustained
CHF million
across markets
2015: CHF 516 million
147
95
59
162
113
68
38
Q2
2014
35
Q3
2014
Q4
2014
Q1
2015
Q2
2015
Q3
2015
February 2016
Q4
2015
Commercially available in over
35 countries
OPENING THE PROSTACYCLIN

PATHWAY TO MANY
MORE PATIENTS
36
February 2016
OPENING THE PROSTACYCLIN

PATHWAY TO MANY MORE PATIENTS
US: FDA APPROVAL 21 DEC 2015

US: LAUNCH 04 JAN 2016
EU: CHMP POSITIVE OPINION 29 JAN 2016
Uptravi (selexipag) is an orally available,

selective IP prostacyclin receptor agonist,
targeting and activating the prostacyclin
pathway.
37
February 2016
GRIPHON STUDY PUBLISHED

24 DECEMBER 2015
38
February 2016
KEY US PRESCRIBING INFORMATION
UPTRAVI is indicated for

the treatment of pulmonary
arterial hypertension (PAH,
WHO Group I) to delay
disease progression and
reduce the risk of
hospitalization for PAH
Source: US Prescribing Information, December 2015
39
February 2016
Adverse reactions
occurring more frequently
(>5%) on UPTRAVI
compared to placebo are
headache, diarrhea, jaw
pain, nausea, myalgia,
vomiting, pain in
extremity, and flushing
LAUNCH PRIORITIES
Prostacyclin
Market
Development
LAUNCH
Expand
prescriber
base
Establish as
prostacyclin of
1st choice
2
Expand
prostacyclin
therapy
patients base
2
Expand
prostacyclin
prescriber
base
11st
Establish as
prostacyclin
therapy of 1st
choice
40
February 2016
11st
Expand
prostacyclin
therapy
patient base
I.V. THERAPY MADE A

LITTLE EASIER
41
February 2016
VELETRI
I.V. THERAPY MADE A LITTLE EASIER
Veletri (Epoprostenol for Injection)

is intravenous prostacyclin.
Unlike other epoprostenol formulations
approved for PAH, Veletri is stable at room
temperature (77 F, 25 C) for up to 48 hours when
administered immediately upon reconstitution and dilution,
making the use of frozen gel packs unnecessary.
Approved in 15 countries including the United States since
2010 and some European markets since 2013
42
February 2016
CONTINUED SIGNIFICANT GROWTH

+37% CER Growth(1)
Available in 15 markets
CHF million
> 1,900 patients on drug Dec 2015
(> 50% from US)

Growth momentum due to:
83
Launch in France
> 80% new i.v. Epo patient share in US and
EU
62
Japan performance
FY 2014
(1) Excluding
43
FY 2015
February 2016
*Trade
name Epoprostenol ACT
SUSTAINING OUR
BUSINESS
MARKETED BY ACTELION IN THE US ONLY
44
February 2016
VENTAVIS
Ventavis (inhaled iloprost) is an

inhaled formulation of iloprost, a synthetic
compound that is structurally similar to prostacyclin
(PGI2), a naturally occurring molecule that causes blood
vessels to dilate, limits cellular hypertrophy, and inhibits
platelet aggregation.
45
February 2016
WELL MANAGED PERFORMANCE
-7% CER Variance(1)
CHF million
20% decline in units shipped
due to competitive pressure

Volume decline expected to
accelerate due to competitive

situation
(1) Excluding
46
106
105
FY 2014
FY 2015
February 2016
EXPANDING THE CLINICAL

UTILITY OF MACITENTAN
MACITENTAN
47
February 2016
OBJECTIVES OF MACITENTAN CLINICAL PROGRAM
Better characterize macitentan in specific PAH patient population

Extend use beyond PAH in other forms of Pulmonary Hypertension
Develop for diseases beyond PH
48
February 2016
CLINICAL CLASSIFICATION OF
PULMONARY HYPERTENSION (PH) 2015
1. PAH
1.1 Idiopathic PAH (iPAH)
1.2 Heritable PAH
1.3 Drugs and toxin induced
1.4 Associated with (APAH):
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 CHD
1.4.5 Schistosomiasis
1.4.6 Chronic hemolytic anemia
1.5 Persistent pulmonary hypertension of
the newborn
1. Pulmonary veno-occlusive disease and/or

pulmonary capillary hemangiomatosis
1. Persistent PH of the newborn (PPHN)
Gali et al. Eur Heart J 2015
February 2016
2. PH due to
left heart disease
3. PH due to lung disease
and/or hypoxemia
4. Chronic thromboembolic
pulmonary hypertension
and other pulmonary
artery obstructions
5. PH with unclear and/or
multifactorial mechanisms
5.1 Hematological disorders
5.2 Systemic disorders
5.3 Metabolic disorders
5.4 Other
EXPANDING THE CLINICAL UTILITY OF OPSUMIT

