Actelion

7/25/2019 Actelion

http://slidepdf.com/reader/full/actelion 1/124

Copyright © 2016 Actelion Pharmaceuticals Ltd

ACTELION LTDDELIVERING ON OUR STRATEGY

Company PresentationFebruary 2016

7/25/2019 Actelion


© 2016 Actelion Pharmaceuticals Ltd

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

company’s 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 company’sinvestment 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 company’s 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.

Company presentationFebruary 20162

7/25/2019 Actelion



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


7/25/2019 Actelion



ACTELION AT A GLANCE


7/25/2019 Actelion



FOUNDED IN 1997 IN ALLSCHWIL, SWITZERLAND

Total employees (December ‘15)

• Drug Discovery

• Clinical Development• Marketing & Sales

• Support Functions

2,547

371

4221,425

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 BillionCore earnings: CHF 814 million

Over 65‘000 Patients currently treated with an Actelion

medication

Extensive Research & Development portfolio

ACTELION IS A FULLY INTEGRATED BIOPHARMACEUTICAL

COMPANY WITH INNOVATION AT ITS CORE

ACTELION PHARMACEUTICALS LTD

Leader in the

science and medicine of

pulmonary arterial hypertension

(PAH)

Actelion Center, Allschwil


7/25/2019 Actelion



STAGES OF COMPANY DEVELOPMENT

Company formed,

development

& approval of

Tracleer

Build pipeline

and commercial

infrastructure

Commercial

leverage

and prepare forTracleer LOE

1997 2001

2007

2014

PAH, Life CycleManagement

and New

Franchises

Opsumit, Uptravi

and development of

new franchises

2020


7/25/2019 Actelion

http://slidepdf.com/reader/full/actelion 7/124© 2016 Actelion Pharmaceuticals Ltd

