Presentation at IR Thematic Seminar on New Medicines

IR THEMATIC SEMINAR
ON NEW MEDICINES
November 20, 2014
Forward Looking Statements
This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of
1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include
projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and
expectations with respect to future financial results, events, operations, services, product development and potential,
and statements regarding future performance. Forward-looking statements are generally identified by the words
"expects", "anticipates", "believes", "intends", "estimates", "plans" and similar expressions. Although Sanofi's
management believes that the expectations reflected in such forward-looking statements are reasonable, investors are
cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which
are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and developments to
differ materially from those expressed in, or implied or projected by, the forward-looking information and statements.
These risks and uncertainties include among other things, the uncertainties inherent in research and development,
future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the
EMA, regarding whether and when to approve any drug, device or biological application that may be filed for any such
product candidates as well as their decisions regarding labeling and other matters that could affect the availability or
commercial potential of such product candidates, the absence of guarantee that the product candidates if approved will
be commercially successful, the future approval and commercial success of therapeutic alternatives, the Group's ability
to benefit from external growth opportunities, trends in exchange rates and prevailing interest rates, the impact of cost
containment policies and subsequent changes thereto, the average number of shares outstanding as well as those
discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under
"Risk Factors" and "Cautionary Statement Regarding Forward-Looking Statements" in Sanofi's annual report on Form
20-F for the year ended December 31, 2013. Other than as required by applicable law, Sanofi does not undertake any
obligation to update or revise any forward-looking information or statements.
2
Agenda
Introductory Comments
● Serge Weinberg, Chairman of the Board of Directors - CEO
Advancing Late Stage R&D Portfolio
● Elias Zerhouni, MD, President, Global R&D
Cerdelga™ / Lemtrada®
● David Meeker, MD, CEO, Genzyme
Praluent™ (alirocumab)
● Jay Edelberg, MD, PhD, Vice President, Head of the PCSK9 Development & Launch Unit
● Harold Bays, MD, Medical Director, President of Louisville Metabolic & Atherosclerosis Research Center
● Victoria Carey, Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
Break
3
Agenda (cont’d)
Toujeo® / Afrezza® / LixiLan
●
●
●
●
Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine, University of Western Ontario
Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
Dengue vaccine
● Duane Gubler, ScD, MS, Professor, Emerging Infectious Diseases Program, Duke NUS, Singapore
● Nicholas Jackson, Associate Vice President R&D, Dengue Vaccine Company, Sanofi Pasteur
● Guillaume Leroy, Vice President, Dengue Vaccine Company, Sanofi Pasteur
Sarilumab / dupilumab
● Elias Zerhouni, MD, President, Global R&D
Conclusion
● Elias Zerhouni, MD, President, Global R&D
Q&A Session
4
IR Thematic Seminar Focus on Selected New Medicines
and Vaccines
Our main objectives for today are:
IR Thematic
Seminar
on New
Medicines
1●
Highlight the unmet medical needs addressed
by Sanofi’s key late stage assets
2●
Provide a high-level clinical profile of those products
3●
Share information on our strategy to seize their
commercial potential
Help the Street to better evaluate near-term contribution from R&D
5
Introductory Comments
Serge Weinberg
Chairman of the Board of Directors
CEO
6
Agenda
Introductory Comments
● Serge Weinberg, Chairman of the Board of Directors - CEO
Advancing Late Stage R&D Portfolio
● Elias Zerhouni, MD, President, Global R&D
Cerdelga™ / Lemtrada®
● David Meeker, MD, CEO, Genzyme
Praluent™ (alirocumab)
● Jay Edelberg, MD, PhD, Vice President, Head of the PCSK9 Development & Launch Unit
● Harold Bays, MD, Medical Director, President of Louisville Metabolic & Atherosclerosis Research Center
● Victoria Carey, Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
Break
7
Sanofi – Opportunity for Sustainable Growth Driven by
Platforms and Pipeline
Sanofi has transformed into a company
positioned for sustainable growth
through its growth platforms(1)
and late-stage pipeline of new biologics
 Growth platforms now account for 76% of sales(1)

47% of sales derived from biologics(2)

72% of R&D projects are biologics(3)
(1) Growth Platforms include Emerging Markets, Diabetes Solutions, Vaccines, Consumer Healthcare, Animal Health, Genzyme & Other Innovative Products.
In 9M 2014, sales from Growth Platforms accounted for 76.1% of Group sales or €18,801m
(2) Biologic sales in 9M 2014 were €11,625m and included insulins (Lantus®, Apidra®, Insuman®), Genzyme rare disease products, Lovenox®, Sanofi Pasteur
vaccines, Merial vaccines, selected oncology products (Thymoglobulin®, Mozobil®, Zaltrap®), Lemtrada® and half of SPMSD sales (non-consolidated)
(3) R&D projects in clinical development: 33 NMEs and vaccines out of a total of 46 in Nov 2014
8
R&D Plays a Major Role in the Successful Execution of
Sanofi’s Strategy
1
Grow a global healthcare leader
with synergistic platforms
2
Bring innovative products to market
3
Seize value-enhancing growth
opportunities
4
Adapt structure for future
challenges and opportunities
Deliver sustainable
long-term growth
by improving
patients' lives
99
R&D Is Entering a New Era by Increasing its Expected
Contribution to the Sustainable Growth of Sanofi
2007 - 2009
2010 - 2013
2014+
Low R&D
Productivity
R&D
Transformation
Strong R&D Pipeline
Emerging
• Confronted multiple R&D
setbacks
• Faced low returns despite
growing R&D spend
• Cleaned up R&D pipeline
• Advanced high-value
development projects
• Created efficient global R&D
organization
• Shifted portfolio from small
molecules to biologics
• Grew value of external R&D
collaborations
• Launch new products
• Maintain discipline in
portfolio prioritization
• Accelerate early-stage
development
• Expand open innovation
model
10
Over the Last 7 Years, Sanofi Launched Several
New Drugs but Only One with Peak Sales Potential >$1bn
®
(ex-U.S.)
(ex-U.S.)
®
10 Launches
2007-2013
(U.S.)
(U.S.)
11
Sanofi Expects to Launch High Potential New Medicines
and Vaccines at an Accelerated Pace Beginning in 2014
ILLUSTRATIVE
Up to 18 Launches
2014 - 2020
Praluent™ Shan5
(U.S.)
sarilumab
(U.S.)
alirocumab
Dengue
PR5i
Vaccine Vaccine
insulin patisiran Anti-CD38 Rotavirus
Vaccine
mAb
lispro
Praluent™ is the intended trade name for alirocumab. The trade name is currently pre-approved in the EU but not in other regions.
Vaccine
12
Significantly Improving Returns from R&D
2007 - 2013
 10 launches achieved
2014 - 2020
 Up to 18 launches expected
(1) At CER, 5 years for each product from and including the first full year of launch
(2) Non-risk adjusted sales projections
Potential cumulative
first 5 years sales
~€7.5bn(1,2)
Potential cumulative
first 5 years sales
>€30bn(1,2)
13
Sanofi Has Additional Potentially Transformative Drugs
at Earlier Stages of Development
10 Early Assets to Watch
1
Vatelizumab(1)
6
Multiple Sclerosis
2
IL4/IL13 bi-specific mAb
Niemann-Pick type B
7
Idiopathic Pulmonary Fibrosis
3
Anti-CD38 mAb
Anti-GDF8 mAb
8
Revusiran (TTRsc)
Familial Amyloid Cardiomyopathy
(1) Anti-VLA2 mAb
C-MET kinase inhibitor
Solid Tumors
9
Sarcopenia
5
Neo GAA
Pompe Disease
Multiple Myeloma
4
rhASM
Anti-CXCR5 mAb
Systemic Lupus Erythematosus
10
GLP-1/GIP co-agonist
Diabetes
14
Sanofi Has Established a Model of Productive R&D
Collaborations
Example 1
Example 2
● Global strategic collaboration
● World-class RNAi technology
● Secured access to highly
productive therapeutic human
antibody platform
● Focus on genetically defined
diseases with a clear translational
model for RNA interference
● A platform to regularly bring new
mAbs into clinical development
● A platform for sustained drug
development for rare diseases
for Genzyme
15
Strengthening the R&D Leadership Team with New Talent
Maya Said
VP, Strategy
External Innovation
& Science Policy
Jorge Insuasty
SVP,
Development
Gary Nabel
SVP, CSO
Andrew Plump
SVP, Research and
Translational Medicine
Dominique Carouge
VP, Administration
& Management
Hilary Malone
VP, Global Regulatory Affairs
John Shiver
SVP, R&D,
Sanofi Pasteur
Jay Edelberg
VP, Head of Alirocumab Unit
Fabian Kausche
Head of Merial R&D
Christian Antoni
VP, Head Development
Immunology & Inflammation
Anthony Muslin
VP, Cardiovascular
& Fibrosis Unit
Mike Panzara
VP, Multiple Sclerosis
and Neurology, Genzyme
Eckhard Leifke
Diabetes - Head of
Development
Philip Just Larsen
Diabetes - Head of Research
& Early Development
Victoria Richon
Oncology - Head of Research
& Early Development
16
Agenda
Genzyme
● David Meeker, MD, CEO, Genzyme
Cerdelga™ (eliglustat)
Lemtrada® (alemtuzumab)
17
Genzyme Understands Unmet Needs of Gaucher Patients
61% of Gaucher patients would like their treatment to be an oral formulation(1)
(1) PeopleMetrics survey in Gaucher patients (n= 238)
What improvements would you like to see in treatments for Gaucher Disease?
18
The Only First-Line Oral Therapy for Adults
with Gaucher Disease Type 1
● Novel substrate inhibitor(1)
● Largest ever development program in Gaucher
● Almost 400 adults in 29 countries
● Efficacy demonstrated in untreated patients (ENGAGE)
and in patients switching from ERT (ENCORE)
● Majority of adverse reactions are mild and transient(2)
● Genotyping required before starting therapy to determine
CYP2D6 phenotype
● U.S. FDA approval granted in Aug 2014
● EU CHMP opinion expected in Q4 2014
GD-1: Gaucher Disease type 1
ERT: Enzyme Replacement Therapy
(1) Cerdelga™ is a highly specific ceramide analogue inhibitor of GL-1 synthesis with broad tissue distribution
(2) AEs generally mild to moderate, most common related to treatment being diarrhea (6%), headache (4%), arthralgia (3%),
flatulence (3%), abdominal pain (3%), fatigue (3%), nausea (3%). Less than 2% of people treated with Cerdelga™
discontinued treatment because of a side effect.