MANAGING THE LIFE CYCLE
OPUS (US observational, drug registry of Opsumit new users in clinical practice)
SYMPHONY (psychometric validation of QoL questionnaire USA)
ORCHESTRA (psychometric validation of QoL questionnaire FR, IT, ES)
MAESTRO (Eisenmenger Syndrome)
MERIT (CTEPH - Chronic Thromboembolic Pulmonary Hypertension)
MELODY (CpcPH-LVD - Combined Pre- and Post-capillary Pulmonary
Hypertension due to Left Ventricular Dysfunction)

SOPRANO (PH after left ventricular assist device implantation)
50
February 2016
EXTEND USE IN PULMONARY HYPERTENSION

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION
(MERIT STUDY)
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of
pulmonary hypertension caused by old blood clots in the lungs (pulmonary

embolism)
Goal is assessment of efficacy and safety of macitentan in CTEPH
Results should be available later this year.
51
February 2016
EXTEND USE IN PULMONARY HYPERTENSION

COMBINED PRE- AND POST-CAPILLARY PULMONARY HYPERTENSION
DUE TO LEFT VENTRICULAR DYSFUNCTION (CpcPH)
CpcPH is pulmonary hypertension secondary to left ventricular dysfunction
based on the difference between the diastolic pulmonary artery pressure (dPAP)
and the pulmonary artery wedge pressure (PAWP), or diastolic pulmonary
vascular pressure gradient (DPG).
Phase II MELODY study complete
Goal is assessment of efficacy and safety of macitentan in CpcPH
52
February 2016
STRATEGY FOR VALUE

CREATION
SUSTAIN AND
GROW THE PAH
FRANCHISE
BUILD ADDITIONAL
SPECIALTY
FRANCHISES
53
February 2016
BUILD ADDITIONAL SPECIALTY

FRANCHISE
54
February 2016
VALCHLOR
Valchlor (mechlorethamine) gel 0.016%

is applied topically once-a-day and dries
on the skin. Valchlor is the only US FDA
approved topical formulation of mechlorethamine,
a chemotherapeutic agent for the treatment of early stage
mycosis fungoides, a type of Cutaneous T-Cell Lymphoma.
Launched in the US in November 2013
55
February 2016
MYCOSIS FUNGOIDES
EXPANDING OUR SPECIALTY BUSINESS
Mycosis fungoides is the most common type of
Cutaneous T-Cell Lymphoma (CTCL), a rare form of

non-Hodgkin's lymphoma
The cause of mycosis fungoides remains unknown and
there is no known cure

Unlike most non-Hodgkin's lymphomas, mycosis
fungoides is caused by a mutation of T-cells. The

malignant T-cells in the body initially migrate to the skin,
causing various lesions to appear
These lesions typically begin as what appears to be a
rash and may progress to form plaques and disfiguring

tumors
56
February 2016
CONSISTENT PROGRESS
CHF million
Sales of CHF 27 million

Focused strategy to shape the
space for Valchlor in patients

with lower disease burden
7.4
3.5
4.1
7.1
8.0
underway* - approval anticipated

by Q1 2017
4.6
Q3 2014 Q4 2014 Q1 2015 Q2 2015 Q3 2015 Q4 2015
57
February 2016
Registration process with the EMA
*Trade name Ledaga

FRANCHISE
58
February 2016
ZAVESCA
Miglustat, the active ingredient of

Zavesca, is an orally available molecule
with a large volume of distribution
Zavesca is approved for the treatment of
Niemann-Pick type C disease in 45 countries, including the
European Union since 2009 and Japan since 2012.
Zavesca is approved for the treatment of mild to moderate
type 1 Gaucher disease in 47 countries, including the US
and the European Union since 2003
59
February 2016
NIEMANN-PICK TYPE C DISEASE (NP-C)

A RARE AND DIFFICULT TO DIAGNOSE GENETIC LYSOSOMAL
STORAGE DISORDER
Devastating neurological genetic disorder which is ultimately fatal
Onset from early childhood until adult age
Pathophysiology
Abnormal intracellular lipid transport
Cytotoxic accumulation of glycosphingolipids in neurons
Symptoms become progressively more severe and include:
60
Severe disabilities in swallowing, ambulation, eye movements, language,

cognition, muscle control
Lipid accumulation can also lead to an enlarged liver and/or spleen.
February 2016
TYPE 1 GAUCHER DISEASE (GD1)

A RARE GLYCOSPHINGOLIPID DISORDER
An inherited metabolic lysosomal storage disorder