ACTELION TODAY


7/25/2019 Actelion


Based on innovation

Fully integrated and global

Highly profitable

Comprehensive infrastructure

Unencumbered assets

A UNIQUE COMPANY

ACTELION TODAY

1

2

3

4

5


7/25/2019 Actelion


Based on innovation


Highly profitable


Unencumbered assets

A UNIQUE COMPANY

ACTELION TODAY

1

2

3

4

5

► Searching only for innovative products

► In-house research infrastructure from

discovery to clinical development

► With a broad pipeline of interesting

projects on novel targets


7/25/2019 Actelion


FULLY INTEGRATED AND GLOBAL

From Research to CommercializationMore than 30 operative affiliates worldwide

Product availability in >60 marketsBased on innovation


Highly profitable


Unencumbered assets

A UNIQUE COMPANY

ACTELION TODAY

1

2

3

4

5

Commercial Operations

R&D Centers


7/25/2019 Actelion


Based on innovation


Highly profitable


Unencumbered assets

A UNIQUE COMPANY

ACTELION TODAY

1

2

3

4

5

CORE EARNINGS

0

100

200

300

400

500

600

700

800

900

2009 2010 2011 2012 2013 2014 2015


7/25/2019 Actelion


Based on innovation


Highly profitable


Unencumbered assets

A UNIQUE COMPANY

ACTELION TODAY

1

2

3

4

5

► Swiss company

► One discovery center in Switzerland

► Full global development capabilities

► Fully established infrastructure from

process to buildings

► Focus on quality


7/25/2019 Actelion



Based on innovation


Highly profitable


Unencumbered assets

A UNIQUE COMPANY

ACTELION TODAY

1

2

3

4

5

► Full rights to all products*

► Strong balance sheet and financing capacity

► No major alliances for own products

*Cooperation with Nippon Shinyaku in

Japan for macitentan and selexipag


7/25/2019 Actelion



STRATEGY FOR VALUE

CREATION

SUSTAIN AND

GROW THE PAH

FRANCHISE

BUILD ADDITIONAL

SPECIALTY

FRANCHISES

OPTIMIZE PROFITABILITY


7/25/2019 Actelion



Maximize the value of innovation

Develop projects ourselves and seek

partners or out-license when necessary to

maximize value

Insist on the highest quality in all we do

Quality is crucial and needs to be

ingrained across all functions

Drive innovation forward

Pursue top quality science, internally

and externally, balanced with medical

need and commercial potential

Leverage our global presence

Expand innovative commercialcapabilities to new customers and

regions. Manage alliances putting the

product first

FOUR GOALS FOR ACTELION

STRATEGIC PRINCIPLES


7/25/2019 Actelion



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 early-stage development

STRONG PERFORMANCE CONTINUES2015


7/25/2019 Actelion



KEY FINANCIAL HIGHLIGHTS

CASH RETURNEDTO SHAREHOLDERS

ALMOST

CHF 1BILLION

Core EPS

CHF 6.16

CORE EARNINGS

>CHF 800MILLION

2015

PRODUCT SALES

>CHF 2BILLION


7/25/2019 Actelion



STRATEGY FOR VALUE

CREATION

SUSTAIN AND

GROW THE PAH

FRANCHISE

BUILD ADDITIONAL

SPECIALTY

FRANCHISES


SUSTAIN AND

GROW THE PAH

FRANCHISE


7/25/2019 Actelion



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

A LIFE-THREATENING AND OFTEN MISUNDERSTOOD CONDITION

PULMONARY ARTERIAL HYPERTENSION

Normal artery Artery showing

vasoconstriction

Diseased artery showing tissue

thickening and fibrosis


7/25/2019 Actelion



I

Patients with pulmonary hypertension but without resulting limitation of physical activity.

Ordinary physical activity does not cause dyspnoea or fatigue, chest pain, or nearsyncope.

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 orfatigue, 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.

FUNCTIONAL

CLASSSYMPTOMATIC PROFILE

CLASSIFIED BY WORLD HEALTH ORGANIZATION (WHO)

CLINICAL SEVERITY OF PAH

This system grades PAH severity according to the functional status of the patient


7/25/2019 Actelion



PROSTACYCLINRECEPTOR AGONISTSPHOSPHODIESTERASE-5-INHIBITORS (PDE-5i)

ENDOTHELIN RECEPTOR

ANTAGONISTS (ERA)

TREATMENT PATHWAYS IN PAH

IP

RECEPTOR

AGONIST

PGI2

ANALOGUES


7/25/2019 Actelion



SIGNIFICANT PROGRESS IN THE FIELD OF PAH

ERA: endothelin receptor antagonist

PDE-5i: phosphodiesterase-5 inhibitor

PGI2: prostacyclinESC 2004

GUIDELINESESC/ERS 2009GUIDELINES

PROCEEDINGS FROM

4TH WORLD

CONGRESS 2008

PROCEEDINGS FROM

3RD WORLD

CONGRESS 2003

PAH targeted therapies

1st PGI2 1st Oral PDE-5i 1st Oral ERA Multiple approved

therapies in 2010

CONTROLLED

CLINICAL TRIALS

1990 2000 2010

DISEASE PROGRESSION OVER YEARS,

MEASURED BY MORBIDITY/MORTALITY

DISEASE WORSENING, MEASURED BY

TIME TO CLINICAL WORSENINGIMPROVEMENT IN SYMPTOMS,

MEASURED BY 6MWD

PATIENT

ASSOCIATIONS

REFERENCE

CENTERS

INCREASING DISEASE

AWARENESS

SCREENING

HIGH-RISK GROUPS

EVIDENCE-BASED

GUIDELINES

DISEASE

REGISTRIES

NATIONAL

NETWORKS

PRECLINICAL/

CLINICAL RESEARCH


7/25/2019 Actelion



RANDOMIZED CONTROLLED TRIALS

ORAL THERAPIES IN PAH

Drug Study Duration Primary endpoint No. ofpatients

Bosentan

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

Ambrisentan

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

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. Galiè N, et al. Lancet 2008.

5. Galiè N, et al. N Engl J Med 2005. 6. Galiè N, et al. Circulation 2009.7. Galiè N, et al. Circulation 2008. 8. Oudiz R, et al. Chest 2006.

