ACTELION LTD DELIVERING ON OUR STRATEGY Company Presentation January 2017
Copyright © 2017 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’s 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 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.
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© 2017 Actelion Pharmaceuticals Ltd
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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
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
ACTELION AT A GLANCE
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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 (June ‘16) • Drug Discovery • Clinical Development • Marketing & Sales • Support Functions
2,560 366 440 1,432 322
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 65‘000 Patients currently treated with an Actelion medication Extensive Research & Development portfolio
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
STAGES OF COMPANY DEVELOPMENT 2020
2014
2007
2001 1997 Build pipeline and commercial Company formed, infrastructure development & approval of Tracleer
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© 2017 Actelion Pharmaceuticals Ltd
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Commercial leverage and prepare for Tracleer LOE
Company presentation
Opsumit, Uptravi and development of new franchises
PAH, Life Cycle Management and New Franchises
ACTELION TODAY
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
ACTELION TODAY A UNIQUE COMPANY
1 Based on innovation 2 Fully integrated and global 3 Highly profitable 4 Comprehensive infrastructure 5 Unencumbered assets
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACTELION TODAY A UNIQUE COMPANY
1 Based on innovation 2 Fully integrated and global
►
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 4 Comprehensive infrastructure 5 Unencumbered assets
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACTELION TODAY FULLY INTEGRATED AND GLOBAL A UNIQUE COMPANY From Research to Commercialization More than 30 operative affiliates worldwide Product availability in >60 markets
1 Based on innovation 2 Fully integrated and global 3 Highly profitable 4 Comprehensive infrastructure 5 Unencumbered assets
Commercial Operations R&D Centers 10
© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
ACTELION TODAY A UNIQUE COMPANY CORE EARNINGS 1 Based on innovation 2 Fully integrated and global 3 Highly profitable 4 Comprehensive infrastructure 5 Unencumbered assets
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© 2017 Actelion Pharmaceuticals Ltd
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900 800 700 600 500 400 300 200 100 0
Company presentation
2009
2010
2011
2012
2013
2014
2015
ACTELION TODAY A UNIQUE COMPANY
1 Based on innovation
►
Swiss company
2 Fully integrated and global
►
One discovery center in Switzerland
3 Highly profitable
►
Full global development capabilities
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Fully established infrastructure from process to buildings
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Focus on quality
4 Comprehensive infrastructure 5 Unencumbered assets
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACTELION TODAY A UNIQUE COMPANY
1 Based on innovation 2 Fully integrated and global
►
Full rights to all products*
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Strong balance sheet and financing capacity
►
No major alliances for own products
3 Highly profitable 4 Comprehensive infrastructure 5 Unencumbered assets
*Cooperation with Nippon Shinyaku in Japan for macitentan and selexipag
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
STRATEGY FOR VALUE CREATION
SUSTAIN AND GROW THE PAH FRANCHISE
BUILD ADDITIONAL SPECIALTY FRANCHISES
OPTIMIZE PROFITABILITY
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
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© 2017 Actelion Pharmaceuticals Ltd
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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
Company presentation
9M 2016
KEY HIGHLIGHTS: TRANSFORMING ACTELION
Excellent performance across all areas of business Products: Strong sales of Opsumit & Uptravi Innovation: Significant pipeline progression Finance: Upgraded guidance
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
STRATEGY FOR VALUE CREATION
SUSTAIN AND GROW THE PAH FRANCHISE
BUILD ADDITIONAL SPECIALTY FRANCHISES
OPTIMIZE PROFITABILITY
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
A LIFE-THREATENING AND OFTEN MISUNDERSTOOD CONDITION Pulmonary arterial hypertension is a 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
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© 2017 Actelion Pharmaceuticals Ltd
Artery showing vasoconstriction
January 2017
Company presentation
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
I
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.
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
TREATMENT PATHWAYS
ENDOTHELIN RECEPTOR ANTAGONISTS (ERA)
PHOSPHODIESTERASE-5INHIBITORS (PDE-5i)
PROSTACYCLIN RECEPTOR AGONISTS
IP RECEPTOR AGONIST
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
PGI2 ANALOGUES
SIGNIFICANT PROGRESS IN THE FIELD OF PAH
PAH targeted therapies Multiple approved 1st
1st
PGI2
1990
INCREASING DISEASE AWARENESS PRECLINICAL/ CLINICAL RESEARCH
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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
© 2017 Actelion Pharmaceuticals Ltd
January 2017
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
Company presentation
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. 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.