Characterized by an accumulation of lycosphingolipids
The accumulation leads to multiple clinical manifestations:
an enlarged spleen and liver
anemia and a low platelet count
bone pain and bone deterioration
Symptoms can appear at any age
61
February 2016
CONTINUED GROWTH IN NP-C

Increasing generic competition for
type 1 Gaucher disease
CHF million
-3% CER Variance(1)
Underlying volume remained flat
due to strong growth in NP-C

patients outside of US
Positive price in US but generic
102
driven erosion in some EU markets

(i.e. ES)
92
Potential miglustat generic entry in
US during H2 2016
FY 2014
(1) Excluding
62
FY 2015
February 2016

FRANCHISE
CADAZOLID
CLOSTRIDIUM DIFFICILE-ASSOCIATED
DIARRHEA
63
February 2016
International, Multi-center Program Assessing

Cadazolid Treatment in patients suffering from
Clostridium difficile-associated diarrhea (CDAD)
mpact
64
February 2016
CADAZOLID: OUR NOVEL ANTIBIOTIC
Investigated for the treatment of Clostridium difficile-associated diarrhea (CDAD)

Clostridium difficile is a spore-forming bacteria that is best known for
causing antibiotic-associated diarrhea

Cadazolid:
Strong inhibitor of Clostridium difficile protein synthesis leading to strong

suppression of both toxin and spore formation
Narrow spectrum very limited effect on normal gut microflora potential for
selective treatment for Clostridium difficile in the gut = less recurrence
In vitro tests demonstrate low propensity for resistance development
Early results indicate it may be safe and well tolerated with negligible
absorption
US FDA designated cadazolid as both a Qualified Infectious Disease

Product (QIDP) and a Fast Track development program
Cadazolid is investigational, in development and not approved or marketed in any country.
65
February 2016
CADAZOLID SHOWS MINIMAL EFFECTS ON THE GUT MICROFLORA

QRT-PCR QUANTIFICATION OF BACTERIAL NUMBERS IN STOOL SAMPLES FROM PHASE II (T. LOUIE)
C. leptum
C. difficile
10.0
Bifidobacterium
10.0
8.0
8.0
8.0
6.0
*
6.0
6.0
Prevotella
Bacteroidetes
4.0
4.0
4.0
10.0
10.0
2.0
2.0
8.0
0.0
6.0
CFU/g stool
10.0
2.0
8.0
8.0
0.0
0.0
6.0
6.0
4.0
4.0
4.0
2.0
2.0
2.0
0.0
0.0
0.0
Cadazolid is an investigational drug in development and not approved or marketed in any country
66
Lactobacillus
February 2016
PHASE II EFFICACY ENDPOINTS

MODIFIED CURE RATE, RECURRENCE RATE, SUSTAINED CURE (MITT)
100.0
Cadazolid 250mg bid
94
86
Vancomycin 125mg qid
80.0
77
60.0
55
37
40.0
19
20.0
N=
17
22
16
19
17
22
0.0
Clinical Cure
Recurrence
Louie T. et al., Antimicrob Agents Chemother. 2015;59(10):6266-73

Cadazolid is an investigational drug in development and not approved or marketed in any country
67
February 2016
Sustained Cure
CADAZOLID: PROGRESSING AS PLANNED

PHASE III PROGRAM
Two identical multi-center, randomized, double-blind studies designed to
demonstrate:
Non-inferior clinical response with cadazolid compared to vancomycin
Superior sustained clinical response with cadazolid compared to vancomycin
Efficacy on hypervirulent strains
Completion of enrollment is expected by the end of 2016
Cadazolid is investigational, in development and not approved or marketed in any country.
68
February 2016

FRANCHISE
S1P1
RECEPTOR
IMMUNOMODULATION
69
February 2016
PONESIMOD
KEY PROPERTIES
Profile suitable for once-daily oral dosing
Selective S1P1 receptor modulator
Prevents lymphocytes from leaving lymph nodes
Lymphocyte reduction is rapid and dose-
dependent
Lymphocyte reduction is rapidly reversible upon
discontinuation
Potential in multiple immunological diseases
70
February 2016
STRONG PHASE II DATA

IN MULTIPLE SCLEROSIS
PONESIMOD
Ponesimod is investigational, in development and not approved or marketed in any country.
71
February 2016
PHASE II DOSE FINDING STUDY IN MS

STUDY DESIGN
Randomization
Placebo
(n=121)
10 mg o.d. ponesimod (n=108)

Baseline
Treatment
Screening
Follow-up
Follow-up
24 weeks
Core
72
February 2016
Extension
PRIMARY ENDPOINT: CUMULATIVE NUMBER OF