19
Efficacy Demonstrated in Untreated Patients
(ENGAGE)
ENGAGE - Change in Primary and Secondary Endpoints at 9 Months(1)
Parameter
Eliglustat
Placebo
Difference
P Value
-28%
+2%
30%
<0.0001
Hemoglobin
Level
+0.7 g/dL
-0.5 g/dL
1.2 g/dL
0.0006
Liver Volume
-5.2%
+1.4%
6.6%
0.0072
Platelet
Count
+32%
-9%
41%
<0.0001
Spleen
Volume
(1) Pastores et al. ACMG 2013 (poster)
20
Efficacy Demonstrated in Patients Switching
From ERT (ENCORE)
ENCORE - % of Patients Who Met Stability at 12 Months(1,2)
100%
95%
100%
100%
96%
93%
100%
96%
94%
94%
85%
80%
60%
40%
20%
0%
Stable
Hemoglobin
Stable
Platelets
Stable Spleen
Volume
Eliglustat
Stable Liver
Volume
Composite
Imiglucerase
(1) Baris Feldman EWGGD 2014 (presentation)
(2) Non-Inferiority with respect to primary composite endpoint (i.e. lower bound of 95% CI of difference > -25% non-inferiority margin)
21
Genzyme Leading Innovation in Treating Gaucher Disease
with Cerezyme® and Now Cerdelga™
% of Gaucher Patients in Whom Physicians Would Use Cerdelga™(1)
~38%
~42%
Potential to grow
Gaucher market
and expand
Genzyme
Gaucher
franchise to
>€1bn(2)
Existing patients
Newly diagnosed patients
(1) 2013 Gaucher Treatment Tracker Survey, n = 241 physicians from15 countries - Q4 2013 / Q1 2014
(2) Genzyme Gaucher franchise includes Cerezyme® (imiglucerase) and Cerdelga™ (eliglustat)
22
Agenda
Genzyme
● David Meeker, MD, CEO, Genzyme
Cerdelga™ (eliglustat)
Lemtrada® (alemtuzumab)
23
New MS Treatment Goals - Focus on Patient Outcomes
Unmet Needs in MS
New Goals
Symptom Alleviation
Decrease MS activity and improve quality
of life
Halt or reverse damage
and disability
Promote repair, remyelination, durable
disability improvement
Improve disease control
Freedom from disease
activity
Convenient treatment regimens
to improve compliance
Dosing options, new routes of
administration, less frequent dosing
Maximize patient outcomes
Superior effectiveness and favorable
benefit/risk vs. existing treatment
MS: Multiple Sclerosis
24
A Large and Growing Global MS Market
Multiple Sclerosis Market
Global Sales(3)
Multiple Sclerosis
~€17bn
● Serious disease with significant
unmet medical needs
● Symptoms include fatigue,
weakness, walking and balance
difficulties, vision problems
● A major impact on family, social
and professional life
● ~2.1m patients worldwide(1)
~€12bn
~57%
~€5bn
2020e
~50% ~50%
● ~410,000 patients in the U.S.(1)
● ~630,000 patients in EU(2)
~43%
2013
2007
U.S.
ROW
2013-20 growth driven by new therapies, satisfying the unmet needs
of convenient administration and more efficacious therapy
(1) National Multiple Sclerosis Society
(2) http://msj.sagepub.com/content/18/5/628.full.pdf
(3) Adapted from Evaluate Pharma July 2014; Reported sales of Copaxone®, Avonex®, Rebif®, Betaseron/Betaferon®, Extavia®,
Tysabri® and Gilenya® for 2013; 2007 sales converted using €/$ of 1.37, 2013 sales and 2020e sales converted using €/$ of 1.33
25
Sustained Reduction in Disability
Through Year 4
Disease-Free Outcomes: 3-Year Follow-up of the CARE-MS Studies(1)
Parameter
CARE-MS I
CARE-MS II
% of Lemtrada® patients relapse-free
87%
82%
% of Lemtrada® patients 6-month SAD-free(2)
99%
96%
% of patients who did not receive alternative
DMTs
99%
97%
% of Lemtrada® patients who did not receive
retreatment in Year 3
82%
80%
DMT: Disease Modifying Treatment
SAD: sustained accumulation of disability
(1) Eva Havrdova, ACTRIMS-ECTRIMS 2014
(2) ln CARE-MS l, Lemtrada® was significantly more effective than interferon beta-1a at reducing annualized relapse rates;
the difference observed in slowing disability progression did not reach statistical significance. ln CARE-MS ll, Lemtrada® was
significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was
significantly slowed in patients given Lemtrada® vs. interferon beta-1a.
26
FDA Approval Is a Major Step Forward for
People with Relapsing Forms of MS
● Regulatory approvals granted in >40 countries(1)
● FDA approval received on Nov 14, 2014
●
Because of its safety profile, the use of Lemtrada® should generally be reserved
for patients who have had an inadequate response to two or more drugs indicated
for the treatment of MS(2,3)
●
Only available in the U.S. through a restricted distribution program:
the Lemtrada® Risk Evaluation and Mitigation Strategy (REMS)
● New dedicated salesforce recruited for the U.S.(4)
●
Targeted U.S. launch approach for the first 3 months
●
Ensuring appropriate education and confidence to prescribe
●
Full launch expected throughout 2015
With Aubagio® and Lemtrada®, Genzyme is well positioned to grow its MS franchise
(1) EU, Canada, Australia and other countries
(2) The most common side effects of Lemtrada® are rash, headache, thyroid disorder, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia,
upper respiratory tract infection, herpes viral infection, urticaria, pruritus, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal
pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting. Other serious side effects associated with Lemtrada® include autoimmune thyroid disease,
autoimmune cytopenias, infections and pneumonitis.
(3) Label includes a boxed warning noting a risk of serious, sometimes fatal autoimmune conditions, serious and lifethreatening
infusion reactions and noting Lemtrada® may cause an increased risk of malignancies including thyroid cancer, melanoma and
lymphoproliferative disorders. Lemtrada® is contraindicated in patients with HlV infection.
(4) Genzyme holds the worldwide rights to alemtuzumab and has responsibility for its development and commercialízation in MS.
Bayer Healthcare receives contingent payments based on global sales revenue.
27
Agenda
Praluent™ (alirocumab)
CV Disease Burden
& ODYSSEY Program
● Jay Edelberg, MD, PhD
Vice President, Head of the PCSK9 Development & Launch Unit
Clinical Perspective
● Harold Bays, MD, Medical Director and President of
Louisville Metabolic and Atherosclerosis Research Center(1)
Evaluating the PCSK9
Opportunity
● Victoria Carey
Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
Praluent™ is the intended trade name for alirocumab.
The trade name is currently pre-approved in the EU but not in other regions.
(1) Harold Bays is an investigator of the ODYSSEY OPTIONS I and II clinical study
28
CV Disease Remains an Area of High Unmet Need
Cardiovascular disease causes 17.3m deaths per year(1)
The estimated economic cost of CVD is huge in the U.S.(2)
● $193bn in direct health expenditures
17.3m
$315bn
● $122bn in indirect cost of mortality
LDL-C contributes to 60% of coronary heart disease
and 40% of all ischemic stroke(3)
60%
Despite available treatment options, including statins,
24m high-risk patients fail to reach LDL-C goals(4)
24m
(1)
(2)
(3)
(4)
WHO. http://who.int/mediacentre/factsheets/fs317/en/ (EU, East. Mediterranean, The Americas, SE Asia, West Pacific, Africa)
NHLBI. http://www.nhlbi.nih.gov/about/documents/factbook/2012/chapter4.htm
WHO. http://www.who.int/whr/2002/en/whr02_en.pdf?ua=1
U.S. NHANES, Market Scan, IMS and Sanofi estimates
29
Lowering LDL-C with Statins Is Effective in Decreasing
CV Risk
LDL-C Prevention Trials(1)
25
Primary prevention trials
4S
CHD Events (%)
Active treatment
Placebo
20
4S
15
2.8
WOSCOPS
TNT-10A
5
ASCOT
WOSCOPS
AFCAPS
ASCOT
0
Placebo
110
CARE
TNT-80A
Active treatment
CARE
LIPID
10
Secondary prevention trials
LIPID
AFCAPS
50
70
90
130
150
170
190
1.3
1.8
2.3
3.4
3.9
4.4
4.9
210 (mg/dL)
5.4
(mmol/L)
LDL-C
Despite high efficacy of statin therapy, unmet needs persist
in familial hypercholesterolemia, high CV risk and statin intolerance
(1) Adapted from O’Keefe et al. J Am Coll Cardiol 2004;43:2142-6; LaRosa JC et al. N Engl J Med 2005;352:1425-35
30
Despite Current Therapy, a Significant Proportion of
Hypercholesterolemic Patients Are at High CV Risk
2016 Estimates for U.S., EU Top 5 and Japan (in million patients)(1)
Heterozygous Familial
Hypercholesterolemia
1.2m
Statin Intolerant
2.9m
Primary
Prevention
4.8m
24m
Patients With
High CV Risk
Diabetes(2)
Secondary
Prevention
5.3m
10.1m
Secondary Prevention
without Diabetes
10.3m
(1) U.S. NHANES, Market Scan, IMS and Sanofi estimates
(2) Diabetes with 2 Risk Factors with or w/o CV Event
31
Sense of Urgency to Lower LDL-C to Reduce CV Risk
Varies According to Patient Types
HeFH
Statin Intolerant
High CV Risk
● Well defined but
underdiagnosed population
● High LDL-C levels
comparable to HeFH
● Large and diverse population
with associated CV risks
● High engagement of patients
● Pragmatic approach used by
physicians but no objective
definition
● Large proportion of patients
with previous CV event
● Large proportion of
uncontrolled patients with
current therapies
● Low satisfaction level with
existing treatment options
HeFH: heterozygous familial hypercholesterolemia
● Strong awareness of risk,
especially for recent events
● Significant overlap with
diabetes population
32
The Development of Alirocumab, an Anti-PCSK9 mAb,
Is a Prime Example of Modern Translational Medicine
The PCSK9 Discovery Decade
First Phase III
study results
Loss-of-function
mutations observed
Proof of principle
in animals(3,4)
Gain-of-function
mutations observed
Phase II study
results(9)
Human target
validation(5,6,7)
PCSK9
discovery(1,2)
2003
U.S./EU regulatory
submissions
First subject treated
with PCSK9 mAb
PCSK9-targeted
mAb preclinical(8)
2004
(1)
(2)
(3)
(4)
(5)
2005
2006
2007
2008
Seidah NG. Proc Natl Acad Sci USA 003;100:928-33
Abifadel M. Nat Genet 2003;34:154-6
Maxwell KN. Proc Natl Acad Sci USA 2004;101:7100-5
Rashid S. Proc Natl Acad Sci USA 2005;102:5374-79
Cohen JC. N Engl J Med 2006;354:1264-72
2009
(6)
(7)
(8)
(9)
2010
2011
2012
Zhao Z. Am J Hum Genet 2006;79:514-23
Hooper AJ. Atherosclerosis 2007;193:445-8
Chan JC. Proc Natl Acad Sci USA 2009;106:9820-5
Lambert G et al. J Lipid Res 2012; 53(12): 2515-24
2013
2014
33
A Differentiated Clinical Development Program
HeFH
High CV Risk
On top of max
tolerated statin
On top of max
tolerated statin
On top of regular
statin doses
Not receiving
statin
FH I (n=486)
COMBO I (n=316)
OPTIONS I (n=355)
MONO(2) (n=103)
FH II (n= 249)
COMBO II (n=720)
OPTIONS II (n=305)
CHOICE II(3) (n=200)
HIGH FH (n=107)
CHOICE I (n=700)
Statin Intolerant
LONG TERM (n=2,341)
OLE(1) (n≥1,000)
ALTERNATIVE (n=314)
OUTCOMES (n=18,000)
●
Largest Phase III program
●
14 trials with >23,500 patients
●
Primary endpoint evaluated at 24 weeks
●
Double-blind design (6, 12, 18 and 24 months)
●
Evaluation of q2w and q4w dosing
regimens and 75mg and 150mg doses
●
Interim data on lower rate of adjudicated
major CV events in LONG TERM trial
●
≥4,500 patient years exposure(4)
All studies: every two weeks (q2w) regimens (75/150mg with potential dose ↑ from 75 to 150 mg) except CHOICE I (300mg q4w) and II (150mg q4w)
(1) Open-Label Extension open to HeFH patients included in other studies
(2) ODYSSEY MONO included patients at moderate CV risk
(3) ODYSSEY CHOICE II includes some patients on additional non-statin lipid-lowering therapy
(4) ≥4,500 double-blind patient years at completion of pivotal studies in initial submission
34
Next Regulatory Milestones and Development Steps
1 Regulatory submissions in the U.S. and EU on track
● U.S. submission expected before year end 2014
 6-month FDA priority review from filing date expected
● EU submission also targeted before year end 2014
2 ODYSSEY CHOICE I & II and Open Label Extension (OLE) ongoing
● CHOICE I & II explore monthly dosing of alirocumab
● Expect to report primary endpoints in 2015 and beyond
3 ODYSSEY OUTCOMES ongoing (n=18,000)(1)
● Assess the potential of alirocumab to demonstrate CV benefit
(1) Rationale and design in Schwartz GG et al. Am Heart J 2014;0:1-8.e1.