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
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. Galiè N, et al. Eur Heart J 2009. 2. Galiè N, et al. J Am Coll Cardiol 2013.
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
ACTELION’S PAH PORTFOLIO
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
ACTELION’S PRODUCT PORTFOLIO
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
TRANSFORMING OUR PAH PORTFOLIO MOVING TO OUTCOME-BASED THERAPY
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
UNIQUELY POSITIONED TO BUILD & SERVE PAH COVERING CONTINUUM OF CARE WITH OUTCOME-BASED MEDICINES
FC II
FC III +/- PDE-5 inhibitor
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
FC IV
TRACLEER: OUR FIRST SUCCESS
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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 29
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
TRANSITIONING TO OPSUMIT
CHF million
934 790
9M 2015
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© 2017 Actelion Pharmaceuticals Ltd
Dynamics driven by Opsumit impact, generic erosion in selected markets and DU growth (esp. Japan)
Generic Update:
- 9% in Volume -18% at CER
9M 2016
January 2017
Company presentation
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Spain: strong generic competition in Q3 YTD sales: - 82%
–
US: Shared REMS submitted to FDA end July, file under review
ENGINE OF TRANSFORMATION
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
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 32
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
OPSUMIT: A LANDMARK IN PAH
The effect of macitentan to reduce combined morbidity/mortality events
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–
a multi-center, event driven long-term, placebo controlled study
–
average duration of exposure approximately 2 years,
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in 742 patients
–
with symptomatic PAH
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WHO functional class (FC) II-III
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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
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
SUSTAINED SALES GROWTH DYNAMICS
CHF million
147 95 5
38
59
162
178
200
218
113
68
15
Q4 2013 Q1 2014 Q2 2014 Q3 2014 Q4 2014 Q1 2015 Q2 2015 Q3 2015 Q4 2015 Q1 2016 Q2 2016 Q3 2016
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
OPENING THE PROSTACYCLIN PATHWAY TO MANY MORE PATIENTS
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
OPENING THE PROSTACYCLIN PATHWAY TO MANY MORE PATIENTS
US: FDA APPROVAL 21 DEC 2015 US: LAUNCH 04 JAN 2016 EU: MARKET AUTHORIZATION 12 MAY 2016
Uptravi® (selexipag) is an orally available, selective IP prostacyclin receptor agonist, targeting and activating the prostacyclin pathway.
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
OPENING THE PROSTACYCLIN PATHWAY TO MANY MORE PATIENTS
US Sales
CHF million
US inventory
Ex-US sales
70 56 10
35
66 20
45
15 Q1 2016
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© 2017 Actelion Pharmaceuticals Ltd
Q2 2016
January 2017
Q3 2016
Company presentation
GRIPHON STUDY PUBLISHED 24 DECEMBER 2015
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
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
3
Expand prescriber base
3
Establish as prostacyclin of 1st choice
2
2 Expand prostacyclin therapy patients base
2
2 Expand prostacyclin prescriber base
11st
Establish as prostacyclin therapy of 1st choice
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
11st
Expand prostacyclin therapy patient base
EXPANDING THE CLINICAL UTILITY OF UPTRAVI MANAGING THE LIFE CYCLE TRANSIT study assesses tolerability and safety of the transition from inhaled
treprostinil to oral selexipag in adult patients with PAH TRITON study compares efficacy and safety of initial triple oral treatment
regimen of macitentan together with tadalafil and selexipag versus initial dual oral treatment regimen in newly diagnosed, treatment-naïve patients with PAH Intravenous (i.v.) formulation of selexipag is being developed for the treatment of
patients with PAH who are prescribed oral selexipag and who are temporarily unable to take oral medication. Working closely with health authorities, Actelion is in the process of developing a
strategy for investigating the use of Uptravi in children with PAH
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
I.V. THERAPY MADE A LITTLE EASIER
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
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 17 countries including the United States since 2010 and some European markets since 2013 43
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
CONTINUED SIGNIFICANT GROWTH +13% CER Growth
Growth continues due to
CHF million
strong performances led by France and
well enhanced by Spain, Italy and UK Japan* +2% despite a 12% price cut on 1
71 60
March 2016 Veletri launched in Germany late