9. Oudiz RJ, et al. J Am Coll Cardiol 2009. 10. Galiè 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.

Short-term

fixed

treatment

period trialdesign


7/25/2019 Actelion



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

FROM RANDOMISED CONTROLLED TRIALS TO EVIDENCE-BASED

GUIDELINES

EVOLUTION OF THE TREATMENT GUIDELINES

1. Galiè N, et al. Eur Heart J 2009. 2. Galiè N, et al. J Am Coll Cardiol 2013.


7/25/2019 Actelion



TRACLEER: OUR FIRST

SUCCESS


7/25/2019 Actelion



THE FIRST DECADE OF SHAPING PAH TREATMENT

TRACLEER®: FIRST ORAL PRODUCT IN PAH

Tracleer (bosentan) is an orally availableendothelin 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


7/25/2019 Actelion



TRANSITION TO OPSUMIT –

RESILIENCE vs. GENERICS

1,4181,212

FY 2014 FY 2015

- 6% in Units

-11% at CER(1)

(1) Excluding impact of prior-year US rebate reversals

CHF million

~ 7,000DU patients

(+9%)

~ 39,000PAH patients

(-9%)


7/25/2019 Actelion



ACTELION’S PAH PORTFOLIO


7/25/2019 Actelion



ACTELION’S PAH FRANCHISE


7/25/2019 Actelion



MOVING TO OUTCOME-BASED THERAPY

TRANSFORMING OUR PAH PORTFOLIO


7/25/2019 Actelion



COVERING CONTINUUM OF CARE WITH OUTCOME-BASED MEDICINES

UNIQUELY POSITIONED TO BUILD & SERVE PAH

FC IIIFC II FC IV

+/- PDE-5 inhibitor


7/25/2019 Actelion


7/25/2019 Actelion



ENGINE OF TRANSFORMATION

OPSUMIT®

Opsumit (macitentan) is an orally availableendothelin 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


7/25/2019 Actelion



The effect of macitentan to reduce combined morbidity/mortality events

– 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

OPSUMIT: A LANDMARK IN PAH


7/25/2019 Actelion



STRONG LAUNCH DYNAMICS

SUSTAINED

3859 68

95113

147162

Q22014

Q32014

Q42014

Q12015

Q22015

Q32015

Q42015

Strong launch trajectory sustained

across markets

2015: CHF 516 million

Commercially available in over

35 countries

CHF million


7/25/2019 Actelion



OPENING THE PROSTACYCLIN

PATHWAY TO MANYMORE PATIENTS


7/25/2019 Actelion



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.


7/25/2019 Actelion



GRIPHON STUDY PUBLISHED

24 DECEMBER 2015


7/25/2019 Actelion



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

Adverse reactions

occurring more frequently

(>5%) on UPTRAVI

compared to placebo are

headache, diarrhea, jaw

pain, nausea, myalgia,

vomiting, pain inextremity, and flushing

KEY US PRESCRIBING INFORMATION


7/25/2019 Actelion



Prostacyclin

Market

DevelopmentLAUNCH

2

Expand

prescriber

base

Establish asprostacyclin

therapy of 1st

choice

1st

Expandprostacyclin

therapy

patients base

2

1

3

LAUNCH PRIORITIES

2

Establish as

prostacyclin of

1st choice

Expandprostacyclin

therapy

patient base

1st

Expandprostacyclin

prescriber

base

2

1

3


7/25/2019 Actelion



I.V. THERAPY MADE A

LITTLE EASIER


®

7/25/2019 Actelion



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 whenadministered 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

I.V. THERAPY MADE A LITTLE EASIER

VELETRI®


7/25/2019 Actelion



CONTINUED SIGNIFICANT GROWTH

62

83

FY 2014 FY 2015

Available in 15 markets

> 1,900 patients on drug Dec 2015

(> 50% from US)

Growth momentum due to:

– Launch in France

– > 80% new i.v. Epo patient share in US and

EU

– Japan performance

+37% CER Growth(1)

CHF million

*Trade name Epoprostenol “ACT”(1) Excluding impact of prior-year US rebate reversals


7/25/2019 Actelion



SUSTAINING OUR

BUSINESS

MARKETED BY ACTELION IN THE US ONLY


VENTAVIS®

7/25/2019 Actelion



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.

VENTAVIS®



7/25/2019 Actelion



106 105

FY 2014 FY 2015

20% decline in units shipped

due to competitive pressure

Volume decline expected toaccelerate due to competitive

situation

-7% CER Variance(1)


