Post on 10-Aug-2020
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
Copyright © 2016 Actelion Pharmaceuticals Ltd
Jean-Paul Clozel Chief Executive Officer
ACTELION’S CARDIOVASCULAR PIPELINE INVESTOR WEBCAST
© 2016 Actelion Pharmaceuticals Ltd
PULMONARY AND SYSTEMIC CIRCULATION PATHWAYS
Investor webcast 07 Nov 2016 4
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 5
© 2016 Actelion Pharmaceuticals Ltd
LONG-TERM COMMITMENT TO PULMONARY ARTERIAL HYPERTENSION (PAH)
Investor webcast 07 Nov 2016 6
© 2016 Actelion Pharmaceuticals Ltd
ACTELION’S OUTCOME-BASED PAH PRODUCTS: TREATMENT PATHWAYS
Investor webcast 07 Nov 2016 7
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 8
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 9
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 10
Copyright © 2016 Actelion Pharmaceuticals Ltd
Guy Braunstein Head Global Clinical Development
ACTELION’S CARDIOVASCULAR PIPELINE INVESTOR WEBCAST
© 2016 Actelion Pharmaceuticals Ltd
MAXIMIZING THE CLINICAL UTILITY OF OUR PRODUCT PORTFOLIO
New Populations New Indications New Formulations
Investor webcast 07 Nov 2016 12
© 2016 Actelion Pharmaceuticals Ltd
MACITENTAN LABEL-ENABLING CHARACTERIZATION
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© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 14
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 15
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 16
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 17
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 18
© 2016 Actelion Pharmaceuticals Ltd
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
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© 2016 Actelion Pharmaceuticals Ltd
MACITENTAN POST-LAUNCH CHARACTERIZATION
Investor webcast 07 Nov 2016 20
© 2016 Actelion Pharmaceuticals Ltd
POST-LAUNCH CHARACTERIZATION OF MACITENTAN
OPUS
REPAIR
SYMPHONY & ORCHESTRA
SOPRANO
Macitentan: Further profiling the benefits for
patients
Investor webcast 07 Nov 2016 21
© 2016 Actelion Pharmaceuticals Ltd
POST-LAUNCH CHARACTERIZATION OF MACITENTAN
OPUS
REPAIR
SYMPHONY & ORCHESTRA
SOPRANO
Macitentan: Further profiling the benefits for
patients
Psychometric validation of PAH-SYMPACT
Investor webcast 07 Nov 2016 22
© 2016 Actelion Pharmaceuticals Ltd
POST-LAUNCH CHARACTERIZATION OF MACITENTAN
OPUS
REPAIR
SYMPHONY & ORCHESTRA
SOPRANO
Macitentan: Further profiling the benefits for
patients
Prospective Observational Drug Registry
Investor webcast 07 Nov 2016 23
© 2016 Actelion Pharmaceuticals Ltd
POST-LAUNCH CHARACTERIZATION OF MACITENTAN
OPUS
REPAIR
SYMPHONY & ORCHESTRA
SOPRANO
Macitentan: Further profiling the benefits for
patients PH Post Left Ventricular Assist Device Implantation
Investor webcast 07 Nov 2016 24
© 2016 Actelion Pharmaceuticals Ltd
POST-LAUNCH CHARACTERIZATION OF MACITENTAN
OPUS
REPAIR
SYMPHONY & ORCHESTRA
SOPRANO
Macitentan: Further profiling the benefits for
patients
Right Ventricular Stroke Volume
Investor webcast 07 Nov 2016 25
© 2016 Actelion Pharmaceuticals Ltd
MACITENTAN NEW INDICATIONS
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© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 27
© 2016 Actelion Pharmaceuticals Ltd
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
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© 2016 Actelion Pharmaceuticals Ltd
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%)
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© 2016 Actelion Pharmaceuticals Ltd
MERIT: NEXT STEPS
Fully analyze the data and discuss the findings with health authorities
Make data available through upcoming congress and publication
Investor webcast 07 Nov 2016 30