September
9M 2015
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© 2017 Actelion Pharmaceuticals Ltd
9M 2016
January 2017
*Trade
Company presentation
name Epoprostenol “ACT”
SUSTAINING OUR BUSINESS
MARKETED BY ACTELION IN THE US ONLY
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
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. MARKETED BY ACTELION IN THE US ONLY 46
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
EXPANDING THE CLINICAL UTILITY OF MACITENTAN
MACITENTAN
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
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
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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) Galiè et al. Eur Heart J 2015 © 2017 Actelion Pharmaceuticals Ltd
January 2017
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 TOMORROW (Pediatric PAH) PORTICO (Portopulmonary Hypertension) OPUS (US observational, drug registry of Opsumit new users in clinical practice) SYMPHONY & ORCHESTRA (psychometric validation of QoL questionnaire –
USA and FR, IT, ES respectively) REPAIR (Right Ventricular Stroke Volume) SOPRANO (PH after left ventricular assist device implantation) MERIT (CTEPH - Chronic Thromboembolic Pulmonary Hypertension) RUBATO (Fontan-palliated patients)
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
LABEL-ENABLING CHARACTERIZATION: TOMORROW SIGNIFICANT MEDICAL NEED IN PEDIATRIC PAH No globally approved treatment for PAH in children Pediatric PAH physicians have to mostly rely on research data collected in
adults when weighing up treatment options Pediatric studies must be conducted with minimal burden on the patient
–
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Clinical studies in children are associated with specific requirements •
Study endpoints must be meaningful for children
•
Study assessments must be suitable and safe for children
•
A child's growth and development can be affected by a drug
•
A child, if considered developmentally capable, must be involved in the decision to participate
•
Appropriate formulation to ensure accurate dosing and drug compliance
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
LABEL-ENABLING CHARACTERIZATION: TOMORROW STUDY OVERVIEW
TOMORROW: long-term benefits of macitentan in children with PAH Wide age range as well as the use of safe, non-invasive measurements Dose determination phase with staggered patient recruitment by age category Dispersible tablet pediatric formulation in multiple strengths Global program received endorsement from the US FDA and in Europe’s EMA
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
LABEL-ENABLING CHARACTERIZATION: PORTICO PORTOPULMONARY HYPERTENSION Portopulmonary hypertension is PAH that is associated to liver disease, often
cirrhosis, and portal hypertension Moderate to severe PAH is a contraindication for transplant – and often only
diagnosed via pre-liver transplant assessment No approved treatment to reduce pulmonary arterial pressure and allow
transplant Compelling data supports the use of PAH-specific therapies in portopulmonary
hypertension with the aim of improving pulmonary hemodynamics
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
LABEL-ENABLING CHARACTERIZATION: PORTICO STUDY OVERVIEW The observed safety profile of macitentan, particularly in respect of its effect on
the liver makes it ideal to be used in this patient population Placebo controlled study to evaluate the efficacy and safety of macitentan for
the treatment of patients with portopulmonary hypertension Primary outcome measure is the relative change from baseline to Week 12 in
pulmonary vascular resistance (PVR)
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
POST-LAUNCH CHARACTERIZATION OVERVIEW SYMPHONY & ORCHESTRA: Psychometric validation of PAH-SYMPACT (new
patient-reported outcome instrument for PAH), with the objective to demonstrate the psychometric characteristics of reliability and construct validity of the method OPUS (Opsumit Users Registry®): Characterizes the safety profile of
macitentan and describes clinical characteristics and outcomes of patients newly treated with macitentan in the real-world post-marketing setting REPAIR: Evaluates effect of macitentan on Right Ventricular Stroke Volume
assessed by magnetic resonance imaging (MRI) and on PVR assessed with right heart catheterization (RHC) in patients with symptomatic PAH SOPRANO: Assesses efficacy and safety of macitentan in patients with
pulmonary hypertension after Left Ventricular Assist Device Implantation
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
NEW INDICATIONS: MERIT CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH) Patients with chronic obstructions of the lung arteries Pulmonary thromboendarterectomy (PTE) is the gold standard in operable
patients – potentially curative. Many patients are considered inoperable though due to distal vasculopathy and/or comorbidities MERIT was Phase II prospective, randomized, placebo-controlled, double-blind,