35
Agenda
Praluent™ (alirocumab)
CV Disease Burden
& ODYSSEY Program
● Jay Edelberg, MD, PhD
Vice President, Head of the PCSK9 Development & Launch Unit
Clinical Perspective
● Harold Bays, MD, Medical Director and President of
Louisville Metabolic and Atherosclerosis Research Center(1)
Evaluating the PCSK9
Opportunity
● Victoria Carey
Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
(1) Harold Bays is an investigator of the ODYSSEY OPTIONS I and II
clinical study
36
Significant and Consistent LDL-C Reduction
across All 10 Reported Trials
LDL-C Change from Baseline at 24 Weeks
Study
Dosing
q2w
Baseline
LDL-C (mg/dL)
Alirocumab
HIGH FH
150 mg
198
↓ 46%
↓ 7%
placebo
FH I
75/150 mg(1)
145
↓ 49%
↑ 9%
placebo
FH II
75/150 mg(1)
134
↓ 49%
↑ 3%
placebo
LONG TERM
150 mg
122
↓ 61%
↑ 1%
placebo
COMBO I
75/150 mg(1)
102
↓ 48%
↓ 2%
placebo
COMBO II
75/150 mg(1)
108
↓ 51%
↓ 21%
ezetimibe
OPTION I
75/150 mg(1)
105
↓ 44-54%
↓ 21-23%
↓ 5%
↓ 21%
ezetimibe
statin x2
statin switch
OPTION II
75/150 mg(1)
111
↓ 36-51%
↓ 11-14%
↓ 16%
ezetimibe
statin switch
Statin
Intolerant
ALTERNATIVE
75/150 mg(1)
191
↓ 45%
↓ 15%
ezetimibe
Moderate
CV Risk
MONO
75/150 mg(1)
140
↓ 48%
↓ 16%
ezetimibe
HeFH
High CV
Risk
Comparator
On top of max
statin doses
On top of
regular statin
doses
Not receiving
statins
Primary efficacy endpoint met in all 10 reported trials
(1) Per protocol dose increase to 150 mg possible based on pre-specified LDL-C levels
37
Robust and Durable LDL-C Reduction
Maintained over 52 Weeks
LONG TERM
Achieved LDL-C Over Time(1)
All Patients on Background of Maximally Tolerated Statin ± other LLT
Mean (SE) LDL-C in mg/dL
140
123.0 mg/dL
(+4.4%)
118.9 mg/dL
(+0.8%)
120
100
Difference
−61.9%
80
Placebo
Alirocumab 150 mg q2w
Difference
−61.3%
60
40
53.1 mg/dL
(−56.8%)
48.3 mg/dL
(−61.0%)
20
0
0
4
8
12
16
24
LLT: Lipid lowering therapy
Intent-to-treat analysis
(1) LDL-C: Calculated LDL-C, least-squares (LS) means (SE standard error)
36
52
Week
38
Consistent LDL-C Reduction
across a Range of Baseline LDL-C Values
LONG TERM
LDL-C Change from Baseline(1)
All Patients on Background of Maximally Tolerated Statin ± Other LLT
Mean % Change in LDL-C from Baseline to Week 24
Placebo
Alirocumab
Interaction
p-value <0.0001
20
10
0
-10
-20
-30
-40
-50
-60
-70
n=241
100 to
<130 mg/dL
n=562 n=285
13.6%
0.5%
<100 mg/dL
n=470
130 to
<160 mg/dL
n=271 n=143
≥160 mg/dL
n=227
-18.2%
-5.2%
-61.3%
LLT: Lipid lowering therapy
Intent-to-treat analysis
(1) LDL-C: Least-squares (LS) means
-62.0%
-59.8%
n=111
-59.5%
39
Safety Profile from Long Term Study
LONG TERM
% of Patients with Treatment Emergent Adverse Events of Interest
Alirocumab
Placebo
(n=1550)
(n=788)
General allergic reaction events
9.0
9.0
Treatment-emergent local injection site reactions
5.8
4.3
Myalgia
4.9
3.0
Neurological events(2)
4.2
3.9
All cardiovascular events(1)
4.0
4.4
Ophthalmological events(2)
2.5
1.9
Neurocognitive disorders(2)
1.2
0.5
ALT increase
1.1
0.5
CPK increase
0.5
0.5
AST increase
0.2
0
All patients on background of maximally tolerated statin ± other lipid-lowering therapy
Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients overall who completed W78 visit)
(1) Confirmed by adjudication. Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD
death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization,
ischemia driven coronary revascularization procedure [PCI, CABG]
(2) Company MedDRA Queries (CMQ)
40
Post-hoc Adjudicated
Major Adverse Cardiovascular Events(1)
LONG TERM
Cumulative probability of event
Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event
0.06
Safety Analysis(2)
0.05
Cox model analysis:
HR=0.46 (95% CI: 0.26 to 0.82)
Nominal p-value = <0.01
0.04
Placebo + max-tolerated statin ± other LLT
0.03
Alirocumab + max-tolerated statin ± other LLT
150 mg q2w
0.02
Mean treatment duration:
65 weeks
0.01
0.00
Weeks
No. at Risk
Placebo
0
12
24
36
48
60
72
84
788
776
731
703
682
667
321
127
Alirocumab
1550
1534
1446
1393
1352
1335
642
252
TEAEs: Treatment emergent adverse events
(1) Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring
hospitalization. LLT, lipid-lowering therapy
(2) ≥ 52 weeks for all patients continuing treatment, incl. 607 patients who completed W78 visit
41
ALTERNATIVE
Safety and Efficacy in Statin Intolerant
Patients with Very High LDL-C (~190mg/dL)
Patient at LDL-C Goal
Skeletal Muscle Adverse Events
Significantly More SI Patients
Achieved LDL-C Goals
with Alirocumab
Fewer Skeletal Muscle Adverse Events(2)
with Alirocumab
than with Atorvastatin
Goals
alirocumab
ezetimibe
LDL-C <70 mg/dL
or <100 mg/dL
(depending on risk)
42%
4%
LDL-C <100 mg/dL
61%
10%
∆: P<0.0001(1)
alirocumab
vs.
atorvastatin
alirocumab
vs.
ezetimibe
Hazard Ratio
0.61
0.71
Nominal P(3)
0.042
0.096
Only 0.7% myalgia leading to discontinuation
with alirocumab in open-label treatment period(4)
Baseline LDL-C levels (ITT): 191.1 and 194.2 mg/dL in alirocumab and ezetimibe arms
(1) Intent-to Treat analysis
(2) Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue
(3) Cox model analysis (95% CI for alirocumab vs atorvastatin: 0.38 to 0.99 ; for alirocumab vs ezetimibe: 0.47 to 1.06)
(4) 89.5% of randomized patients entered the Open-label Treatment Period (including 94% of those randomized to atorvastatin) and received alirocumab
42
Alirocumab Has the Potential to Transform
LDL-C Management
Significant and sustained reductions in LDL-C over 1 year
on top of existing therapies across different patient populations
Balanced safety and tolerability profile across patient groups
with preliminary data on CV safety from long-term treatment trial
Flexible dosing providing options for physicians and patients
1mL dosage forms for subcutaneous self-injection at home
43
Agenda
Praluent™ (alirocumab)
CV Disease Burden
& ODYSSEY Program
● Jay Edelberg, MD, PhD
Vice President, Head of the PCSK9 Development & Launch Unit
Clinical Perspective
● Harold Bays, MD, Medical Director and President of
Louisville Metabolic and Atherosclerosis Research Center(1)
Evaluating the PCSK9
Opportunity
● Victoria Carey
Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
(1) Harold Bays is an investigator of the ODYSSEY OPTIONS I and II
clinical study
44
Key Factors Impacting Uptake of PCSK9 mAbs
in High CV Risk Patients
1
Physician awareness
2
Likelihood to prescribe
3
Efficacy attributes
4
Patient acceptance
5
Payor dynamics
45
1 Very High and Growing Awareness
Percent of Specialists Aware of PCSK9 Inhibitor Class(1)
73%
Q4 2013
Q2 2014
62%
49%
54%
52%
36%
Estimated Number of Specialists Aware
~13,000
~1,100
~3,500
(1) Aided and Unaided Awareness. Questions: ”Please name and describe all the potential treatments in development for hypercholesterolemia
of which you are aware” and “Please indicate your familiarity with the following classes of therapy in development for hypercholesterolemia”
Source: Proprietary survey conducted in U.S., UK and Germany
46
2 High Likelihood to Prescribe
Percent of Specialists Likely/Very Likely to Prescribe a PCSK9 Inhibitor(1)
Q4 2013
64%
71%
Q2 2014
64%
71%
63%
49%
(1) Question: “Based on your experiences and anything you might have heard, how likely would you be to prescribe a PCSK9 Inhibitor for the treatment
of hypercholesterolemia, if available in the future? (Answers based on own physician’s knowledge without being exposed to any product profile)
Source: Proprietary survey conducted in U.S., UK and Germany
47
3 Efficacy Attributes Are Most Important for Specialists
U.S. Specialists
Demonstrates significant decrease in CV morbidity / mortality
247
232
Substantial data in high CV risk patients like diabetes, CHD, stroke
211
Achieves significant reduction of LDL-C, particularly high CV risk patients
163
Achieves significant reduction of LDL-C for majority of patients
146
Good treatment option for statin intolerant patients
116
Demonstrates good tolerability profile resulting in minimal monitoring of AEs
95
Covered, affordable for patients (reasonable level of OOP cost to patients)
Acts on atheroma plaque
Achieves significant increase of HDL-C
OOP: Out of pocket
Source: Proprietary survey conducted in the U.S.