WELL MANAGED PERFORMANCE

CHF million


7/25/2019 Actelion



EXPANDING THE CLINICAL

UTILITY OF MACITENTAN

MACITENTAN


OBJECTIVES OF MACITENTAN CLINICAL PROGRAM

7/25/2019 Actelion



Better characterize macitentan in specific PAH patient population

Extend use beyond PAH in other forms of Pulmonary Hypertension

Develop for diseases beyond PH

OBJECTIVES OF MACITENTAN CLINICAL PROGRAM


CLINICAL CLASSIFICATION OF

7/25/2019 Actelion



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

2. PH due to

left heart disease

3. PH due to lung disease

and/or hypoxemia

Galiè et al. Eur Heart J 2015

4. Chronic thromboembolic

pulmonary hypertension

and other pulmonary

artery obstructions

5. PH with unclear and/ormulti factorial mechanisms

5.1 Hematological disorders

5.2 Systemic disorders

5.3 Metabolic disorders

5.4 Other

1’. Pulmonary veno-occlusive disease and/or

pulmonary capillary hemangiomatosis

1” . Persistent PH of the newborn (PPHN)

February 2016

EXPANDING THE CLINICAL UTILITY OF OPSUMIT

7/25/2019 Actelion



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)

MANAGING THE LIFE CYCLE

EXPANDING THE CLINICAL UTILITY OF OPSUMIT


EXTEND USE IN PULMONARY HYPERTENSION

7/25/2019 Actelion



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.

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

(MERIT STUDY)




7/25/2019 Actelion



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

COMBINED PRE- AND POST-CAPILLARY PULMONARY HYPERTENSION

DUE TO LEFT VENTRICULAR DYSFUNCTION (CpcPH)



7/25/2019 Actelion



STRATEGY FOR VALUE

CREATION

SUSTAIN AND

GROW THE PAH

FRANCHISE

BUILD ADDITIONAL

SPECIALTY

FRANCHISES


BUILD ADDITIONAL

SPECIALTY

FRANCHISES


7/25/2019 Actelion



BUILD ADDITIONAL SPECIALTY

FRANCHISE



VALCHLOR®

7/25/2019 Actelion



Valchlor (mechlorethamine) gel 0.016%

is applied topically once-a-day and dries

on the skin. Valchlor is the only US FDAapproved 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

VALCHLOR®


MYCOSIS FUNGOIDES

7/25/2019 Actelion



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 andthere 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

EXPANDING OUR SPECIALTY BUSINESS

MYCOSIS FUNGOIDES

56 Company presentationFebruary 201656

7/25/2019 Actelion



Sales of CHF 27 million

Focused strategy to shape the

space for Valchlor in patientswith lower disease burden

Registration process with the EMA

underway* - approval anticipated

by Q1 2017

57

3.5

4.14.6

7.4 7.18.0

Q3 2014 Q4 2014 Q1 2015 Q2 2015 Q3 2015 Q4 2015

CONSISTENT PROGRESS

*Trade name Ledaga®

CHF million


7/25/2019 Actelion




FRANCHISE


ZAVESCA®

7/25/2019 Actelion



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 theEuropean 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

ZAVESCA


NIEMANN-PICK TYPE C DISEASE (NP-C)

7/25/2019 Actelion



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:

– Severe disabilities in swallowing, ambulation, eye movements, language,cognition, muscle control

– Lipid accumulation can also lead to an enlarged liver and/or spleen.

A RARE AND DIFFICULT TO DIAGNOSE GENETIC LYSOSOMAL

STORAGE DISORDER

NIEMANN-PICK TYPE C DISEASE (NP-C)


TYPE 1 GAUCHER DISEASE (GD1)

7/25/2019 Actelion



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

A RARE GLYCOSPHINGOLIPID DISORDER

TYPE 1 GAUCHER DISEASE (GD1)


7/25/2019 Actelion



CONTINUED GROWTH IN NP-C

10292

FY 2014 FY 2015

Increasing generic competition for

type 1 Gaucher disease

Underlying volume remained flat

due to strong growth in NP-C

patients outside of US

Positive price in US but generic

driven erosion in some EU markets

(i.e. ES)

Potential miglustat generic entry inUS during H2 2016

-3% CER Variance(1)


CHF million


7/25/2019 Actelion




FRANCHISE

CADAZOLID

CLOSTRIDIUM DIFFICILE- ASSOCIATED

DIARRHEA


7/25/2019 Actelion



International, Multi-center Program Assessing

Cadazolid Treatment in patients suffering from

Clostridium difficile-associated diarrhea (CDAD)

mpact


CADAZOLID: OUR NOVEL ANTIBIOTIC

7/25/2019 Actelion



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 strongsuppression 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 negligibleabsorption

– US FDA designated cadazolid as both a Qualified Infectious Disease

Product (QIDP) and a Fast Track development program

CADAZOLID: OUR NOVEL ANTIBIOTIC

Cadazolid is investigational, in development and not approved or marketed in any country.