NEW T1 GD+ LESIONS FROM WEEK 12 TO WEEK 24
Cumulative new T1 Gd+ lesions

from week 12 to week 24 (Mean SE)
Per-protocol population
43% reduction
*
77% reduction
83% reduction
***
*p<0.05, ***p<0.0001 vs placebo

73
February 2016
***
SECONDARY ENDPOINT: ANNUALIZED RELAPSE

RATE UP TO WEEK 24
All-treated population
0.9
Annualized relapse rate (+ 95% CI)
0.8
52%
0.7
0.6
p<0.05
0.5
0.4
0.3
0.2
0.1
0
0.525
0.332
0.417
0.251
Placebo
Ponesimod 10 mg
Ponesimod 20 mg
Ponesimod 40 mg
Annualized confirmed relapse rate estimated from negative binomial

regression model

February 2016
Investor Webcast
ADVERSE EVENTS OBSERVED IN 5% OF PATIENTS

All-treated population
n (%)
Placebo
(n=121)
Ponesimod 10 mg
(n=108)
Ponesimod 20 mg
(n=114)
Ponesimod 40 mg
(n=119)
Patients with 1 AE
90 (74.4)
83 (76.9)
88 (77.2)
88 (73.9)
310
275
304
325
Headache
18 (14.9)
15 (13.9)
15 (13.2)
15 (12.6)
Nasopharyngitis
17 (14.0)
16 (14.8)
11 (9.6)
13 (10.9)
Upper RTI
11 (9.1)
4 (3.7)
9 (7.9)
11 (9.2)
Diarrhoea
8 (6.6)
3 (2.8)
3 (2.6)
2 (1.7)
Fatigue
7 (5.8)
7 (6.5)
9 (7.9)
6 (5.0)
Arthralgia
7 (5.8)
2 (1.9)
1 (0.9)
1 (0.8)
Back pain
6 (5.0)
2 (1.9)
5 (4.4)
6 (5.0)
Nausea
6 (5.0)
2 (1.9)
3 (2.6)
4 (3.4)
UTI
6 (5.0)
2 (1.9)
1 (0.9)
3 (2.5)
Oral herpes
6 (5.0)
1 (0.9)
2 (1.7)
Sinusitis
5 (4.1)
4 (3.7)
5 (4.4)
6 (5.0)
Dyspnoea
4 (3.3)
5 (4.6)
7 (6.1)
17 (14.3)
Dizziness
3 (2.5)
8 (7.4)
7 (6.1)
11 (9.2)
Peripheral oedema
2 (1.7)
2 (1.9)
3 (2.6)
13 (10.9)
Cough
2 (1.7)
1 (0.9)
3 (2.6)
8 (6.7)
Increased ALT
1 (0.8)
5 (4.6)
7 (6.1)
7 (5.9)
Total number of AEs
AE, adverse event; ALT, alanine aminotransferase; RTI, respiratory tract infection; UTI, urinary tract infection
75
February 2016
OVERALL SAFETY SUMMARY
No increase in the proportion of patients with infection-associated AEs (placebo
45.5%; ponesimod 10 mg, 37.0%; 20 mg, 32.5%; 40 mg, 36.1%)

Two malignancies were reported: one case of breast cancer in the ponesimod
10 mg group and one case of cervix carcinoma in the placebo group

The proportion of patients with respiratory AE was higher in the ponesimod than
in the placebo group (placebo, 6.6%; ponesimod 10 mg, 9.3%; ponesimod 20

mg, 16.7%; ponesimod 40 mg, 31.9%)
No cases of total bilirubin elevation 2 ULN and no cases of Hys law
One case of macular edema confirmed by optical coherence tomography
resolved after treatment discontinuation
76
February 2016
MAXIMUM EFFECT ON LYMPHOCYTES AT 20 MG
77
February 2016
Week 24
Week 20
Week 16
Week 12
Week 8
Week 4
Day 13
Day 8
Mean change from baseline in

lymphocyte count (%)
All-treated set
EFFECT ON LYMPHOCYTES IS RAPIDLY REVERSIBLE
78
February 2016
FU2
FU 1
Week 24 /
Week 20
Week 16
Week 12
Week 8
Week 4
Day 13
Day 8
Mean change from baseline in

lymphocyte count (%)
All-treated set subset of patient with follow-up visit
DOUBLE-BLIND EXTENSION OF
THE PHASE II STUDY
PONESIMOD
79
February 2016
DOUBLE-BLIND PHASE II EXTENSION STUDY DESIGN
Randomization
10 mg ponesimod
Placebo
20 mg ponesimod
40 mg ponesimod
10 mg ponesimod
20 mg ponesimod
40 mg ponesimod
Treatment
Treatment Period 1
24 weeks
Up to 96 weeks
Core
Extension
80
February 2016
DOUBLE-BLIND PHASE II EXTENSION STUDY DESIGN