multi-center, parallel-group study to assess the efficacy, safety and tolerability of 10 mg macitentan in inoperable CTEPH 80 patients were randomized in a 1:1 ratio into 2 treatment groups (macitentan
10 mg or placebo) over a 24 week treatment period Patients with symptomatic PH in WHO Functional Class III or IV at baseline
were allowed to receive PH background therapy throughout the study, including PDE-5 inhibitors or oral/inhaled prostanoids. Operability was adjudicated by an experienced surgeon or central adjudication
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
NEW INDICATIONS: MERIT STUDY RESULTS Significant 16% reduction in PVR at 16 weeks with macitentan compared with
placebo (95% CL: −30%, −1%; p=0.04, ITT)
Significant positive effect of macitentan compared to placebo on exercise
capacity – 6-MWD least-squares mean difference at Week 24 was 34.0 meters between macitentan and placebo (95% CL: 2.9, 65.2 m; p=0.03, ITT) Observed efficacy was consistent across all sub-groups, inc. patients receiving
background PH specific therapy at baseline (61%), inc. PDE-5 inhibitors (59%) Macitentan was well tolerated in this patient population, most frequently reported
AE’s that occurred with higher frequency on macitentan vs. placebo were peripheral edema (22.5% vs. 10.0%) and events related to anemia (17.5% vs. 2.5%) Actelion will now fully analyze the data and discuss the findings with health
authorities
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
NEW INDICATIONS: RUBATO FONTAN-PALLIATED PATIENTS "Fontan" is a surgical procedure in children born with complex congenital heart
defects, enabling a single ventricle to support blood circulation to the body and the lung This is a life-saving procedure; patients who survive are relatively stable through
childhood Decline in exercise capacity accelerates at adolescence with risk of poor long-
term outcome An estimated 1’200 Fontan procedures performed annually in the US – with
between 17’000 and 24’000 Fontan-palliated patients currently living worldwide
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
NEW INDICATIONS: RUBATO STUDY OVERVIEW Assess the efficacy and safety of macitentan in stable Fontan-palliated
adolescents and adults Primary objective to assess the effect of macitentan on exercise capacity
through peak VO2 Secondary objectives to evaluate:
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–
effect of macitentan on N-terminal prohormone of brain natriuretic peptide (NT-proBNP)
–
safety and tolerability of macitentan in this patient population
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
STRATEGY FOR VALUE CREATION
SUSTAIN AND GROW THE PAH FRANCHISE
BUILD ADDITIONAL SPECIALTY FRANCHISES
OPTIMIZE PROFITABILITY
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
BUILD ADDITIONAL SPECIALTY FRANCHISE
MARKETED BY ACTELION IN THE US ONLY
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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 62
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
BUILD ADDITIONAL SPECIALTY FRANCHISE
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© 2017 Actelion Pharmaceuticals Ltd
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Company presentation
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 65
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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:
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–
Severe disabilities in swallowing, ambulation, eye movements, language, cognition, muscle control
–
Lipid accumulation can also lead to an enlarged liver and/or spleen.
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
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© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
BUILD ADDITIONAL SPECIALTY FRANCHISE
CADAZOLID CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA
68
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
CADAZOLID: PROGRESSING AS PLANNED
International, Multi-center Program Assessing Cadazolid Treatment in patients suffering from Clostridium difficile associated diarrhea (CDAD)
Cadazolid is an investigational drug in development and not approved or marketed in any country
69
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
mpact
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.
70
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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 71
Lactobacillus
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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 72
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
Cadazolid is investigational, in development and not approved or marketed in any country.
73
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
BUILD ADDITIONAL SPECIALTY FRANCHISE
PONESIMOD
Ponesimod is investigational, in development and not approved or marketed in any country.