CADAZOLID SHOWS MINIMAL EFFECTS ON THE GUT MICROFLORA

7/25/2019 Actelion



0.0

2.0

4.0

6.0

8.0

0.0

2.0

4.0

6.0

8.0

10.0

0.0

2.0

4.0

6.0

8.0

10.0

0.0

2.0

4.0

6.0

8.0

10.0

0.0

2.0

4.0

6.0

8.0

10.0

QRT-PCR QUANTIFICATION OF BACTERIAL NUMBERS IN STOOL SAMPLES FROM PHASE II (T. LOUIE)

C. difficile

Prevotella

C. leptum

Bacteroidetes

Bifidobacterium

Lactobacillus

0.0

2.0

4.0

6.0

8.0

10.0

*

CFU/g stool

*

**

*

Cadazolid is an investigational drug in development and not approved or marketed in any country


PHASE II EFFICACY ENDPOINTS

7/25/2019 Actelion



94

19

77

86

37

55

0.0

20.0

40.0

60.0

80.0

100.0

Clinical Cure Recurrence Sustained Cure

N= 17 22 16 19 17 22

MODIFIED CURE RATE, RECURRENCE RATE, SUSTAINED CURE (MITT)

PHASE II EFFICACY ENDPOINTS

Louie T. et al., Antimicrob Agents Chemother. 2015;59(10):6266-73

Cadazolid 250mg bid

Vancomycin 125mg qid

Cadazolid is an investigational drug in development and not approved or marketed in any country


CADAZOLID: PROGRESSING AS PLANNED

7/25/2019 Actelion



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

PHASE III PROGRAM

CADAZOLID: PROGRESSING AS PLANNED

Cadazolid is investigational, in development and not approved or marketed in any country.


7/25/2019 Actelion




FRANCHISE

S1P1 RECEPTOR

IMMUNO-

MODULATION


PONESIMOD

7/25/2019 Actelion



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

KEY PROPERTIES

O S O


7/25/2019 Actelion



STRONG PHASE II DATA

IN MULTIPLE SCLEROSIS

PONESIMOD

Ponesimod is investigational, in development and not approved or marketed in any country.


7/25/2019 Actelion


PRIMARY ENDPOINT: CUMULATIVE NUMBER OF

NEW T1 GD LESIONS FROM WEEK 12 TO WEEK 24

7/25/2019 Actelion



C u m u l a t i v e n e w T 1

G d + l e s i o n s

f r o m w e e k 1 2 t o w e e k

2 4 ( M e a n ± S E )

*p<0.05, ***p<0.0001 vs placebo

******

Per-protocol population

*

43% reduction

83% reduct ion77% reduct ion

NEW T1 GD+ LESIONS FROM WEEK 12 TO WEEK 24



SECONDARY ENDPOINT: ANNUALIZED RELAPSE

RATE UP TO WEEK 24

7/25/2019 Actelion



RATE UP TO WEEK 24

0.525 0.332 0.417 0.2510

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Placebo Ponesimod 10 mg Ponesimod 20 mg Ponesimod 40 mg

A n n u a l i z e d r e l a p s e

r a t e ( + 9 5 % C

I )

Al l-treated population

p<0.05

52%

• Annualized confirmed relapse rate estimated from negative binomial

regression model

Investor Webcast


February 2016

ADVERSE EVENTS OBSERVED IN ≥5% OF PATIENTS

7/25/2019 Actelion



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)

Total number of AEs 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)

Arthralg ia 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)

AE, adverse event ; ALT, alanine aminot ransferase; RTI, respiratory t ract infect ion; UTI, ur inary tract in fection



OVERALL SAFETY SUMMARY

7/25/2019 Actelion



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 Hy’s law

One case of macular edema confirmed by optical coherence tomography

resolved after treatment discontinuation



MAXIMUM EFFECT ON LYMPHOCYTES AT 20 MG

7/25/2019 Actelion



M e a n c h a n g e f r o m

b a s e l i n e i n

l y m p h o c y t e c o u n t ( % )