End of
Treatment
Randomization
Randomization
10 mg ponesimod
Placebo
20 mg ponesimod
10 mg ponesimod
40 mg ponesimod
20 mg ponesimod
10 mg ponesimod
20 mg ponesimod
10 mg ponesimod
40 mg ponesimod
20 mg ponesimod
Treatment
Treatment Period 1
Treatment Period 2
24 weeks
Up to 96 weeks
Up to 432 weeks
Core
Extension
81
February 2016
Followup
EXTENSION STUDY: ARR REDUCTION OVER ~2 YEARS
Annualized Relapse Rates (ARR) (Confirmed Relapses)

Negative Binominal Regressions All-Randomized Set
,0.60
Annualized Relapse Rate
,0.50
RR = 42.3%
p=0.045
RR = 22.5%
p=0.322
,0.40
V 10mg
V 10mg
40 mg
(n=119)
20 mg
(n=116)
,0.30
,0.20
,0.10
,0.00
10 mg
(n=108)
82
February 2016
Pla/40 mg
(n=32)
Pla/20 mg
(n=31)
Pla/10 mg
(n=31)
EXTENSION STUDY: CURRENT STATUS
Safety profile consistent with the safety profile from the core study
Continuing in a blinded fashion with two dose groups 10 and 20 mg
More than 4 years of exposure drop-out rate minimal
Long-term data with 10 and 20mg will be very useful for registration and launch
High value of the study due to length, blinded fashion, size, and safety and
efficacy endpoints collected at regular intervals
83
February 2016
NEW TITRATION SCHEME
PONESIMOD
84
February 2016
PHARMACODYNAMIC STUDY
New titration schemes to mitigate first dose effect

Simulation work based on PK and PD data used to determine optimal titration
scheme
Confirmed in a specific trial comparing new vs. previous titration scheme
Results presented at the European Association for Clinical Pharmacology and
Therapeutics (EACPT) Congress in June 2015
85
February 2016
PHASE III OPTIMUM STUDY

IN MULTIPLE SCLEROSIS
PONESIMOD
86
February 2016
STUDY OVERVIEW
OPTIMUM: A Multicenter, randomized, double-blind, parallel-group,
active-controlled, superiority study to compare the efficacy and safety of

ponesimod to teriflunomide in subjects with relapsing multiple sclerosis
Pivotal Phase III study
200 centers in North America, Latin America, Eastern and Western

Europe, Pacific (planned)
1100 patients randomized in 2 groups in a 1:1 ratio to receive either

ponesimod 20 mg or teriflunomide 14 mg
New titration scheme implemented
Recruitment should finish in 2016
87
February 2016
STUDY OBJECTIVES
Primary objective
To determine whether ponesimod is more efficacious than teriflunomide in

terms of reducing relapses in subjects with relapsing multiple sclerosis
Secondary objectives
To assess the effect of ponesimod on disability progression and on other

aspects of multiple sclerosis disease control;
To assess the safety and tolerability of ponesimod in subjects with relapsing

multiple sclerosis
88
February 2016
CHOICE OF ACTIVE CONTROL
Ponesimod compared to Teriflunomide 14 mg
Oral comparator facilitates recruitment and blinding
Recently approved first-line therapy for relapsing multiple sclerosis
Superiority study possible given incomplete effect of teriflunomide on ARR
14 mg but not 7 mg approved in EU and Australia
89
February 2016
PONESIMOD DIFFERENTIATION
MAXIMIZE OPPORTUNITY WITH PONESIMOD
OPTIMUM study is enriched with additional endpoints aiming at further
differentiation:
PRO, MRI endpoints, disease activity, prospectively included in protocol
Compliance enhancement and monitoring tool using electronic device
Additional study in multiple sclerosis to further characterize:
Clinical utility
Differentiation
Discussed with Health Authorities
90
February 2016
PHASE II STUDY
IN GRAFT VS. HOST DISEASE
PONESIMOD
91
February 2016
WHY PONESIMOD IN GRAFT VS. HOST DISEASE?

