ACTELION’S CARDIOVASCULAR PIPELINE INVESTOR WEBCAST · © 2016 Actelion Pharmaceuticals Ltd PULMONARY AND SYSTEMIC CIRCULATION PATHWAYS 4 07 Nov 2016 Investor webcast

Copyright © 2016 Actelion Pharmaceuticals Ltd

November 2016

ACTELION’S CARDIOVASCULAR PIPELINE INVESTOR WEBCAST

© 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’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.

Investor webcast 07 Nov 2016 2


Jean-Paul Clozel Chief Executive Officer



PULMONARY AND SYSTEMIC CIRCULATION PATHWAYS



WHAT ARE WE SHARING TODAY?

We are committed to leading the way

in pulmonary arterial

hypertension

We are expanding our reach in pulmonary

hypertension

We are diversifying to new

cardiovascular indications



LONG-TERM COMMITMENT TO PULMONARY ARTERIAL HYPERTENSION (PAH)



ACTELION’S OUTCOME-BASED PAH PRODUCTS: TREATMENT PATHWAYS



Opsumit has demonstrated long-term outcomes by delaying disease progression in PAH WHO Group 1 in multiple patient populations such as:

– Treatment-naïve patients

– Patients treated in combination with PDE-5 inhibitors

– Functional Class II and Class III

– Different etiologies (iPAH, CTD, CHD)

– Incident & prevalent patients

Opsumit demonstrated a “best-in-class” safety profile

Convenient, simple once-a-day dosing

THE FUNDAMENTAL BASE IN THE TREATMENT OF PAH



Unique medical utility: Delays disease progression on top of ERA+PDE-5i, thus allowing an “all oral“ triple combination therapy, harvesting the benefits of all 3 pathways

Tolerability and simple dosing regimen (maintenance) allows long-term treatment

Uptravi is changing the treatment paradigm and opens the prostacyclin pathway to many more patients through intensification of treatment

Powerful launch in the US Jan 2016 and roll out ex-US since June 2016

UPTRAVI IS CHANGING THE PAH TREATMENT PARADIGM



Novel mechanisms with potential for disease modification; obligation to be active on top of existing therapies

Potential new principles:

Possible targets specific to difficult-to-treat subgroups of PAH (e.g. scleroderma)

CONTINUED COMMITMENT TO RESEARCH IN PAH: NEW COMPOUNDS AND MECHANISMS

Anti-proliferative

Anti-inflammatory Pathogenic

Interfering with abnormal cell metabolism

Anti-fibrotic



Guy Braunstein Head Global Clinical Development



MAXIMIZING THE CLINICAL UTILITY OF OUR PRODUCT PORTFOLIO

New Populations New Indications New Formulations



MACITENTAN LABEL-ENABLING CHARACTERIZATION



Although the disease is similar, 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

OUR COMMITMENT TO CHILDREN WITH PAH



Measuring 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

Patient enrollment to begin in the coming months

TOMORROW: STUDY OVERVIEW



When a congenital heart defect causes a shunt to develop between two chambers of the heart an increased blood flow returns to the lungs

Blood vessels in the lung arteries become stiff and narrow resulting in pulmonary hypertension

Eisenmenger syndrome occurs when the pressure in the pulmonary circulation becomes so great that the direction of blood flow through the shunt reverses

Down syndrome patients represent an important subset of the Eisenmenger population

EISENMENGER SYNDROME



Phase III study to evaluate the effects of macitentan on exercise capacity in patients with Eisenmenger syndrome

Primary outcome measure is change from baseline to Week 16 in exercise capacity, as measured by 6 minute walk distance

Secondary outcome measures are change from baseline to Week 16 in

– WHO functional class – dyspnea (assessed by the Borg dyspnea index) – quality of life (assessed by the SF-36 questionnaire)

The study is fully recruited with results expected in early 2017

MAESTRO: STUDY OVERVIEW



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

PORTOPULMONARY HYPERTENSION



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)

PORTICO: PORTOPULMONARY HYPERTENSION



MACITENTAN POST-LAUNCH CHARACTERIZATION



POST-LAUNCH CHARACTERIZATION OF MACITENTAN

OPUS

REPAIR

SYMPHONY & ORCHESTRA

SOPRANO

Macitentan: Further profiling the benefits for

patients




OPUS

REPAIR


SOPRANO


patients

Psychometric validation of PAH-SYMPACT




OPUS

REPAIR


SOPRANO


patients

Prospective Observational Drug Registry




OPUS

REPAIR


SOPRANO


patients PH Post Left Ventricular Assist Device Implantation




OPUS

REPAIR


SOPRANO


patients

Right Ventricular Stroke Volume



MACITENTAN NEW INDICATIONS



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 due to distal vasculopathy and/or comorbidities