74
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PONESIMOD UNIQUE MEDICAL UTILITY
Short half-life and rapid reversibility (easy 'on-off') allow:
–
restoration of immune system
–
management of opportunistic infections
–
vaccinations
–
pregnancy management
–
combination with other immunomodulators
Provides physicians with greater flexibility and better control of patient treatment
75
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
Ponesimod is investigational, in development and not approved or marketed in any country.
76
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
Ponesimod is investigational, in development and not approved or marketed in any country.
77
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
Ponesimod is investigational, in development and not approved or marketed in any country.
78
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
Ponesimod is investigational, in development and not approved or marketed in any country.
79
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PONESIMOD DIFFERENTIATION A NEW DIRECTION IN MS TREATMENT?
Relative reduction of Annual Relapse Rates drives current perception of efficacy
of MS therapies However, on current therapies – on average – 1 in 5 patients will experience a
relapse Combination therapy could improve long-term outcome for patients Ponesimod – with its rapid reversibility – is ideally suited for use in combination
therapy
Ponesimod is investigational, in development and not approved or marketed in any country.
80
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PONESIMOD DIFFERENTIATION PHASE III STUDY: POINT
First oral combination therapy (on top of Tecfidera)
Primary objective: Determine whether add-on therapy reduces relapse frequency as compared to
placebo in patients with active relapsing multiple sclerosis who are treated with Tecfidera. The primary endpoint is the Annualized Relapse Rate (ARR), which is defined as
the number of confirmed relapses per patient and year, from randomization up to the end of the study.
Ponesimod is investigational, in development and not approved or marketed in any country.
81
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PONESIMOD DIFFERENTIATION PHASE III STUDY: POINT
Prospective, multicenter, randomized, double-blind, parallel group, add-on, placebocontrolled, superiority study with ponesimod in patients with RMS. –
∼ 600 patients receiving dimethyl fumarate twice daily for at least 6 months
–
randomized in a 1:1 ratio to ponesimod 20 mg or placebo.
–
Treatment given until last patient enrolled treated for 60 weeks, expected average treatment duration of 2 years, maximum duration 3 years
–
Enrollment expected to start before end 2016
Ponesimod is investigational, in development and not approved or marketed in any country.
82
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PHASE II STUDY IN SYSTEMIC LUPUS
ERYTHEMATOSUS CENERIMOD
An investigational compound, in development and not approved or marketed in any country.
83
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACTELION’S SECOND S1P1 MODULATOR: CENERIMOD KEY PROPERTIES Very potent S1P1 receptor modulator with highly
selective profile O
Prevents lymphocytes from leaving lymph nodes
N
Lymphocyte reduction is rapid, dose-dependent
and reversible
N
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.
84
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
Cenerimod is investigational, in development and not approved or marketed in any country.
85
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
Cenerimod is investigational, in development and not approved or marketed in any country.
86
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
BUILD ADDITIONAL SPECIALTY FRANCHISE
CLAZOSENTAN CEREBRAL VASOSPASM POSTANEURISMAL SUBARACHNOID HEMORRHAGE (aSAH)
Clazosentan is investigational, in development and not approved or marketed in any country.
87
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
CLAZOSENTAN FOR CEREBRAL VASOSPASM POSTANEURISMAL SUBARACHNOID HEMORRHAGE (aSAH)
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
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
88
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
5
6
7
7
3
0 Death (within 6 weeks) DIND = Delayed ischemic neurological deficits; Macdonald R et al. Stroke 2012.
New cerebral infarct
Vasospasm-related
Clazosentan is an investigational drug in development and not approved or marketed in any country
89
© 2017 Actelion Pharmaceuticals Ltd
January 2017
DIND
Company presentation
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 HA’s 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 Clazosentan is an investigational drug in development and not approved or marketed in any country
90
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
BUILD ADDITIONAL SPECIALTY FRANCHISE
DUAL OREXIN RECEPTOR ANTAGONIST
Insomnia
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country.