UNMET MEDICAL NEED & SCIENTIFIC RATIONALE
Unmet need
Patients with chronic GvHD have a 30-50% mortality during first 5 years of
diagnosis
Currently no approved therapies for chronic GvHD in US
Glucocorticoids (with calcineurin inhibitors) are considered standard treatment
Half of patients receiving initial therapy do not have a sustained response
Scientific rationale
T and B cells play a key role in pathogenesis
S1P1 receptor modulators have shown efficacy in models of GvHD
92
February 2016
PONESIMOD IN GRAFT VS. HOST DISEASE

PHASE II DOSE-ESCALATION STUDY DESIGN
Open-label, single-arm, intra-subject dose-escalation study to investigate the
biological activity, safety, tolerability, & pharmacokinetics of ponesimod in

subjects with symptomatic moderate or severe chronic graft vs. host disease
inadequately responding to first or second line therapy
The study will also investigate the clinical response to ponesimod treatment in
these patients
30 subjects enrolled to receive escalating doses of 5, 10 and 20 mg over the
course of 24 weeks
10 sites in US expected to last approximately 18 months
Enrollment imminent
93
February 2016
PHASE II STUDY
IN SYSTEMIC LUPUS
ERYTHEMATOSUS
CENERIMOD
An investigational compound, in development and not approved or marketed in any country.
94
February 2016
ACTELIONS SECOND S1P1 MODULATOR: CENERIMOD

KEY PROPERTIES
Very potent S1P1 receptor modulator with highly
selective profile
O
Prevents lymphocytes from leaving lymph nodes
Lymphocyte reduction is rapid, dose-dependent
and reversible
Pharmacokinetic profile suitable for once-daily
oral dosing with no need for up-titration regimen

O
Potential in multiple autoimmune diseases

HO
Cenerimod is investigational, in development and not approved or marketed in any country.
95
February 2016
OH
O
N
WHY S1P1 MODULATOR FOR SYSTEMIC LUPUS

ERYTHEMATOSUS?
UNMET MEDICAL NEED & SCIENTIFIC RATIONALE
Unmet need:
Severe organ damage and significant mortality in subset of patients
Impaired physical and mental QoL
Therapy is largely empirical with use of corticosteroids and other

immunosuppressants
Only one biologic with limited efficacy gained approval
Scientific rationale for S1P1 receptor modulation in SLE:
T and B cells play a key role in pathogenesis
S1P1 receptor modulators have shown efficacy in different preclinical models

of SLE: MRL/lpr and BXSB mice
96
February 2016
CENERIMOD IN SYSTEMIC LUPUS ERYTHEMATOSUS

PHASE II DOSE-ESCALATION STUDY DESIGN
Prospective, multicenter, multinational, randomized, double-blind, placebo-
controlled, dose-response study to investigate the biologic activity,

pharmacokinetics, safety, & tolerability of cenerimod in adult subjects with
systemic lupus erythematosus
64 subjects enrolled to receive either 0.5, 1, 2 or 4 mg over the course of 12
weeks
20 sites and expected to last approximately 20 months
97
February 2016

FRANCHISE
CLAZOSENTAN
CEREBRAL VASOSPASM POSTANEURISMAL SUBARACHNOID
HEMORRHAGE (aSAH)
Clazosentan is investigational, in development and not approved or marketed in any country.
98
February 2016
CLAZOSENTAN FOR CEREBRAL VASOSPASM POSTANEURISMAL SUBARACHNOID HEMORRHAGE (aSAH)
Highly soluble ETA selective ERA ideal for intravenous administration

>1500 patients treated with clazosentan providing significant experience in
vasospasm post aSAH and a well documented safety profile

CONSCIOUS-2
aneurysm secured by clipping
Lancet Neurology 2011;10(7):618-625
CONSCIOUS-3
aneurysm secured by coiling
Stroke. 2012 Jun;43(6):1463-9
Clazosentan is an investigational drug in development and not approved or marketed in any country
99
February 2016
CONSCIOUS-3 STUDY - EVENT RATE FOR THE

COMPONENTS OF THE 1o COMPOSITE ENDPOINT
RRR
(95% CI)
25
Clazosentan 5 mg/h
Clazosentan 15 mg/h
-21%
(-97 to 26%)
15%
(-28 to 44%)
29%
(-9 to 54%)
-34%
(-211 to 42%)
44%
(-5 to 70%)
54%
(22 to 72%)
65%
(38 to 80%)
21
20
Event rate (%)
Placebo
35%
(-79 to 76%)
21
18
16
15
15
13
10
10
5
0
Death (within
6 weeks)
DIND = Delayed ischemic neurological deficits;
Macdonald R et al. Stroke 2012.
New cerebral
infarct
Vasospasm-related
100
February 2016
DIND
Rescue
therapy
ADAPTED STRATEGY: REVERSAL VS.