78
Average
score of
importance
= 100
67
48
4 High Patient Acceptance and Perception of Benefit
ShareShare
of Patients
of Patients
Likely/Very
LikelyLikely
/ Very to
Likely
Accept
to Accept
and Filland
PCSK9
Fill PCSK9
Treatment
Treatment
Prescription
70%
Managed
by Endos
70%
HeFH
52%
52%
Statin
Intolerants
Secondary
Prevention
65%
65%
Statin
Intolerants
Secondary
Prevention
65%
53%
Primary
Prevention
(DM/CKD)
DM: Diabetes Mellitus
CKD: Chronic Kidney Disease
Source: Proprietary surveys conducted in the U.S/EU (2012/2013)
The HeFH patient population was not part of the survey conducted in Europe
Primary
Prevention
(DM/CKD)
49
4 Broad Experience of Home Self-Injection with Alirocumab
Flexibility in Dose & Delivery Options
75 mg(1)
Available Auto-Injector
Satisfaction Rating ODYSSEY MONO(2)
q2w
150 mg
98%
(1) Some patients have been titrated up to 150mg; >70% of patients remained on 75 mg
(2) 53 respondents out of 105 patients who completed the ODYSSEY MONO study
Question: “How do you rate your overall experience in performing an injection on yourself with the study drug auto-injector pen?”; 98% respondents satisfied
50
5 Payor Dynamics
Important Factors for the Alirocumab Payor Value Proposition
 Payor price pressure on innovations
 Large unmet medical need in a generic market
 Importance of LDL-C as a primary risk factor for CV disease
and of LDL-C lowering to reduce the risk
 Sense of urgency to treat a condition with significant adverse outcomes
and system costs
 Recognition of PCSK9 inhibitors as effective tool in the treatment algorithm
for appropriate patients
 Definition of appropriate patients that can be targeted to ensure maximum
allowable access to target populations
51
Engaging Significant Resources to Ensure Alirocumab
Launch Success in the U.S.
Praluent™
alirocumab
Praluent™ is the intended trade name for alirocumab.
The trade name is currently pre-approved in the EU but not in other regions.
52
Q&A
53
BREAK
Return in 15 Minutes
54
Agenda
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin
Management
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo®
● Stewart B. Harris, MD, Professor of Medicine, Schulich School of
Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation
of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
Afrezza®
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
LixiLan
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion
● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
55
There Is Need for an Improved Basal Insulin Experience
to Get More Patients to Control(1)
Frustration
Imprisonment
Embarrassment
At start, a challenge
● Frustration of poor
control
● Fear of hypoglycemia
At stay, a variable
experience
● Satisfaction?
“I hate this so much. It’s
like a constant thorn in
my side that I can’t rip
out”
“When I experience a
high(2), I go into a state of
euphoria and worry
others notice”
(1) Motivation and characterization of insulin patients, patient interviews
(2) Highs = Hyperglycemia / Lows = Hypoglycemia
● Motivation?
56
Despite Treatment, Many Patients with Diabetes
Are Still not at A1c Goal(1)
Diabetes Patients in the U.S. (Random Sample)
T1D Patients
T2D Patients
53%
53%
Uncontrolled (>7%)
Controlled (<=7%)
47%
47%
2013
(437)
2013
(2215)
A1c: glycated haemoglobin
(1) Adelphi Real World Diabetes Disease Specific Programme (DSP) X, 2013
Base: U.S. diabetic patients where doctor has stated most recent A1c (random sample)
All patients are treated patients and must be on an OAD, GLP-1 or insulin
57
Most Patients Delay Increasing their Dose After Initiation
of Therapy Despite Not Being at Goal(1)
Timing of Dose Increase after First Week
on Basal Insulin
63%
Patients wish for
a quick titration
experience to achieve
immediate control
but fear hypos
37%
<1 month
>1 month
(1) Idea Exchange Report Toujeo® Titration Exploration (9.4.2014); Sanofi market research
58
Patients Respond to Hypoglycemia
by Modifying their Dose or Discontinuing Therapy
4 in10
people experienced hypoglycemia
within the first month(1)
6 in10
patients
modify their insulin dose after experiencing
a severe hypoglycemia event(2)
77%
of people who experienced hypoglycemia within
6 months of initiation had discontinued within 1 year(3)
(1) Data on file – Real-World Data on Hypos Following Basal Insulin Initiation
(2) Peyrot M et al. Diabet Med 2012;29:682–689.
(3) Leiter LA et al. Can J Diabetes 2005;29:186–192
59
Inappropriate Diabetes Management Leads to Costly
Consequences
Risk of Complications and A1c(1)
Microvascular
Complications
● Diabetic Retinopathy
Relative Risk in %
15
Retinopathy
13
Nephropathy
Neuropathy
11
Microalbuminuria
Macrovascular
Complications
● Stroke
9
● Diabetic Nephropathy
7
● Heart Disease
5
● Diabetic Neuropathy
● Peripheral Vascular
Disease
3
1
6
7
8
9
10
11
12
A1c (%)
25% to 45% of diabetes-attributed medical expenditures
spent treating complications of diabetes(2)
(1) Endocrinol Metab Clin 1996;25:243 - 254 (DCC Trial)
(2) Diabetes Care Publish Ahead of Print, published online March 6, 2013
60
Hypoglycemia Contributes to Poor Compliance and Affects
Treatment Efficacy(1)
50% of basal
30% to 60%
experience
hypoglycemia
insulin patients are
not at A1c goal
59% of new to Lantus®
patients in the U.S. have
significant compliance gaps
The launch of Toujeo® will offer opportunities to address unmet needs
(1) IMS Lifelink; U300 segmentation; Sanofi market research; expert interviews; Sanofi analysis
61
Agenda
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin
Management
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo®
● Stewart B. Harris, MD, Professor of Medicine, Schulich School of
Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation
of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
Afrezza®
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
LixiLan
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion
● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
62
Patients Hate Hypoglycemia
Mild
to moderate
hypoglycemia
● Very unpleasant and disruptive symptoms
(e.g. blurry vision, rapid heartbeat, sudden mood
changes, headache, trouble concentrating)
Severe
hypoglycemia
● A medical emergency that can result in fainting,
seizures, unconsciousness, coma and death
Nocturnal
hypoglycemia
● Imagine going to sleep each night needing to protect
yourself against hypoglycemia while you sleep
● Imagine sleeping next to someone and worrying about
whether their blood sugar is high enough
Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212.
63
A Smoother and Prolonged PK/PD Profile
vs. Lantus®
Reduction of Volume by 2/3
More Constant PK/PD Profile(1)
Median insulin concentration, µU/mL
20
Toujeo®
10
Lantus®
0
0
Lantus®
Toujeo®
6
12
24
30
36
Glucose infusion rate, mg/kg/min
3
Lantus®
2
Reduction of Depot Surface Area by 1/2
18
1
Toujeo®
0
0
6
12
18
24
30
36
Blood glucose, mg/dL
160
Lantus®
140
Toujeo®
120
Lantus®
Toujeo®
100
Time, h
0
6
12
18
24
30
PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile
(1) Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; Becker RHA et al. Diabetes Care. 2014 Aug 22.pii:DC_140006
36
64
Offering Greater Consistency Over the Course
of the Day
Type 1 Diabetes - Continuous Glucose Monitoring Study(1)
Lantus®
Toujeo®
11
Average 24-hour
glucose profiles
showed a more
constant glucose
level with Toujeo®
vs Lantus®
10
9
8
7
0
2
4
6
8
10
12
14
16
18
20
22
24
Time, h
(1) Bergenstal RM et al. Poster presentation at EASD 2014; data combining morning and evening injections
65
All Studies of EDITION Phase III Program Met
their Primary Endpoint(1,2)
vs.
Population
EDITION 1
T2DM on basal and mealtime insulin + OADs
EDITION 2
T2DM on basal insulin + OADs
EDITION 3
T2DM insulin-naïve + OADs
EDITION 4
T1DM on basal and mealtime insulin
EDITION JP1
T1DM on basal and mealtime insulin
EDITION JP2
T2DM on basal insulin + OAD
Primary Endpoint
Non inferiority
(Change in A1c)






(1) Non inferiority on A1c
(2) Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990; Bolli GB et al. Poster
presentation at EASD 2014; Abstract 947; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Home PD et al. Oral presentation
at EASD 2014; Abstract 148; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975
66
Benefit on Nocturnal Hypoglycemia
Nocturnal Hypoglycemia(1,3)
Pooled analysis of EDITION 1-2-3
% Participants with ≥1 Confirmed and/or Severe Hypoglycemia(2)
Lantus®
Toujeo®
50
RR 0.75
(0.68 to 0.83)
40
30
RR 0.80
(0.71 to 0.91)
-25%
RR 0.69
(0.58 to 0.81)
-20%
20
-31%
10
0
Baseline to
week 8
Baseline to
month 6
(1) Defined as 00:00–05:59h
(2) ≤70 mg/dL (≤3.9 mmol/L)
(3) Ritzel R et al. Poster presentation at EASD 2014; Abstract 963
Week 9 to
month 6
67
Confirmed or Severe Hypoglycemia per Patient
per Year Significantly Lower
Cumulative Mean Number of Confirmed or Severe Hypoglycemia per Participant(1,3)
Pooled analysis of EDITION 1-2-3
Lantus®
Toujeo®
Nocturnal(2)
At any time(3)
3
10
-14%
8
2
6
-31%
1
4
2
p=0.0002
0
0
4
8
12
16
Time, weeks
20
24
p=0.0116
0
28
0
4
8
12
16
Time, weeks
20
24
(1) Confirmed events based on plasma glucose ≤3.9 mmol/L (≤70 mg/dL); Ritzel RA, et al. Poster presented at EASD 2014; Abstract 963.