All-treated set

D a y 8

D a y 1 3

W e e k 4

W e e k 8

W e e k 1 2

W e e k 1 6

W e e k 2 0

W e e k 2 4



EFFECT ON LYMPHOCYTES IS RAPIDLY REVERSIBLE

7/25/2019 Actelion



M e a n c h a n g e f r o m

b a s e l i n e i n

l y m p h o c y t e c o u n t ( % )

All-treated set – subset of pat ient with fo llow-up visit

D a y 8

D a y 1 3

W e e k 4

W e e k 8

W e e k 1 2

W e e k 1 6

W e e k 2 0

W e e k 2 4 /

F U 1

F U 2



7/25/2019 Actelion



DOUBLE-BLIND EXTENSION OF

THE PHASE II STUDY

PONESIMOD



DOUBLE-BLIND PHASE II EXTENSION STUDY DESIGN

7/25/2019 Actelion



40 mg ponesimod

20 mg ponesimod

10 mg ponesimod

Treatment24 weeks

Randomization

Treatment Period 1Up to 96 weeks

40 mg ponesimod

20 mg ponesimod

10 mg ponesimod

ExtensionCore

Placebo



DOUBLE-BLIND PHASE II EXTENSION STUDY DESIGN

7/25/2019 Actelion



40 mg ponesimod

20 mg ponesimod

10 mg ponesimod

Treatment24 weeks

Randomization

Treatment Period 1Up to 96 weeks

40 mg ponesimod

20 mg ponesimod

10 mg ponesimod

ExtensionCore

Placebo

Randomization

End of

Treatment

Follow-

upTreatment Period 2

Up to 432 weeks

10 mg ponesimod

20 mg ponesimod

10 mg ponesimod

20 mg ponesimod



EXTENSION STUDY: ARR REDUCTION OVER ~2 YEARS

7/25/2019 Actelion



,0.00

,0.10

,0.20

,0.30

,0.40

,0.50

,0.60

40 mg(n=119)

20 mg(n=116)

10 mg(n=108)

Pla/40 mg(n=32)

Pla/20 mg(n=31)

Pla/10 mg(n=31)

A n n u a l i z e d R e l a p s e R a t e

Annualized Relapse Rates (ARR) (Conf irmed Relapses)

Negative Binominal Regressions – All-Randomized Set

V 10mg V 10mg

RR = 42.3%

p=0.045

RR = 22.5%

p=0.322



EXTENSION STUDY: CURRENT STATUS

7/25/2019 Actelion



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



7/25/2019 Actelion



NEW TITRATION SCHEME

PONESIMOD



PHARMACODYNAMIC STUDY

7/25/2019 Actelion



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



7/25/2019 Actelion


STUDY OVERVIEW

7/25/2019 Actelion



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 WesternEurope, 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



STUDY OBJECTIVES

7/25/2019 Actelion



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



CHOICE OF ACTIVE CONTROL

7/25/2019 Actelion



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



PONESIMOD DIFFERENTIATION

7/25/2019 Actelion



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

MAXIMIZE OPPORTUNITY WITH PONESIMOD



7/25/2019 Actelion



PHASE II STUDY

IN GRAFT VS. HOST DISEASE

PONESIMOD



WHY PONESIMOD IN GRAFT VS. HOST DISEASE?

7/25/2019 Actelion



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

UNMET MEDICAL NEED & SCIENTIFIC RATIONALE



PONESIMOD IN GRAFT VS. HOST DISEASE

7/25/2019 Actelion



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 inthese 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

PHASE II DOSE-ESCALATION STUDY DESIGN



7/25/2019 Actelion



PHASE II STUDY

IN SYSTEMIC LUPUSERYTHEMATOSUS

CENERIMOD

An investigational compound, in development and not approved or marketed in any country.


7/25/2019 Actelion


7/25/2019 Actelion


CENERIMOD IN SYSTEMIC LUPUS ERYTHEMATOSUS

7/25/2019 Actelion



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 12weeks

∼ 20 sites and expected to last approximately 20 months

PHASE II DOSE-ESCALATION STUDY DESIGN

Cenerimod is investigational, in development and not approved or marketed in any country.


7/25/2019 Actelion




FRANCHISE

CLAZOSENTAN

CEREBRAL VASOSPASM POST-

ANEURISMAL SUBARACHNOID

HEMORRHAGE (aSAH)

Clazosentan is investigational, in development and not approved or marketed in any country.