PREVENTION
Vasospasm reversal with clazosentan in humans
Baseline
Vasospasm
2 days of Tx
Phase III study under discussion with HAs

Primary objective to determine whether
clazosentan is an efficacious treatment of

cerebral vasospasm
Open question: How early is the effect of clazosentan on reversing vasospasm?
REVERSE: Phase II study to evaluate whether clazosentan has an early effect in
reversing angiographically-confirmed cerebral vasospasm in approximately 25

subjects
101
February 2016
EXTENSIVE RESEARCH
& DEVELOPMENT
102
February 2016
A CHAIN OF EXPERTISE
371 PROFESSIONALS (DECEMBER 2015)
Pharmacologists
Toxicologists
Cell Biologists
Molecular Biologists
DRUG
DISCOVERY
ORGANIZATION
Biochemists
Process Research Chemists
Formulation Specialists
Clinical Scientists
Medicinal Chemists
103
Pharmacokineticists
February 2016
Structural Biologists
ACTELIONS DRUG DISCOVERY STRATEGY
All important research functionalities in-house

(e.g. MedChem, AssayTech, DMPK, Pharmacology)
Highly regulated service activities outsourced

(e.g. Toxicology, Production, Formulation)
104
February 2016
THE BASE FOR HIGH DISCOVERY EFFICIENCY

CULTURE OF INNOVATION
105
Single-center approach
Fully integrated research informatics
Focus on small molecules
Few platforms of expertise
Multiple therapeutic areas
High medical input
February 2016
CLINICAL DEVELOPMENT ORGANIZATION

422 PROFESSIONALS (DECEMBER 2015)
Clinical Science
Life Cycle Management

Clinical Pharmacology
CLINICAL
DEVELOPMENT
Global Drug Safety

Global Drug Regulatory Affairs
106
February 2016
Biometry
Global Clinical Operations
Strategic Clinical Development
EXTENDING THE CORE PAH FRANCHISE

Phase I
Phase II
Macitentan
OPUS
Macitentan
ORCHESTRA
Macitentan
SOPRANO
Macitentan
SYMPHONY
Macitentan
PORTICO
Macitentan & Selexipag
TRITON
Selexipag
GRIPHON
Macitentan
MAESTRO
Macitentan
MELODY
Macitentan
MERIT
107
February 2016
Phase III
Phase IV
DIVERSIFICATION
Phase I
Cadazolid
Clostridium difficile assoc. diarrhea
Ponesimod
Multiple Sclerosis
Clazosentan
Reversal of vasospasm post-aSAH
Ponesimod
Graft vs. host disease
Cenerimod
Systemic lupus erythematosus
Endothelin Receptor Antagonist
Specialty cardiovascular disorders
Lucerastat
Fabrys disease
New Chemical Entity

Neurological disorders
New Chemical Entity

Neurological disorders
New Chemical Entity

Cardiovascular disorders
108
February 2016
Phase II
Phase III
OUR RICH DISCOVERY PIPELINE
>15 promising projects advancing in Drug Discovery

Focus towards specialty markets and rare diseases with high unmet medical
need
Current clinical pipeline to build solid portfolio for future revenue growth
109
February 2016
STRATEGY FOR VALUE

CREATION
SUSTAIN AND
GROW THE PAH
FRANCHISE
BUILD ADDITIONAL
SPECIALTY
FRANCHISES
110
February 2016
FINANCIAL OVERVIEW
BY REPORTING PERIOD
111
February 2016
FY
2015
STRONG PERFORMANCE
Variance
FY 2015
CHF
CER
1,956
2,042
4%
7%
11%
743
814
9%
14%
25%
5.58
6.16
10%
15%
26%
570
656
15%
21%
5.11
4.91
-4%
1%
Product sales
CHF million
Core earnings
CHF million
Core diluted EPS

CHF
Operating income
CHF million
US GAAP diluted EPS

CHF
112
CER
FY 2014
February 2016
Ex US rebate
reversals
CORE EARNINGS
BY REPORTING PERIOD
113
February 2016
FY
2015
CORE EARNINGS
INTRINSIC GROWTH + 25%
CHF million
32
168
66
814
743
FY '14 Core
earnings as
reported
114
US rebate reversals
February 2016
677
677
FY'14 Core
earnings
excluding US
rebate reversals
FY '15 intrinsic
growth
FX
FY'15 Core
earnings
EARNINGS PER SHARE

(EPS) BY REPORTING
PERIOD
115
February 2016
FY
2015
EARNINGS PER SHARE
Variance
FY 2014
FY 2015
CHF
CER
648
693
11
Core Diluted EPS
5.58
6.16
Number of shares in calculation (m)
116.2
112.5
10
15
594
552
-7
-3
US GAAP Diluted EPS
5.11
4.91
Number of shares in calculation (m)
116.2
112.5
-4
Core Net income

CHF million
US GAAP Net income

CHF million
116
February 2016
SHAREHOLDER
RETURNS
117
February 2016
OUTSTANDING YEAR FOR SHAREHOLDERS