(2) 00:00–05:59h
(3) 24 h
28
68
Hypoglycemia Benefit Consistently Demonstrated
 Benefit maintained regardless of hypoglycemia definition(1,2)
● ≤70 mg/dL [3.9 mmol/L] OR <54 mg/dL [3.0 mmol/L]
 Consistent benefit on hypoglycemia independent of definition of
night duration(1,3)
● Standard definition: 00:00–05:59h
● Lower rate up to 10:00h
 Benefit in nocturnal hypoglycemia maintained over time either as
% of Patients or Event Rate(4)
(1) Pooled analysis of Edition 1,2,& 3 - Type 2 Diabetic patients; Ritzel R et al. Poster presentation at EASD 2014; Abstract 963
(2) % Participants with ≥1 Confirmed (≤70 mg/dL [3.9 mmol/L]) and/or Severe Hypoglycemia baseline to month 6: -9% at any time and -25% nocturnal
(00:00–05:59h) / % Participants with ≥1 Confirmed (<54 mg/dL [3.0 mmol/L]) and/or Severe Hypoglycemia:-19% at any time and -27% nocturnal
(00:00–05:59h)
(3) Lower rate of confirmed or severe hypoglycemia with Toujeo® during the night until 10 am
(4) EDITION 1-1 year; Riddle MC et al. Poster presentation at EASD 2014; Abstract 980: % of participants reporting ≥1 event from baseline to month
12: -22% and annualized event rates from baseline to month 12: -26%
69
Sustained Glycemic Control at 1 Year
LS Mean (95% CI) Difference in A1c Between Groups at Month 12
A1c (%) mean ± SE
8,5
8.5
EDITION 1(1)
8,0
8.0
Lantus®
7,5
7.5
Toujeo®
7,0
7.0
8.5
8,5
EDITION 2(2)
8,0
8.0
Lantus®
7,5
7.5
7,0
7.0
−0.17%
p=0.0074
0.06%
p=0.4932
Toujeo®
BL
W12
LS: Least Squares
(1) Type 2 Diabetic patients uncontrolled with basal bolus
(2) Type 2 Diabetic patients uncontrolled with Basal + OAD
M6
M9
M12
70
Weight Change Difference Maintained Over Time
Mean Weight Change (kg ± SE)(1)
Pooled analysis of EDITION 1-2-3
1.5
LS mean difference: –0.28 kg
p=0.039
1.0
Lantus®
Toujeo®
0.5
0.0
-0.5
BAS Week Week
2
4
Week
8
Week
12
Month
4
(1) Type 2 Diabetic patients; Ritzel R et al. Poster presentation at EASD 2014; Abstract 963
Month
6
71
Flexibility in Injection Time (24 hours ± 3 hours)
T2D Patients who Occasionally Adapted the Timing of their Once-Daily Injections of
Toujeo® (24 ± 3 h) Did Not Impact Glycemic Control or Affect Frequency of Hypoglycemia(1)
EDITION 1
EDITION 2
Percentage of patients
experiencing ≥1 event, %
70
Flexible dosing
60
Fixed dosing
50
40
30
20
10
0
Confirmed or severe at any time
(≤70 mg/dL [3.9 mmol/L])
Confirmed or severe nocturnal
(≤70 mg/dL [3.9 mmol/L])
(1) Riddle MC et al. Poster presentation at ADA 2014; Abstract 919-P
Confirmed or severe at any time
(≤70 mg/dL [3.9 mmol/L])
Confirmed or severe nocturnal
(≤70 mg/dL [3.9 mmol/L])
72
A Unique Clinical Profile
● Easy insulin initiation
Smoother glucose lowering and prolonged PK/PD profile
Less hypoglycemia during the initiation period when titration occurs
Less weight gain
● Long lasting benefit
Sustained glucose control at 1 year
Benefit in reduction of hypoglycemia maintained at 1 year
Flexibility in injection time, when occasionally patients need it
PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile
73
Agenda
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin
Management
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo®
● Stewart B. Harris, MD, Professor of Medicine, Schulich School of
Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation
of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
Afrezza®
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
LixiLan
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion
● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
74
The Next Generation of Basal Insulin
with a Smoother PK/PD Profile than Lantus®
TOUJEO
• Smoother PK/PD
LANTUS
• Once daily
• Less hypos
NPH
than NPH
• Treat to target
PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile
profile than
Lantus®
• Full 24h coverage
• Less hypos than
Lantus
• Improved patient
experience
75
Total Addressable U.S. Basal Insulin Market for
Toujeo® Is ~6m Patients(1)
Estimated Annual
New Basal Insulin
Naïve Patients
Existing Patients
Total Addressable
Market
Million patients
Million patients
5m
+ Levemir®
1m/year
~6m
● 14.3m insulin naïve
drug-treated patients
● 1m new basal insulin starts
every year
(1) Sanofi market research, expert interviews
76
A Compelling Value Proposition
(1)
(2)
(3)
(4)
Jax T et al. Poster presented at EASD 2013; Abstract 1029. Available at http://www.easdvirtualmeeting.org/resources/6226 Accessed May 2014
Ritzel R, et al. Diabetes 2014;63 (suppl 1A)
Riddle MC et al. Poster presentation at EASD 2014; Abstract 980
ORIGIN Trial Investigators. N Engl J Med. 2012 Jul 26;367(4):319-28
77
Scientific Data Communication Created Strong
Pre-launch Awareness and Willingness to Prescribe
Aided Awareness of Toujeo®(1)
Willingness to Prescribe Toujeo®(1)
% of Endocrinologist Aware
% of Endocrinologist Willing to Prescribe
77%
75%
60%
52%
50%
40%
US
EU Top 5
(1) Sanofi Market Research – Awareness and Trial Tracking (August 2014)
US
EU Top 5
78
Target Switch Segments Represent Almost 60%
of Existing Basal Insulin Patients Pre-Launch(1)
Segment size % Receptive to
Concerned
®
(2)
basal insulin pop Toujeo TPP
about hypos
Frustrated
and challenged:
Type 2
(Uncontrolled)
29%
Frustrated
and challenged:
Type 1
(Uncontrolled)
6%
Natural
switchers
Motivated but
are falling short
(Type 2 basal bolus,
controlled w/ hypos)
Engaged
and satisfied
(Type 1 / Type 2
controlled)
Looking for
better options
22%
Require
convincing
43%
May
become
unsatisfied
over time
More limited drivers for engaged and satisfied
patients to switch from current treatment
(1) Toujeo® segmentation survey: Segmentation solutions and expert interviews
(2) Target Patient Profile
79
An Enhanced SoloStar® Device: Accurate, Precise and
Easier to Use
Toujeo® SoloStar®: Adapted for the Next-Generation Basal Insulin
● Smaller injection volume(1)
● Ergonomic design improvements
● No additional training needed(1)
● 50% more units per pen (450 IU)(1)
(1) Compared to Lantus® SoloStar®
80
Toujeo® and Customized Patient Support Program
Intended to Ensure a Smoother Start and Better Stay
Regular
touch points
● Support successful initiation of
Toujeo® following prescription
●
Mix of face
to face/
phone/
webinar
interactions
31% of diabetes patients do not
initiate prescription(1)
● Support patients to up-titrate quickly
to target A1c
●
15% to 20% of patients
discontinue insulin in first 3 months(2)
Adapted
locally
● Motivate patients to stay on therapy
A Customized Patient Support Program to achieve personalized glycemic goals
(1) M Fischer et al., J Gen Intern. Med, 25(4):284-90, 2010
(2) Lantus® satisfaction study, Impact Rx, Dec 2012 (US/EU5 & JP)
81
Ensuring U.S. Sales Force Readiness for Launch
Enhancement of U.S. commercial effectiveness to improve
Lantus® performance and prepare for the Toujeo® launch
Improved clarity and impact of
Lantus® promotion messages
Raised PCP preference for Lantus®
Increased sales force call
productivity
From 35% to 90% ≥ 8 calls/day
Increased sales force call targeting
Significant improvement in % calls
to priority customers
Raised perception of Sanofi on
“best in meeting physician needs”
+4 pts over baseline
82
Achieving Payor Access is Necessary
for Franchise Conversion
Toujeo® is a
better insulin vs.
Lantus® based
on the EDITION
program
● Current Lantus® access and volume
provides foundation for Toujeo®
● Price expected not to be a barrier to
access
● Maintain top quality access over time
with a strong documented value
proposition
83
Preparing for Launch
Regulatory Timelines:
July 2014: FDA acceptance of NDA review
● Expected regulatory decision: Q1 2015
May 2014: EMA acceptance of the marketing authorization application
● Expected regulatory decision: Q2 2015
July 2014: NDA submission to Japanese Health Authorities
● Expected regulatory decision: Q2 2015
84
Our Diabetes Team is Focused on Improving
Patient Outcomes
Ambition for
1
Become the preferred basal insulin
2
Convert basal insulin users,
especially Lantus®, to Toujeo®
3
Ensure Toujeo® patients have
an improved insulin experience
to generate a
substantial
proportion of
Sanofi’s glargine
volume in the U.S.
within 3 years
after launch
85
Agenda
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin
Management
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo®
● Stewart B. Harris, MD, Professor of Medicine, Schulich School of
Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation
of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
Afrezza®
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
LixiLan
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion
● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
86
The Majority of Patients on 2+ OADs Resist Starting
Insulin Therapy(1,2)
Patients on 2+ OADs Are Resistant to Starting Insulin Therapy
% of Patients
39%
66%
Resistant to
starting66%
insulin
27%
Resistant because of injections
Resistant not because of injections
Not Resistant to taking insulin
(1) Nielsen DD Quantitative Market Research (T2D patients on 2+OADs, n=77. Note that these data are patient reported captured in a market
research setting and do not necessarily reflect actual future behavior.
(2) When physician recommends initiating insulin therapy
87
A New and Innovative Treatment Option for
Diabetes
Afrezza® (insulin human) Product Label
Indication
●
●
Dosage & Administration
Afrezza® is a rapid acting inhaled
insulin indicated to improve glycemic
control in adult patients with diabetes
Not recommended for patients who
smoke
Warnings & Precautions
Administered at the beginning of a meal
Before initiating, perform a detailed
medical history, physical exam, and
spirometry (FEV1) in all patients to
identify lung disease
Black Box
● Most common adverse event is cough
● Should not be used in patients with
active lung cancer
●
●
● Acute bronchospasm has been
observed in patients with asthma and
COPD using Afrezza®
● Contraindicated in patients with chronic
lung disease such as asthma or COPD
Large 5-year safety study to assess
potential risk of pulmonary malignancy to be conducted
COPD: Chronic Obstructive Pulmonary Disease
88
Many Diabetes Patients Are Not at A1c Goals
Due to Delayed Insulin Initiation and Intensification
Focus of Initial Commercial Strategy for Afrezza®(1,2,3)
Insulin Initiation
Insulin Intensification
Patients on 2+ OADs or GLP1 ± OADs
Patients on Basal Insulin or Basal ± GLP1 ± OAD
~3.1m
Diabetes
Patients
~2.0m
~1.1m
Uncontrolled patients(1) (A1c > 7%)
Controlled patients (A1c < 7%)
Smokers, patients with asthma & COPD(2,4)
(1) Adelphi Real World: Diabetes DSP 9 (2012), Data on File. US Data.
(2) NHANES Data (2009-201), CDC, US Data, 16% of PWD are smokers; 19% are non-smokers w/ COPD (Chronic Obstructive Pulmonary Disease)
and/or Asthma;
(3) Sanofi market research
(4) Patients for whom Afrezza® is contraindicated
89
Device is Unique and Innovative
● Small, discreet, easy-to-use inhaler
● No cleaning required
● No parts need to be replaced
● Breath powered
● Efficient delivery to the deep lung
● Minimal training needed
● Disposed after 15 days of use
90
Afrezza® Delivers a Distinctly Different Patient
Experience than the Previous Inhaled Insulin
Exubera®
Afrezza®
Lower bioavailability and slower
clearance
Higher bioavailability and faster
clearance
Large device
Small device
Complicated titration
system
Easy to use
Doses were in milligrams
Time consuming in-office
training
Doses equivalent to insulin units
Less training required
No cleaning
requirement
Device required
weekly cleaning
91
Majority of Patients Surveyed Prefer Afrezza® over
Insulin Pen Device or Injectable Mealtime Insulins(1)
Insulin Initiation
Insulin Intensification
Preference for Afrezza® vs.
Insulin Pen Device
Preference for Adding Afrezza® vs.