CLAZOSENTAN FOR CEREBRAL VASOSPASM POST

7/25/2019 Actelion



Highly soluble ETA selective ERA ideal for intravenous administration

>1’500 patients treated with clazosentan providing significant experience in

vasospasm post aSAH and a well documented safety profile

CONSCIOUS-2 aneurysm secured by clipping

CONSCIOUS-3 aneurysm secured by coiling

CLAZOSENTAN FOR CEREBRAL VASOSPASM POST-

ANEURISMAL SUBARACHNOID HEMORRHAGE (aSAH)

Stroke. 2012 Jun;43(6):1463-9

Lancet Neurology 2011;10(7):618-625

Clazosentan is an investigational drug in development and not approved or marketed in any country


CONSCIOUS 3 STUDY EVENT RATE FOR THE

7/25/2019 Actelion



DIND = Delayed ischemic neurological deficits;

Macdonald R et al. Stroke 2012.

Placebo

Clazosentan 5 mg/hClazosentan 15 mg/h

25

20

15

10

0

E v e n t r a t e ( % )

Death (within6 weeks)

New cerebralinfarct

DIND Rescuetherapy

5

Vasospasm-related

53

6

13

16

7

2118

10

7

15

21

RRR(95% CI)

35%(-79 to 76%)

-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%)

CONSCIOUS-3 STUDY - EVENT RATE FOR THE

COMPONENTS OF THE 1o COMPOSITE ENDPOINT



ADAPTED STRATEGY: REVERSAL VS

7/25/2019 Actelion



Baseline Vasospasm 2 days of Tx

Vasospasm reversal with clazosentan in humans

ADAPTED STRATEGY: REVERSAL VS.

PREVENTION

Phase III study under discussion with HA’s

Primary objective to determine whetherclazosentan 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 inreversing angiographically-confirmed cerebral vasospasm in approximately 25

subjects



7/25/2019 Actelion



EXTENSIVE RESEARCH

& DEVELOPMENT


A CHAIN OF EXPERTISE

7/25/2019 Actelion



371 PROFESSIONALS (DECEMBER 2015)

Molecular Biologists

Cell Biologists Toxicologists

Pharmacokineticists

Formulation Specialists

Clinical Scientists

Biochemists

Structural Biologists

Medicinal Chemists

Pharmacologists

Process Research Chemists

DRUGDISCOVERY

ORGANIZATION


ACTELION’S DRUG DISCOVERY STRATEGY

7/25/2019 Actelion



Highly regulated service activities outsourced

(e.g. Toxicology, Production, Formulation)

All important research functionalities in-house

(e.g. MedChem, AssayTech, DMPK, Pharmacology)