© 2016 Actelion Pharmaceuticals Ltd
"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
Investor webcast 07 Nov 2016 31
© 2016 Actelion Pharmaceuticals Ltd
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
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© 2016 Actelion Pharmaceuticals Ltd
NEW FORMULATIONS
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© 2016 Actelion Pharmaceuticals Ltd
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
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© 2016 Actelion Pharmaceuticals Ltd
SELEXIPAG: POST-LAUNCH CHARACTERIZATION
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© 2016 Actelion Pharmaceuticals Ltd
TRANSIT Study
i.v. Formulation
Pediatric
TRITON Study
POST-LAUNCH CHARACTERIZATION OF SELEXIPAG
Selexipag: Further profiling the benefits for
patients
Investor webcast 07 Nov 2016 36
© 2016 Actelion Pharmaceuticals Ltd
TRANSIT Study
i.v. Formulation
Pediatric
TRITON Study
POST-LAUNCH CHARACTERIZATION OF SELEXIPAG
Selexipag: Further profiling the benefits for
patients
In discussions with health authorities
Investor webcast 07 Nov 2016 37
© 2016 Actelion Pharmaceuticals Ltd
TRANSIT Study
i.v. Formulation
Pediatric
TRITON Study
POST-LAUNCH CHARACTERIZATION OF SELEXIPAG
Selexipag: Further profiling the benefits for
patients
Transition from inhaled treprostinil
Investor webcast 07 Nov 2016 38
© 2016 Actelion Pharmaceuticals Ltd
TRANSIT Study
i.v. Formulation
Pediatric
TRITON Study
POST-LAUNCH CHARACTERIZATION OF SELEXIPAG
Selexipag: Further profiling the benefits for
patients Initial triple oral treatment with selexipag + macitentan + tadalafil
Investor webcast 07 Nov 2016 39
© 2016 Actelion Pharmaceuticals Ltd
TRANSIT Study
i.v. Formulation
Pediatric
TRITON Study
POST-LAUNCH CHARACTERIZATION OF SELEXIPAG
Selexipag: Further profiling the benefits for
patients For patients temporarily unable to take oral medication
Investor webcast 07 Nov 2016 40
Copyright © 2016 Actelion Pharmaceuticals Ltd
Martine Clozel Chief Scientific Officer
ACTELION’S CARDIOVASCULAR PIPELINE INVESTOR WEBCAST
© 2016 Actelion Pharmaceuticals Ltd
ACTELION’S NEW DUAL ERA IN RESISTANT HYPERTENSION
ACT-132577 is investigational, in development and not approved or marketed in any country.
Investor webcast 07 Nov 2016 42
© 2016 Actelion Pharmaceuticals Ltd
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
ACT-132577 is investigational, in development and not approved or marketed in any country.
Investor webcast 07 Nov 2016 43
© 2016 Actelion Pharmaceuticals Ltd
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
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© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 45
© 2016 Actelion Pharmaceuticals Ltd
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
ACT-132577 is investigational, in development and not approved or marketed in any country.
Investor webcast 07 Nov 2016 46
© 2016 Actelion Pharmaceuticals Ltd
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.
Investor webcast 07 Nov 2016 47
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 48
© 2016 Actelion Pharmaceuticals Ltd
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
ACT-132577 is investigational, in development and not approved or marketed in any country.
Investor webcast 07 Nov 2016 49
© 2016 Actelion Pharmaceuticals Ltd
MORE TO COME… NCE IN PHASE I
Investor webcast 07 Nov 2016 50
Copyright © 2016 Actelion Pharmaceuticals Ltd
Jean-Paul Cloze Chief Executive Officer
ACTELION’S CARDIOVASCULAR PIPELINE INVESTOR WEBCAST
© 2016 Actelion Pharmaceuticals Ltd
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
Investor webcast 07 Nov 2016 52