Injectable Mealtime Insulins
(% of patients on 2+ OADs)
(% of basal patients)
60%
57%
66%
32%
17%
23%
11%
Preference for Afrezza®
Preference for Afrezza®
No preference
No preference
Preference for insulin pen device
Preference for injectable mealtime insulin
(1) Nielsen DD Quantitative Market Research (T2D patients on 2+OADs, n=77; T2D patients taking basal insulin +/- OADs, n=79 ). Based on exposure to
an Afrezza® product profile and a video demonstration (blinded as Product X). Note that these data are patient reported captured in a market research
setting and do not necessarily reflect future behavior.
92
Physician Survey Indicates Afrezza® Would Be an
Appealing Option for Insulin Initiation and Intensification(1)
Insulin Initiation
Insulin Intensification
“The product will make it significantly
easier to initiate insulin among my
uncontrolled oral patients”
“I would be comfortable using the product
instead of injectable rapid acting insulin
for my basal bolus patients”
(% of physicians)
(% of physicians)
62%
56%
66%
25%
23%
15%
Agree
Agree
Neither agree nor disagree
Neither agree nor disagree
Disagree
Disagree
19%
(1) Nielsen DD Quantitative Market Research (n=583 physicians – PCPs, n=391; ENDOs, n=192. Based on exposure to a clinical Afrezza® product profile
and a video demonstration (blinded as Product X). Note that these data are physician reported captured in a market research setting and do not
necessarily reflect future behavior.
93
The Launch Will Occur in Two Phases
Expansion Drivers
2015
U.S. Launch
● Novel product delivery
● Early adopters
● Current label
● Potential ex-U.S.
launches
● Supply of Sanofi
insulin
● Label enhancement
studies
● Safety study completed
94
Agenda
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin
Management
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo®
● Stewart B. Harris, MD, Professor of Medicine, Schulich School of
Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation
of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
Afrezza®
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
LixiLan
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion
● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
95
A Strong Drug Profile Emerging from PoC Study
in Type 2 Diabetes
Proof-of-Concept Study of Fixed-Ratio Once-Daily LixiLan
in Type 2 DM on Metformin
● Robust A1c reduction from
8.1% to 6.3%
● Reduced body weight (-1 kg)
● Less frequent nausea and
vomiting compared to what
has been reported for the
GLP-1 Rapid Acting class
● Low incidence of symptomatic
hypoglycemia
 84% of patients reached
A1c goal <7%
 68% reached this target with
no documented hypoglycemia
 56% reached it with no weight
gain
 46% with no weight gain and
no documented hypoglycemia
(1) Mean A1c change of 1.8% at Week 24 (n=161)
(2) Mean change in body weight from baseline to Week 24 (n=161)
(3) Documented symptomatic hypoglycemic events ≤70 mg/dL occured in 21.7% of patients (n=161)
96
High Proportion of Type 2 Diabetes Patients
Reached A1c Target in PoC Study
LixiLan(1)
Data
IDegLira(2)
Liraglutide
8.06
Baseline A1c (%)
8.3
8.3
6.3
End point A1c (%)
6.4
7.0
-1.8
Change in A1c (Abs. %)
-1.9
-1.3
-60
Change in FPG (mg/dL)
-65
-32
84%
% Achieving A1c <7%
81%
60%
7.5%
Nausea (%)
8.8%
19.7%
2.5%
Vomiting (%)
3.9%
8.5%
-1.0
Change in Body Weight (kg)
-0.5
-3.0
(1) Proof of concept study (323 patients) - a 24-week randomized, open-label, trial comparing the efficacy and safety of insulin glargine/ lixisenatide
fixed ratio combination versus insulin glargine, in type 2 diabetes inadequately controlled with metformin
(2) DUAL™ I Phase III study (around 1,600 people) – a 26-week, randomized, open-label trial comparing the efficacy and safety of IDegLira,
insulin degludec and liraglutide, in people with type 2 diabetes inadequately controlled with metformin with or without pioglitazone
97
Combining Insulin Glargine with Lixisenatide
in a Single Daily Injection
U.S. Target Populations of T2D Patients
for
● Phase III program initiated in Q1 2014
● LixiLan-O study in patients insufficiently
controlled on OADs (1,125 patients)
● LixiLan-L study in patients not at goal
on basal insulin (700 patients)
1st injectable
drug
Patients
Not at Target
on OAD
~5.5m
patients
Basal
Intensification
Patients
Uncontrolled
with basal
therapy
~4m patients
● Completion of both studies expected
by Q3 2015
● Results of ELIXA CV outcome trial
with lixisenatide expected in Q2 2015
● Targeted FDA submission of LixiLan
as early as end of 2015
Number of patients estimated for the U.S. (2017 projections based on internal model adapted from Adelphi)
98
Agenda
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin
Management
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo®
● Stewart B. Harris, MD, Professor of Medicine, Schulich School of
Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation
of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
Afrezza®
● Andrew Purcell, Vice President, Commercial Business Unit Head
U.S. Diabetes
LixiLan
● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion
● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
99
Broadening our Portfolio to Sustain a Leadership Position
in Diabetes
1
Establish next generation of basal insulins
2
Capture untapped patient needs
by addressing their reluctance to start insulin
3
Innovate with a new combination
of basal insulin and GLP-1
4
Expand access to Lantus® in developing
countries
5
Drive better outcomes through integrated care solutions
100
Q&A
101
Agenda
Dengue Vaccine
Dengue –
A Major Public Health Concern
● Duane Gubler, MS, ScD, Professor, Emerging Infectious Diseases
Program, Duke NUS, Singapore
Dengue Vaccine –
Clinical Development Program
● Nicholas Jackson, Associate Vice President R&D,
Dengue Vaccine Company, Sanofi Pasteur
From Vaccine Development to
Vaccination Programs
● Guillaume Leroy, Vice President, Dengue Vaccine Company,
Sanofi Pasteur
102
Dengue: A Mosquito-Borne Disease
Dengue Is the Most Important Vector-Borne Viral Disease of Humans(1)
●
Family Flaviviridae: Four serotypes
●
Mosquito-borne virus
●
●
●
Primary vector is Aedes aegypti
●
Secondary vector is Aedes albopictus
Female Aedes aegypti mosquito
acquires virus while feeding on
the blood of an infected person
●
Highly domesticated
●
Strongly anthropophilic
Aedes
mosquito
Humans
Once infected, the virus is transmitted from the
mosquito to other humans(2,3)
●
The mosquito remains infective for the rest of its life(2)
(1) Gubler, 2010, Dengue, Trop Med Health
(2) World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control
(3) Whitehead, 2007, Nat Rev Microbiol.
103
Spread of Dengue Follows Growing Trend of Urbanization
Important Determinants of the Dengue
Disease Epidemiology(1)
● Urbanization
● Travel and globalization
● Vector control effectiveness and
sustainability
● Factors adding to the proliferation of
dengue(2,3)
● Seasonal trends
(1) Kyle, 2008, Ann Rev Microbiol.
(2) Higa, 2011, Trop Med Health
(3) Descloux, 2012, PLoS Negl Trop Dis.
104
Dramatic Expansion of Dengue with a 30-Fold Increase
in Dengue Incidence over the Last 50 Years(1)
WHO Estimates
Estimates Based on 2013
Modeling(5)
2.5 billion people(2)
live in dengue-endemic countries
(over 40% of the world’s population)
50 to 100 million
dengue infections(2)
occur worldwide each year
500,000 people
with severe
dengue(2)
require hospitalization
each year
12,500(2,3)
people with
severe
dengue
WHO
objective:
estimate true
disease burden
by 2015(4)
96 million symptomatic
infections per year
390 million infections
per year
Contributes to a large reservoir
of infection that influences
disease burden
die
Four distinct serotypes with unpredictable distribution(5)
(1)
(2)
(3)
(4)
(5)
World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control
World Health Organization, 2014, Dengue factsheet
~12,500 people or 2.5% people with severe dengue die each year
WHO, 2012, Global Strategy for Dengue Prevention and Control
Bhatt, 2013, Nature
105
Every Year, an Estimated 2 Million People with Dengue
Require Hospitalization(1)
Characteristics of Severe Dengue(2)
● Plasma leakage
● Severe gastrointestinal
involvement
● Severe organ impairment
● Significant bleeding
~2.5%
of severe
dengue cases
result in
death
● Altered level of consciousness
(1) Beatty 2009
(2) World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control
106
Dengue Has an Adverse Economic and Societal Impact
in Endemic Regions
Dengue Disease Is Estimated to Cost Between US$6.3bn(1)
and US$12bn Each Year in Endemic Countries(2)
Dengue
“phobia”(4)
Overcrowded
healthcare
facilities(3)
Fear of
infection(4)
Community
disruption(4)
Lost
productivity(3)
Economic
cost(3,4,6,7)
Decrease in
tourism(5)
Perceived
government
failure(4)
Dengue can affect anyone,
regardless of age and socioeconomic status(4,8)
(1)
(2)
(3)
(4)
Shepard et al. 2014, poster ASTMH 2014
Infectious Disease Cost Calculator, Accessed Nov 2014
Gubler, 2002, Trends Microbiol.
Douglas, 2013, PLoS Negl Trop Dis.
(5)
(6)
(7)
(8)
Mavalankar, 2009, IIMA
Shepard, 2013, PLoS Negl Trop Dis.
Shepard, 2011, Am J Trop Med Hyg.
OK DoH website, 2013, Oklahoma Department of Health
107
Sanofi Pasteur Dengue Vaccine Can Make
the 2020 Objectives of WHO Achievable
WHO Objectives(1)
Estimate
true
burden of
disease
by 2015
Reduce
dengue
mortality
by ≥50%
by 2020*
Reduce
dengue
morbidity
by ≥25%
by 2020*
Technical elements
Diagnosis & case
management
Integrated
surveillance &
outbreak
preparedness
Sustainable
vector control
Future
vaccine
implementation
Basic operational
& implementation
research
Vaccination is a crucial element in achieving the WHO objectives
*2010 is baseline year.
(1) WHO, 2012, Global Strategy for Dengue Prevention and Control
108
Agenda
Dengue Vaccine
Dengue –
A Major Public Health Concern
● Duane Gubler, MS, ScD, Professor, Emerging Infectious Diseases
Program, Duke NUS, Singapore
Dengue Vaccine –
Clinical Development Program
● Nicholas Jackson, Associate Vice President R&D,
Dengue Vaccine Company, Sanofi Pasteur
From Vaccine Development to
Vaccination Programs
● Guillaume Leroy, Vice President, Dengue Vaccine Company,
Sanofi Pasteur
109
A Significant Technological Advance(1,2)
● 4 genetic constructs, 1 for each serotype
Dengue
Dengue
17D
yellow
fever
17D
Yellow
fever
● Envelope and precursor membrane genes from
each serotype combined with the genes encoding
the capsid and non-structural proteins from the
yellow fever (YFV 17D) vaccine strain
● 4 recombinant, live, attenuated dengue viruses
combined into a single vaccine that is freeze-dried
and contains no adjuvant or preservatives(3)
YFV 17D VIRUS
C
NS
DENV-1
PrM
E
DENV-2
PrM
E
DENV-3
PrM
E
DENV-4
PrM
Chimeric Virus
Recombinant
virus
RECOMBINANT DENV-1, -2, -3, and -4
E
(1) Vaccine referred to in the literature as Chimeric Yellow Fever 17D-Tetravalent Dengue Vaccine (CYD-TDV)
(2) Guirakhoo, 2001, J Virol.