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH) WHO GROUP 4

Distal vasculopathy in CTEPH



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 committee

MERIT: STUDY OVERVIEW



MERIT: 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%)



MERIT: NEXT STEPS

Fully analyze the data and discuss the findings with health authorities

Make data available through upcoming congress and publication



"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

FONTAN-PALLIATED PATIENTS

European Heart Journal - Cardiovascular Imaging Vol 16, 3: 281 - 297



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:

– effect of macitentan on N-terminal prohormone of brain natriuretic peptide (NT-proBNP)

– safety and tolerability of macitentan in this patient population

RUBATO: STUDY OBJECTIVES



NEW FORMULATIONS



Pediatric formulations needed to adjust dosing to weight of the child:

– Bosentan (Tracleer®): 32mg dispersible tablet

– Macitentan: 3 new formulations

– Selexipag: 2 new formulations

I.V. formulation of selexipag

FORMULATIONS ADDRESSING SPECIFIC MEDICAL NEEDS



SELEXIPAG: POST-LAUNCH CHARACTERIZATION



TRANSIT Study

i.v. Formulation

Pediatric

TRITON Study

POST-LAUNCH CHARACTERIZATION OF SELEXIPAG

Selexipag: Further profiling the benefits for

patients



TRANSIT Study

i.v. Formulation

Pediatric

TRITON Study



patients

In discussions with health authorities



TRANSIT Study

i.v. Formulation

Pediatric

TRITON Study



patients

Transition from inhaled treprostinil



TRANSIT Study

i.v. Formulation

Pediatric

TRITON Study



patients Initial triple oral treatment with selexipag + macitentan + tadalafil



TRANSIT Study

i.v. Formulation

Pediatric

TRITON Study



patients For patients temporarily unable to take oral medication



Martine Clozel Chief Scientific Officer



ACTELION’S NEW DUAL ERA IN RESISTANT HYPERTENSION

ACT-132577 is investigational, in development and not approved or marketed in any country.



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

ACT-132577: A NOVEL DUAL ERA




Production of ET-1 is increased in saphenous veins of African American hypertensives (salt-dependent)

ENDOTHELIN IS INVOLVED IN RESISTANT HYPERTENSION

CA Caucasian AA African-American

Ergul S et al. ATVB2002



INVERSE RELATIONSHIP BETWEEN ENDOTHELIN AND RENIN ANGIOTENSIN SYSTEMS

High Ang II

High ET-1

Essential Hypertension Resistant hypertension

↑ Vascular Resistance Excess Volume Sodium Retention

Reduced GFR



ACT-132577 SHOWS SUPERIOR EFFICACY IN VOLUME-DEPENDENT MODELS

n=4-6 per group n=6-8 per group

Dose (mg/kg)

MAP d

ecrea

se (m

mHg)

-60

-40

-20

03 10 10030 3001Veh.0.3

Dose (mg/kg)

MAP d

ecrea

se (m

mHg)

-60

-40

-20

03 10 10030 3001Veh.

ACT-132577

Dose (mg/kg)

M A

P d e

c r e a

s e ( m

m H

g )

-60

-40

-20

0 Valsartan 10 Veh.

n=5-10 per group

Dose (mg/kg)

M A

P d e

c r e a

s e ( m

m H

g )

-60

-40

-20

0 Valsartan 10 Veh.

n=6 per group

Valsartan

SHR rat DOCA-salt rat

Single dose administration




Long lasting blood pressure reduction

No reflex tachycardia

Reduces aldosterone and catecholamines (data from other dual ERAs)*

Synergistic action with angiotensin receptors antagonists

Low risk of water retention and edema

Safe in patients with renal impairment

ACT-132577: TARGET PROFILE FOR RESISTANT HYPERTENSION

* Sütsch et al., Am J Cardiol, 2000, Mulder et al. Circulation 1997; Qiu et al. Exp Biol Med 2006 ACT-132577 is investigational, in development and not approved or marketed in any country.



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

RESISTANT HYPERTENSION – A HIGH UNMET MEDICAL NEED



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

ACT-132577 – CURRENT STATUS




MORE TO COME… NCE IN PHASE I



Jean-Paul Cloze Chief Executive Officer



CONCLUSION

We are committed to leading the way

in pulmonary arterial

hypertension

We are expanding our reach in pulmonary

hypertension

We are diversifying to new

cardiovascular indications

A DIFFERENTIATED AND DIVERSIFIED CARDIOVASCULAR PORTFOLIO


Documents

ACTELION’S CARDIOVASCULAR PIPELINE INVESTOR WEBCAST · © 2016 Actelion Pharmaceuticals Ltd PULMONARY AND SYSTEMIC CIRCULATION PATHWAYS 4 07 Nov 2016 Investor webcast