91
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
RAT EEG DATA: SLEEP EFFICACY / ARCHITECTURE
Actelion New DORA (mg/kg)
Active wake 39.9
Vehicle Active phase dosing
10
*** ***
33.5
15.3
*
***
24.0
***
27.5
34.2
27.3
REM sleep 6.2 18.0 21.7
35.1
31.1
100
non-REM sleep 35.9 35.5
35.3
30
Rest phase
Quiet wake
40.4
7.4
**
9.8
***
11.0 10.8
Time spent in sleep and wake stages (% of total time) over the first 6h of the active phase following administration
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
92
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PHASE I PROGRAM
Single-ascending dose study in healthy young male adults
–
Doses evaluated from 5 mg to 200 mg
3-part study in male and female young adults and elderly
–
Multiple-ascending dose in adults
–
Single-ascending dose in elderly
–
Multiple night-time dosing in adult and elderly
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
93
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
IDEAL PHARMACOKINETIC PROFILE FOR AN INSOMNIA MEDICATION
Dose = 25 mg for 5 days
Actelion’s New DORA (ng/ml)
1000
800
600
400
200
0 0
24
48
72
96
120
144
168
Time (h)
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
94
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PHARMACODYNAMIC PROFILE: FAST ONSET OF ACTION IN ADULT & ELDERLY
Person performing eye movement test
Reduced speed of eye movements Adult Healthy Volunteer – Daytime dosing Elderly Healthy Volunteer – Daytime dosing
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
95
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PHARMACODYNAMIC PROFILE: APPROPRIATE DURATION OF ACTION IN ADULT & ELDERLY
Person performing adaptive tracking test
Reduced tracking performance Adult Healthy Volunteer – Daytime dosing Elderly Healthy Volunteer – Daytime dosing
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
96
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
NEXT-DAY PHARMACODYNAMIC PROFILE NO SLEEPINESS REPORTED ON NEXT MORNING
Karolinska Sleepiness Scale Score
Healthy adult with night-time administration 1= very alert, 3=alert, normal level, 5=neither alert nor sleepy, 7=sleepy, but no effort keeping awake, 9=very sleepy
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
97
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
INITIAL SAFETY PROFILE FROM PHASE I PROGRAM
No SAEs, no unexpected AEs after 110 healthy adults and elderly exposed Starting at 25 mg, transient AEs of mild to moderate intensity were observed
such as: Disturbance of attention, somnolence, fatigue, headache and dizziness No significant effect on vital signs, ECG, and laboratory parameters
Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
98
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
PHASE II PROGRAM OVERVIEW
Two studies in adult and elderly patients to evaluate the effect of
Actelion’s DORA versus placebo Assessing sleep maintenance, sleep initiation, next day residual effect
and next day performance Study 1: ~300 adult insomnia patients – treatment duration 4 weeks Study 2: ~50 elderly insomnia patients Adult study will also include an active-reference arm with zolpidem Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
99
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACTELION’S NEW DORA SUMMARY Actelion has significant expertise in the discovery and development of DORAs DORAs have the potential to promote sleep and maintain a natural sleep
architecture PK/PD profile of Actelion’s New DORA suggests an optimal combination of
effect on the CNS and low residual concentration next-day for a sleep medication Phase II program will show whether the Phase I data will translate into both
adult and elderly insomnia patients Phase II program will provide all data required to design a differentiated Phase
III program Actelion’s New DORA is an investigational drug in development and not approved or marketed in any country
100
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACTELION’S NEW DUAL ERA IN RESISTANT HYPERTENSION
ACT-132577
101
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACT-132577 IN RESISTANT HYPERTENSION RESISTANT HYPERTENSION Resistant hypertension is defined by uncontrolled hypertension despite three
antihypertensive drug therapies from different classes at optimal doses including a diuretic Represents a small sub-set of hypertensive population High cardiovascular risk factor in comparison to non-resistant hypertension Endothelin has not been targeted in systemic hypertension despite evidence