(3) Guy, 2011, Vaccine
110
More than 41,000 Individuals Included in Sanofi’s
Dengue Vaccine Clinical Trial Program(1)
Phase III Evaluation Provides Complementary and Pivotal Data for Efficacy, Safety,
and Immunogenicity of the Dengue Vaccine(2,3)
CYD14 Phase III Efficacy Study Asia
Countries: Thailand, Indonesia, Malaysia, Viet Nam, Philippines
Sites : 11
Age group: 2–14 years
Sample size: 10,278
CYD15 Phase III Efficacy Study in LatAm(2)
CYD14 Phase III Efficacy Study in Asia(3)
●
Countries: Colombia, Mexico, Honduras,
Puerto Rico and Brazil
●
Countries: Thailand, Indonesia, Malaysia,
Vietnam and Philippines
●
Sites: 22
●
Sites: 11
●
Age group: 9 to 16 years
●
Age group: 2 to 14 years
●
Sample size: 20,875
●
Sample size: 10,278
(1) Nearly 30,000 individuals across age groups have received the vaccine and approximately 12,000 individuals have received placebo or control vaccine
Status as of October 25, 2013
(2) ClinicalTrials.gov, 2013, NCT01374516
(3) ClinicalTrials.gov, 2013, NCT01373281
111
Phase III Studies Design: Randomized 2:1,
Observer-Blind, Placebo-Controlled, Multicenter(1,2)
Inclusion Criteria
• Children 2–14 years (Asia)
• Children 9–16 years (LatAm)
• Good health
• No plans to leave study area
Exclusion Criteria
• Febrile illness
(until resolution)
• Receiving other vaccines
(until 4 weeks after
vaccination)
• Congenital or acquired
immunodeficiency
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Vaccination with
Dengue Vaccine
Months
0
6
12 13
18
25
Year 6
Hospital Phase
Vaccination with
Placebo*
Active Phase
Active Surveillance/Detection of Dengue Cases
●
Per-protocol analysis: follow-up from month 13–25.
●
Intent-to-treat analysis: follow-up from month 0–25.
Additional followup for safety of
hospitalized
dengue cases for
4 years after the
end of the active
phase
The vaccination follows a 3-dose schedule
*Participants who received placebo were designated as the control group
(1) Capeding, 2014, Lancet
(2) Villar, 2014, N Engl J Med.
112
Meta-Analysis Demonstrates Significant Reduction in
Dengue across All Serotypes after 3 Doses Schedule(1,2)
EFFICACY and 95% CI
STUDY (n episodes)
Any
Serotype
ASIA / CYD14 (n=251)
52.0
Pooled (n=647)
52.3
ASIA / CYD14 (n=67)
DENV-2
61.5
35.0
-9.2
61.0
42.3
14.0
LATAM / CYD15 (n=108)
18.7
61.1
39.6
55.2
78.4
52.9
ASIA / CYD14 (n=33)
61.9
LATAM / CYD15 (n=125)
65.1
Pooled (n=158)
DENV-4
65.0
65.2
50.2
35.6
68.0
66.8
50.3
29.1
Pooled (n=175)
DENV-3
59.2
50.0
24.6
LATAM / CYD15 (n=132)
Pooled (n=233)
66.4
60.8
LATAM / CYD15 (n=397)
ASIA / CYD14 (n=101)
DENV-1
56.5
43.8
65.0
(1) Capeding, 2014, Lancet
(2) Villar, 2014, N Engl J Med.
0
20
40
74.9
82.0
60
87.0
77.7
60.2
Pooled (n=109)
-20
82.4
75.3
54.5
ASIA / CYD14 (n=51)
LATAM / CYD15 (n=58)
74.0
90.8
76.6
80
88.0
84.4
100
113
Higher Efficacy Demonstrated Against Severe Dengue,
Including Reduction in Hospitalized Cases(1,2)
Overview of Efficacy Results Against Virologically Confirmed Dengue
(Severe and Hospitalized)(1,2,3)
EFFICACY and 95% CI
STUDY (n episodes)
Vaccine Efficacy on
Dengue Hemorrhagic
Fever (DHF) cases
80.0
52.7
ASIA / CYD14 (n=28)
Vaccine
on hospitalized
dengue cases
67.2
50.3
ASIA / CYD14 (n=101)
Efficacy(4)
64.7
LATAM / CYD15 (n=60)
0
20
95.0 99.9
64.9
LATAM / CYD15 (n=11)
(WHO 1997 definition)
92.4
40
60
78.6
80.3
80
89.5
100
 Results relevant in public health context (ie, vaccine could help reduce disease burden)(1,2)
(1)
(2)
(3)
(4)
Capeding, 2014, Lancet
Villar and al., 2014, NEJM
Intent to Treat analysis (25m follow-up from months 0–25)
The relative risk (RR) of hospital admissions for virologically confirmed dengue was calculated as the ratio of annual incidence in the vaccine group
and control groups, and presented here as vaccine efficacy (i.e., 1−RR)
114
Higher Efficacy Observed in Those Previously Exposed
to Dengue, During the Active Phase
Efficacy According to Dengue Serostatus at Baseline(2) in Asia & Latam(1,2)
EFFICACY and 95% CI
STUDY (n episodes)
74.3
DENV + (n=52)
ASIA / CYD14
35.5
DENV – (n=41)
83.7
LATAM / CYD15
DENV + (n=31)
43.2
DENV – (n=18)
-80
-60
-40
-20
0
20
40
60
80
100
 Age can be used as a surrogate of prior exposure to dengue
(1) Comparison made on ITT. RR=relative risk: incidence of VC dengue cases in CYD group vs control group.
(2) Dengue +: baseline titer for at least 1 DENV serotype is ≥10 1/dil.
115
Favorable Safety Profile in Vaccinated Subjects during
the Active Phase of Phase III Efficacy Studies
CYD14 & CYD15 Safety Results (Active Phase)(1,2)
Safety analyses* showed similar reporting rates
between the vaccine and control groups
during the studies
* solicited reactions, unsolicited events and Serious Adverse Events (SAEs)
SAEs were consistent with medical disorders
in the age group: mainly infections, injuries and accidents
No safety issue and no evidence of sensitization
over the 25-month follow-up period
Long term safety results analysis on-going for 60 months
post-dose 3
(1) Capeding, 2014, Lancet
(2) Villar and al., 2014, NEJM
Safety profile
over the 25-month
is favorable and
consistent with
the favorable
safety profile
documented in
previous studies
(Phase I, II, III)
116
Both Efficacy Studies in Asia and LatAm Consistently
Demonstrate a Reduction in Dengue Disease
Both Studies Met their Primary Efficacy Endpoints and Showed Consistent
Safety Profile for the Observed Active Phase(2,3)
Key Study Results
2.5 billion people(1)
live in dengue-endemic countries
(over 40% of the world’s population)
50-100 million
dengue infections(1)
occur worldwide each year
500,000 people
with severe
dengue(1)
require hospitalization
each year
CYD 14, Asia(2)
CYD 15, LatAm(3)
56.5%
60.8%
Reduction in
symptomatic dengue(4)
Reduction in
symptomatic dengue(4)
80%*
95%†
Reduction in severe
disease(5)
Reduction in severe
disease(5)
67.2%‡
80.3%§
Reduction in
hospitalized cases(6)
Reduction in
hospitalized cases(6)
2.5%(1)
of people
with severe
dengue
die
*95% CI: 52.7-92.4
(1) World Health Organization, 2014, Dengue factsheet
(2) Capeding, 2014, Lancet
(3) Villar and al., 2014, NEJM
†95% CI: 64.9-99.9
‡95% CI: 50.3-78.6
(4) Post Dose 3
(5) DHF, WHO 1997 criteria, intent to treat
(6) Intent To Treat
§95% CI: 64.7-89.5
117
Agenda
Dengue Vaccine
Dengue –
A Major Public Health Concern
● Duane Gubler, MS, ScD, Professor, Emerging Infectious Diseases
Program, Duke NUS, Singapore
Dengue Vaccine –
Clinical Development Program
● Nicholas Jackson, Associate Vice President R&D,
Dengue Vaccine Company, Sanofi Pasteur
From Vaccine Development to
Vaccination Programs
● Guillaume Leroy, Vice President, Dengue Vaccine Company,
Sanofi Pasteur
118
A Broad Vaccination Program Has the Potential to Lead
to a Significant Reduction in Hospitalizations
Modeling the Prevention of Hospitalized Dengue Cases by Adding Multiple
Catch-up Cohorts to a Routine Vaccination Program in a Given Population(1)
40
19%
35
Number of
hospitalized
cases
(per 100,000
dengue
cases)
34%
30
53%
25
73%
20
81%
Prevented
hospitalized
cases (%)
15
10
5
0
No
vaccination
Hospitalized cases
Routine
vaccination
at 10 y
Routine
plus
catch-up
10–14 y
Routine
plus
catch-up
10–18 y
Routine
plus
catch-up
10–22 y
Routine
plus
catch-up
10–26 y
(1) Sanofi internal analysis, based on Coudeville & Garnett [2010]; prevented cases in the first 10 years of vaccine introduction
ILLUSTRATIVE
119
From Vaccine Efficacy to Vaccination Impact(1-7)
Vaccine
Efficacy
Direct protection &
indirect protection
x
Vaccination
Coverage
# cohorts x coverage
in each cohort
=
ƒ
Disease
Endemicity
Vaccination
Impact
% Population Protected
by Vaccination
(1)
(2)
(3)
(4)
Chao, 2012, PLoS Negl Trop Dis.
Coudeville, 2012, PLoS One
Durham, 2013, Vaccine
Rodriguez-Barraquer, 2013, Vaccine
(5) Dasbach, 2006, Epidemiol Rev.
(6) Farrington, 2003, Math Biosci.
(7) McLean, 1998, Dev Biol Stand.
120
A Successful Vaccination Program Defined by Several
Factors
1
Age for routine
vaccination
Define the optimal age range for routine vaccination
population in an endemic country
2
Catch-up cohort
size
Determine the optimal catch-up cohort size
to maximize impact of vaccination (range of age)
3
Geographic
breadth
Agree on the geographic breadth of the vaccination
program with local government
4
Compliance
Ensure highest impact through compliance
with 3-dose schedule
5
Outbreaks
Incorporate the outbreak nature of the disease
into an integrated strategy
121
An Unprecedented Industrial Commitment to Ensure
the Success of Large Scale Vaccination Programs
Ready to Produce >1bn Doses over the Next 10 Years
● State-of-the-art facilities dedicated
to the production of the dengue
vaccine
● €300m investment
● Manufacturing capacity for 100m
doses annually
● Initial inventory build-up underway
● Investment in additional
manufacturing capacity in the U.S.