THE BASE FOR HIGH DISCOVERY EFFICIENCY

7/25/2019 Actelion



CULTURE OF INNOVATION

• Single-center approach

• Fully integrated research informatics

• Focus on small molecules

• Few platforms of expertise

• Multiple therapeutic areas

• High medical input


CLINICAL DEVELOPMENT ORGANIZATION

7/25/2019 Actelion



422 PROFESSIONALS (DECEMBER 2015)

Life Cycle Management

Clinical Pharmacology

Global Drug Safety

Global Drug Regulatory Affairs

Global Clinical Operations

Strategic Clinical Development

Biometry

Clinical Science

CLINICAL

DEVELOPMENT


EXTENDING THE CORE PAH FRANCHISE

7/25/2019 Actelion



Macitentan

OPUS

Macitentan

ORCHESTRA

Macitentan

SOPRANO

Macitentan

SYMPHONY

MacitentanPORTICO

Macitentan & Selexipag

TRITONSelexipag

GRIPHON

Macitentan

MAESTROMacitentan

MELODY

Macitentan

MERIT

Phase I Phase II Phase III Phase IV


DIVERSIFICATION

7/25/2019 Actelion



CadazolidClostridium difficile assoc. diarrhea

Ponesimod

Multiple Sclerosis

ClazosentanReversal of vasospasm post-aSAH

Ponesimod

Graft vs. host diseaseCenerimodSystemic lupus erythematosus

Endothelin Receptor Antagonis t

Specialty cardiovascular disorders

LucerastatFabry’s disease

New Chemical Enti tyNeurological disorders

New Chemical Enti tyNeurological disorders

New Chemical Enti tyCardiovascular disorders

Phase I Phase II Phase III


OUR RICH DISCOVERY PIPELINE

7/25/2019 Actelion



>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


STRATEGY FOR VALUE

7/25/2019 Actelion



SUSTAIN AND

GROW THE PAH

FRANCHISE

BUILD ADDITIONAL

SPECIALTY

FRANCHISES


CREATION



FINANCIAL OVERVIEW

7/25/2019 Actelion



FINANCIAL OVERVIEW

BY REPORTING PERIOD


STRONG PERFORMANCEFY

7/25/2019 Actelion



Variance

FY 2014 FY 2015 CHF CERCER

Ex US rebate

reversals

Product salesCHF million

1,956 2,042 4% 7% 11%

Core earningsCHF million

743 814 9% 14% 25%

Core diluted EPSCHF

5.58 6.16 10% 15% 26%

Operating incomeCHF million 570 656 15% 21% -

US GAAP diluted EPSCHF

5.11 4.91 -4% 1% -

STRONG PERFORMANCE2015


7/25/2019 Actelion



CORE EARNINGS

BY REPORTING PERIOD


CORE EARNINGS –

INTRINSIC GROWTH 25%FY

7/25/2019 Actelion



743677 677

814

66168

32

FY '14 Coreearnings as

reported

US rebate reversals FY'14 Coreearnings

excluding USrebate reversals

FY '15 intrinsicgrowth

FX FY'15 Coreearnings

INTRINSIC GROWTH + 25%2015

CHF million


7/25/2019 Actelion


EARNINGS PER SHAREFY

7/25/2019 Actelion



Variance

FY 2014 FY 2015 CHF CER

Core Net incomeCHF million

648 693 7 11

Core Diluted EPSNumber of shares in calculation (m)

5.58116.2

6.16112.5

10 15

US GAAP Net incomeCHF million

594 552 -7 -3

US GAAP Diluted EPSNumber of shares in calculation (m)

5.11116.2

4.91112.5

-4 1

EARNINGS PER SHARE2015


7/25/2019 Actelion


OUTSTANDING YEAR FOR SHAREHOLDERS

7/25/2019 Actelion



Second-line share repurchase continues

Dividend: Board proposes increase to CHF 1.50 per share

SHARE PRICE PERFORMANCE CASH RETURNED TO SHAREHOLDERS

2016 – FURTHER RETURNS TO COME

358

588

133

927

2012 2013 2014 2015


7/25/2019 Actelion



FINANCIAL GUIDANCE

February

2016


FINANCIAL GUIDANCE2016

7/25/2019 Actelion



FINANCIAL GUIDANCE2016

Low single-digit percentage core operating

income growth, at constant exchange rates

and barring unforeseen events


7/25/2019 Actelion



MANAGEMENT &

BOARD


THE RIGHT PEOPLE FOR THE NEXT GROWTH PHASE

7/25/2019 Actelion



ACTELION MANAGEMENT TEAM

Jean-Paul ClozelFounder, CEO

Joined in 1997

André MullerCFO

Joined in 2013

Otto SchwarzCOO

Joined in 2008

Martine Clozel

Founder, CSO

Joined in 1997

Nicholas Franco

Chief BD Officer

Joined in 2011

Guy Braunstein

Head of Global CD

Joined in 2009

Marian Borovsky

General Counsel

Joined in 2003

Christian Albrich

Head of Global HR

Joined in 2005

Andrew Weiss

Head of IR & CC

Joined in 2014

Rudi Frank

Head of Global Quality Management

Joined in 2000


THE RIGHT PEOPLE FOR THE NEXT GROWTH PHASE

7/25/2019 Actelion



John J. Greisch

Joined in 2013

ACTELION BOARD OF DIRECTORS

Juhani Anttila

Joined in 2005

Jean-Paul Clozel

Joined in 2000

Robert J. Bertolini

Joined in 2011

Peter Gruss

Joined in 2012

Michael Jacobi

Joined in 2009

Jean Malo

Joined in 2004

David Stout

Joined in 2015

Herna Verhagen

Joined in 2015

Jean-Pierre Garnier

Chairman

Joined in 2011


7/25/2019 Actelion


THANK YOU FOR YOUR

INTEREST IN ACTELION

Date post:	24-Feb-2018
Category:	Documents
Upload:	silviu-ciocianu
View:	221 times
Download:	0 times

Actelion

Documents