SHARE PRICE PERFORMANCE
CASH RETURNED TO SHAREHOLDERS
927
588
358
133
2012
2013
2016 FURTHER RETURNS TO COME

Second-line share repurchase continues
Dividend: Board proposes increase to CHF 1.50 per share
118
February 2016
2014
2015
FINANCIAL GUIDANCE
February
2016
119
February 2016
2016
FINANCIAL GUIDANCE
Low single-digit percentage core operating

income growth, at constant exchange rates
and barring unforeseen events
120
February 2016
MANAGEMENT &
BOARD
121
February 2016
THE RIGHT PEOPLE FOR THE NEXT GROWTH PHASE

ACTELION MANAGEMENT TEAM
Jean-Paul Clozel
Founder, CEO
Joined in 1997
Otto Schwarz
COO
Joined in 2008
Nicholas Franco
Chief BD Officer
Joined in 2011
Guy Braunstein
Head of Global CD
Joined in 2009
Martine Clozel
Founder, CSO
Joined in 1997
Christian Albrich
Head of Global HR
Joined in 2005
Rudi Frank
Head of Global Quality Management
Joined in 2000
Marian Borovsky
General Counsel
Joined in 2003
122
Andr Muller
CFO
Joined in 2013
February 2016
Andrew Weiss
Head of IR & CC
Joined in 2014
THE RIGHT PEOPLE FOR THE NEXT GROWTH PHASE

ACTELION BOARD OF DIRECTORS
Jean-Pierre Garnier
Chairman
Joined in 2011
Juhani Anttila
Joined in 2005
John J. Greisch
Joined in 2013
Robert J. Bertolini
Joined in 2011
Peter Gruss
Joined in 2012
Jean Malo
Joined in 2004
123
David Stout
Joined in 2015
February 2016
Jean-Paul Clozel
Joined in 2000
Michael Jacobi
Joined in 2009
Herna Verhagen
Joined in 2015
THANK YOU FOR YOUR

INTEREST IN ACTELION
124
February 2016

Actelion

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Actelion

Uploaded by

Copyright:

Available Formats

ACTELION LTD

DELIVERING ON OUR STRATEGY

Copyright 2016 Actelion Pharmaceuticals Ltd

The following information contains certain forward-looking statements, relating to the

2016 Actelion Pharmaceuticals Ltd

Sustain & Grow the PAH Franchise

Build Additional Specialty Franchises

Management & Board

2016 Actelion Pharmaceuticals Ltd

2016 Actelion Pharmaceuticals Ltd

ACTELION PHARMACEUTICALS LTD

FOUNDED IN 1997 IN ALLSCHWIL, SWITZERLAND

Global reach with more than 30 affiliates worldwide

2016 Actelion Pharmaceuticals Ltd

STAGES OF COMPANY DEVELOPMENT

2016 Actelion Pharmaceuticals Ltd

PAH, Life Cycle

2016 Actelion Pharmaceuticals Ltd

2016 Actelion Pharmaceuticals Ltd

Searching only for innovative products

In-house research infrastructure from

With a broad pipeline of interesting

2016 Actelion Pharmaceuticals Ltd

2016 Actelion Pharmaceuticals Ltd

2016 Actelion Pharmaceuticals Ltd

2 Fully integrated and global

One discovery center in Switzerland

Full global development capabilities

Fully established infrastructure from

2016 Actelion Pharmaceuticals Ltd

Full rights to all products*

Strong balance sheet and financing capacity

No major alliances for own products

*Cooperation with Nippon Shinyaku in

2016 Actelion Pharmaceuticals Ltd

STRATEGY FOR VALUE

2016 Actelion Pharmaceuticals Ltd

Drive innovation forward

Maximize the value of innovation

Pursue top quality science, internally

Leverage our global presence

Insist on the highest quality in all we do

Expand innovative commercial

2016 Actelion Pharmaceuticals Ltd

Develop projects ourselves and seek

Quality is crucial and needs to be

STRONG PERFORMANCE CONTINUES

Strong, sustained Opsumit launch trajectory across

2016 Actelion Pharmaceuticals Ltd

KEY FINANCIAL HIGHLIGHTS

2016 Actelion Pharmaceuticals Ltd

STRATEGY FOR VALUE

2016 Actelion Pharmaceuticals Ltd

PULMONARY ARTERIAL HYPERTENSION

- the pulmonary arteries

2016 Actelion Pharmaceuticals Ltd

Diseased artery showing tissue

CLINICAL SEVERITY OF PAH

Patients with pulmonary hypertension resulting in slight limitation of physical activity.

Patients with pulmonary hypertension resulting in marked limitation of physical activity.

2016 Actelion Pharmaceuticals Ltd

TREATMENT PATHWAYS IN PAH

2016 Actelion Pharmaceuticals Ltd

SIGNIFICANT PROGRESS IN THE FIELD OF PAH