supporting ERAs as a therapeutic strategy Renal denervation studies continue despite initial failure, exemplifying medical
need in resistant hypertension Results of the NIH-sponsored SPRINT study show that even more hypertensive
patients than thought are not well controlled
102
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
ACT-132577 IN RESISTANT HYPERTENSION ACT-132577 PROFILE Dual ETA and ETB receptor antagonist Potential for an oral, potent, once-a-day drug with long-lasting effect on blood
pressure Active metabolite of macitentan Evaluated in a Phase II dose-finding study to explore the effects ACT-132577
– at different dose strengths – on the efficacy, safety and tolerability in patients with essential hypertension Patients are randomized to 6 groups in a 1:1:1:1:1:1 ratio:
placebo; dose 1, dose 2, dose 3, dose 4 of Actelion's ERA; and lisinopril 20 mg Clinical development pathway in resistant hypertension aligned with FDA
103
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
EXTENSIVE RESEARCH & DEVELOPMENT
104
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
A CHAIN OF EXPERTISE 371 PROFESSIONALS (DECEMBER 2015) Pharmacologists Toxicologists
Cell Biologists
Molecular Biologists
DRUG DISCOVERY ORGANIZATION
Biochemists
Process Research Chemists
© 2017 Actelion Pharmaceuticals Ltd
Formulation Specialists Clinical Scientists
Medicinal Chemists
105
Pharmacokineticists
January 2017
Company presentation
Structural Biologists
ACTELION’S 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)
106
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
THE BASE FOR HIGH DISCOVERY EFFICIENCY CULTURE OF INNOVATION
• • • • • •
107
Single-center approach Fully integrated research informatics Focus on small molecules Few platforms of expertise Multiple therapeutic areas High medical input
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
CLINICAL DEVELOPMENT ORGANIZATION 422 PROFESSIONALS (DECEMBER 2015)
Clinical Science
Life Cycle Management Clinical Pharmacology
CLINICAL DEVELOPMENT
Global Drug Safety Global Drug Regulatory Affairs
108
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Biometry Global Clinical Operations Strategic Clinical Development
Company presentation
EXTENDING THE CORE PAH FRANCHISE Phase I
Phase II
Macitentan OPUS Macitentan ORCHESTRA Macitentan SOPRANO Macitentan SYMPHONY Macitentan PORTICO Macitentan REPAIR Macitentan & Selexipag TRITON Macitentan TOMORROW Macitentan RUBATO Macitentan SERENADE Macitentan MERIT Selexipag I.V. formulation
109
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
Phase III
Phase IV Post approval
DIVERSIFICATION INTO NEW AREAS Regulatory filing Cadazolid Clostridium difficile assoc. diarrhea Ponesimod Multiple Sclerosis Cenerimod Systemic lupus erythematosus Clazosentan Reversal of vasospasm post-aSAH Dual orexin receptor antagonist Insomnia Endothelin Receptor Antagonist Specialty cardiovascular disorders Lucerastat Fabry’s disease New Chemical Entity Cardiovascular disorders New Chemical Entity Inflammatory disorders Selective orexin 1 receptor antagonist Neurological disorders T-type Calcium Channel Blocker Neurological disorders
110
© 2017 Actelion Pharmaceuticals Ltd
Phase I
January 2017
Company presentation
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
111
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
STRATEGY FOR VALUE CREATION
SUSTAIN AND GROW THE PAH FRANCHISE
BUILD ADDITIONAL SPECIALTY FRANCHISES
OPTIMIZE PROFITABILITY
112
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
FINANCIAL OVERVIEW BY REPORTING PERIOD
113
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
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
114
© 2017 Actelion Pharmaceuticals Ltd
CER
FY 2014
January 2017
Company presentation
Ex US rebate reversals
Q1 2016
EXCELLENT START TO 2016
Variance
Product sales CHF million
Core operating income CHF million
Core diluted EPS CHF
Operating income CHF million
US GAAP diluted EPS CHF
115
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Q1 2015
Q1 2016
CHF
CER
515
589
14%
11%
218
249
14%
8%
1.61
1.98
23%
17%
190
208
10%
3%
1.38
1.64
19%
11%
Company presentation
H1 2016
STRONG FIRST HALF 2016
Variance
Product sales CHF million
Core operating income CHF million
Core diluted EPS CHF
Operating income CHF million
US GAAP diluted EPS CHF
116
© 2017 Actelion Pharmaceuticals Ltd
January 2017
H1 2015
H1 2016
CHF
CER
1,008
1,179
17%
13%
423
499
18%
11%
3.11
4.05
30%
23%
344
412
20%
12%
2.50
3.32
33%
23%
Company presentation
9M 2016
STRONG FIRST NINE MONTHS
Variance
Product sales CHF million
Core operating income CHF million
Core diluted EPS CHF
Operating income CHF million
US GAAP diluted EPS CHF
117
© 2017 Actelion Pharmaceuticals Ltd
January 2017
9M 2015
9M 2016
CHF
CER
1,522
1,785
17%
14%
651
781
20%
14%
4.94
6.38
29%
23%
533
660
24%
17%
3.99
5.37
35%
27%
Company presentation
CORE OPERATING INCOME BY REPORTING PERIOD
118
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
FY 2015
CORE EARNINGS – INTRINSIC GROWTH + 25%
CHF million
32 ,168
,66
,814
,743
FY '14 Core earnings as reported
119
US rebate reversals
© 2017 Actelion Pharmaceuticals Ltd
January 2017
,677
,677
FY'14 Core earnings excluding US rebate reversals
FY '15 intrinsic growth
Company presentation
FX
FY'15 Core earnings
Q1 2016
CORE OPERATING INCOME INTRINSIC GROWTH + 8%
CHF million
,13 ,18
,218
Q1'15 Core operating income
120
© 2017 Actelion Pharmaceuticals Ltd
Q1 '16 intrinsic growth
January 2017
Company presentation
,236
249
FX
Q1'16 Core operating income
H1 2016
CORE OPERATING INCOME INTRINSIC GROWTH + 11%
CHF million
,29 ,47
,423
H1'15 Core operating income
121
© 2017 Actelion Pharmaceuticals Ltd
H1 '16 intrinsic growth
January 2017
Company presentation
,470
,499
FX
H1'16 Core operating income
9M 2016
CORE OPERATING INCOME INTRINSIC GROWTH + 14%
CHF million
,38 ,92
,651
9M'15 Core operating income
122
© 2017 Actelion Pharmaceuticals Ltd
9M'16 intrinsic growth
January 2017
Company presentation
,743
,781
FX
9M'16 Core operating income
EARNINGS PER SHARE (EPS) BY REPORTING PERIOD
123
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
FY 2015
EARNINGS PER SHARE
Variance
FY 2014
FY 2015
CHF
CER
648
693
7
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
1
Core Net income CHF million
US GAAP Net income CHF million
124
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
Q1 2016
EARNINGS PER SHARE
Variance
Q1 2015
Q1 2016
CHF
CER
185
215
16%
10%
Core Diluted EPS
1.61
1.98
Number of shares in calculation (m)
115.3
108.9
23%
17%
159
178
12%
5%
US GAAP Diluted EPS
1.38
1.64
Number of shares in calculation (m)
115.3
108.9
19%
11%
Core Net income CHF million
US GAAP Net income CHF million
125
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
H1 2016
EARNINGS PER SHARE
Variance
H1 2015
H1 2016
CHF
CER
357
440
23%
16%
Core Diluted EPS
3.11
4.05
Number of shares in calculation (m)
114.7
108.6
30%
23%
287
361
25%
17%
US GAAP Diluted EPS
2.50
3.32
Number of shares in calculation (m)
114.7
108.6
33%
23%
Core Net income CHF million
US GAAP Net income CHF million
126
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
9M 2016
EARNINGS PER SHARE
Variance
9M 2015
9M 2016
CHF
CER
560
691
23%
17%
Core Diluted EPS
4.94
6.38
Number of shares in calculation (m)
113.4
108.3
29%
23%
452
581
29%
21%
US GAAP Diluted EPS
3.99
5.37
Number of shares in calculation (m)
113.4
108.3
35%
27%
Core Net income CHF million
US GAAP Net income CHF million
127
© 2017 Actelion Pharmaceuticals Ltd
January 2017
Company presentation
SHAREHOLDER RETURNS
128
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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
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2014
2015
FINANCIAL GUIDANCE
October 2016
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2016
FINANCIAL GUIDANCE
Mid-teen percentage range core operating income growth, at constant exchange rates and barring unforeseen events
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Company presentation
MANAGEMENT & BOARD
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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
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André Muller CFO Joined in 2013
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Company presentation
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
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David Stout Joined in 2015
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Company presentation
Jean-Paul Clozel Joined in 2000
Michael Jacobi Joined in 2009
Herna Verhagen Joined in 2015
THANK YOU FOR YOUR INTEREST IN ACTELION
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