● Large scale filling and packing to
start from 2015
●
1-dose and 5-dose vial presentations
Manufacturing Site, Neuville-sur-Saone, France
122
The Global Roll-out of Sanofi’s Dengue Vaccine
Steady Uptake at Launch Due to Broad Coverage in Endemic Countries
● First launches in dengue most
endemic countries
● Initial sales evolution expected
to be driven by public markets
● Private markets to complement
public programs and adding
strong growth momentum
2015
2020
ILLUSTRATIVE
123
Dengue Vaccine Launch Expected to Start by End of 2015
Make
Dengue
the Next Vaccine-
Preventable
Disease
124
Agenda
● Elias Zerhouni, MD, President, Global R&D
Sarilumab
Dupilumab
Wrap-up and Q&A Session
125
Immunology & Inflammation Set to Become
a New Growth Platform for Sanofi
Immuno-Modulation
is at the core of
Sanofi’s R&D strategy
Rheumatoid
Arthritis
Systemic
Lupus
Erythematosus
Atopic Dermatitis
Asthma
Inflammatory
Bowel Disease
Multiple
Sclerosis
126
Rheumatoid Arthritis Is a Chronic, Debilitating
Autoimmune Disease and a Major Cause of Disability
Rheumatoid Arthritis (RA)
● Up to 70m people worldwide(1)
estimated to be affected by RA
 Joints become chronically inflamed,
painful and swollen
 Patients can become increasingly
disabled as cartilage and bone is
damaged(2)
(1) World Health Organisation. Chronic rheumatic conditions
(2) Patient UK. Rheumatoid arthritis
127
Incomplete Response or Intolerance Leads Patients
to Cycle through Multiple Biologics
MTX/DMARDS
1st line treatment
RA
Combination
Tx
Market
~70%
Add Anti-TNF
1st line biologic
Switch to Other MOA’s
(Add on to MTX)
T cell
Current guidelines make
no distinction between
which biologic to start on
IL-6R
JAK
CD 20
MTX/DMARDS
1st line treatment
RA
Mono Tx
Market
IL-6R
~30%
JAK
TNF
MTX: Methotrexate DMARD: Disease-Modifying Anti-Rheumatic Drugs
Humira® (adalimumab) is marketed by AbbVie
Actemra® (tocilizumab) is marketed by Roche
Remicade® (infliximab) is marketed by J&J
Simponi® (golimumab) is marketed by J&J
Orencia® (abatacept) is marketed by BMS
Xeljanz® (tofacitinib) is marketed by Pfizer
(1) EULAR guidelines
Current guidelines
recommend using IL-6R
as a 1st choice
monotherapy(1)
Enbrel® (etanercept) is marketed by Amgen
Cimzia® (certolizumab) is marketed by UCB
Rituxan® (rituximab) is marketed by Roche
128
Sarilumab: An Investigational IL-6R mAb for RA
● Fully human, high affinity, IL-6R mAb
sarilumab
●
2 effective doses: 150mg or 200mg
●
Delivered subcutaneously every other week
●
Evaluated for use with ergonomic pre-filled syringe or autoinjector
● Efficacy demonstrated across three co-primary endpoints
in first Phase III trial(1)
●
Additional Phase III data expected in 2015
● Regulatory submission expected in late 2015 in the U.S.
and late 2016 in EU and Japan
IL-6R – Interleukin-6 receptor
Sarilumab is developed in collaboration with Regeneron
(1) SARIL-RA-MOBILITY in MTX IR moderate-to-severe RA - Clinically relevant and statistically significant improvements in
both sarilumab groups compared to placebo in all three co-primary endpoints: ACR 20 at 24 weeks, improvement of
physical function at 16 weeks and inhibition of progression of structural damage at 52 weeks
129
A Broad Clinical Development Program Aiming
for a Robust Label at Launch
Study
MOBILITY
TARGET
ASCERTAIN
EXTEND
ONE
MONARCH
EASY
Design
n
sarilumab + MTX
1,197
MTX IR patients
sarilumab + DMARD
546
Anti-TNFα IR patients
sarilumab + MTX
Anti-TNFα IR patients
Safety calibrator vs.
200
Actemra®
sarilumab + DMARD
2,000
Long-term extension study
sarilumab monotherapy (open-label)
120
DMARD-IR patients
sarilumab monotherapy vs. Humira®
MTX-IR, intolerant and inappropriate patients
sarilumab + MTX
Auto-injector real-life use
340
200
Objectives
● Evaluation of use as 1st
& 2nd line biologic therapy
● Assessment of long term
safety up to 5 years
● Safety calibration
● Duration of inhibition of
structural damage
● Evaluation of use with or
without DMARD (MTX)
● Assessment of pre-filled
syringe vs. autoinjector
Status
Completed
2015
2015
Ongoing
2015
2016
2015
~2,500 RA patients targeted in SARIL-RA program
MTX: Methotrexate DMARD-IR: Disease-Modifying Anti-Rheumatic Drugs Inadequate Responders
Actemra® (tocilizumab) is marketed by Roche
Humira® (adalimumab) is marketed by AbbVie
130
Significant Improvements in Signs
and Symptoms of RA with Sarilumab(1)
SARIL-RA-MOBILITY - ACR Scores (% of Patients)
ACR Response at Week 24
ACR Response at Week 52
66*
58*
54*
59*
53*
46*
40*
37*
33
32
20*
17
25*
25*
18*
7
ACR 20**
* p<0.0001 vs. placebo
** Co-primary endpoint
ACR 50
28*
9
ACR 70
ACR 20
ACR 50
Placebo + MTX
Sarilumab 150mg + MTX
Sarilumab 200mg + MTX
(n=398)
(n=400)
(n=399)
ACR – American College Of Rheumatology (ACR) Scoring System
(1) Clinically relevant and statistically significant improvements in both sarilumab groups compared to placebo in all three
co-primary endpoints: ACR 20, improvement of physical function and inhibition of progression of structural damage
ACR 70
131
Inhibiting Progression of Structural Damage
in RA with Sarilumab
SARIL-RA-MOBILITY - Change from Baseline in mTSS
3
mTSS:
modified
Total Sharp Score
Sarilumab:
van der Heijde
modified
Total Sharp Score
(0-448)
Placebo + MTX
2.5
2
70%
90%
1.5
1
Sarilumab 150 mg + MTX*
0.5
Sarilumab 200 mg + MTX*
0
Week
0
13
26
36
52
* p<0.0001 vs Placebo
132
Safety Findings Consistent with Prior
Investigational Studies with Sarilumab
SARIL-RA-MOBILITY - Safety Data
● Higher incidence of TEAEs leading
to withdrawal
● Higher incidence of infections, the
most frequently reported adverse
events(1)
●
●
Dose-dependent decrease in mean
neutrophil counts
Serious infections not associated with
grades 3 and 4 neutropenia in this study
● Increases in mean LDL-C and
transaminases observed
13.9%
12.5%
TEAEs
leading to
withdrawal
4.7%
Sarilumab 150mg Sarilumab 200mg
+ MTX
+MTX
40.1%
39.6%
31.1%
Infections
of which
serious
infections
2.6%
4.0%
Sarilumab 150mg Sarilumab 200mg
+MTX
+MTX
TEAEs – Treatment Emergent Adverse Events
(1) Sarilumab and placebo, both in combination with MTX
Placebo
+MTX
2.3%
Placebo
+MTX
133
Further Establish the IL-6R Class
in an $18bn Rheumatoid Arthritis Biologic Market
Rheumatoid Arthritis - Worldwide Sales of Biologics(1)
~$18bn
IL-6R
5%
~$21bn
IL-6R
IL-6R
19%
Other(2)
Anti-TNFα
● Share of IL-6R inhibitors
projected to increase
four-fold to nearly 20% of
the RA market by 2021
driven by expanded use
and new entrants
● Blockbuster status
reached with ~5% share
2013
2021
Develop sarilumab to become the preferred IL-6R mAb
(1) Decision Resources - Internal estimates
(2) Other includes: JAK inhibitors, B Cell, Co-stimulation, IL-17, IL-1
134
Agenda
● Elias Zerhouni, MD, President, Global R&D
Sarilumab
Dupilumab
Wrap-up and Q&A Session
135
Dupilumab Offers Potential to Change Management
of Multiple Th2-Mediated Allergic Inflammatory Diseases
Dupilumab is a fully human monoclonal antibody targeting IL-4Rα
blocking intracellular signaling of both IL-4 and IL-13
1
IL‐4
DERMATOLOGY
Moderate-to-Severe Atopic Dermatitis
IL‐13
or
c
IL‐4R
Type I
Receptor
IL‐4R
IL‐13R1
2
PULMONOLOGY
Moderate-to-Severe Asthma
Type II
Receptor
3
OTOLARYNGOLOGY
Chronic Sinusitis with Nasal Polyps
IL-4/IL-13 pathway may be a fundamental driver in allergic diseases
Dupilumab is developed in collaboration with Regeneron
Th2: T-helper 2 cells, involved in “humoral-mediated” immunity
136
Atopic Dermatitis Is a Serious, Chronic, Inflammatory
Skin Condition
Atopic Dermatitis (AD)
●
>5m people in the U.S. and EU(1)
estimated to be affected by
moderate-to-severe atopic dermatitis
● Characterized by eczematous
dermatitis with intractable pruritus
● Current therapies often inadequate
and associated with unwanted side
effects
● 40% of moderate-to-severe patients
uncontrolled with topicals
(1) Adapted from White Book on Allergy published in 2011, http://www.worldallergy.org/UserFiles/file/WAO-White-Book-on-Allergy_web.pdf
137
137
The Negative Impact of Atopic Dermatitis on Quality of
Life Is Largely Underestimated
1
Low self-esteem
• Impact on social life
Negative impact on QoL
2
Greater risk for psychological distress
• Mood disorders, such as anxiety and depression(1)
• Suicidal ideation(2,3)
3
 Similar or higher than
in psoriasis
 Determined by degree
of skin involvement,
severity and localization
Sleep disturbance and fatigue(4)
(1)
(2)
(3)
(4)
Journal of Psychomatic Research 57 (2004) 195-200
Acta Derm Venereol 2004;84(3):205-12
Suicide Life Threat Behav 2006 2006 Feb;36(1):120-4
J Allergy Clin Immunol 2006 Jul;118(1):226-32
138
Dose-Dependent Efficacy in Adults with Moderate-toSevere Atopic Dermatitis Uncontrolled by Topicals
Phase IIb Study in AD - Mean Percent Change in EASI
At Week 16
Placebo
Over 16 Weeks
100 mg 300 mg 200 mg 300 mg 300 mg
q4w
q4w
q2w
q2w
qw
0
0
0
-10
-10
-20
-20
-30
-30
-40
-40
-50
-50
-60
-60
-70
-70
-80
p < 0.0001 vs placebo
-80
-90
-90
EASI=Eczema Area Severity Index
IL-4Rα – Interleukin-4 receptor sub-unit α
2
4
6
8
10
12
14
16
Placebo
100mg q4w
p<0.0001 vs placebo at Week 16
All other time points p<0.05 vs placebo
300mg q4w
200mg q2w
300mg q2w
300mg qw
139
Dupilumab Significantly Improved Signs and Symptoms
in Moderate-to-Severe AD Patients Uncontrolled by Topicals
Phase IIb Study in AD - Change in Efficacy Endpoints at 16 Weeks(1-5)
Parameter
Placebo
300mg q2w
300mg qw
EASI Score
18%
68.2%
73.7%
50/75/90 EASI
Improvement
29.5%/11.5%/3.3%
78.1%/53.1%/29.7%
82.5%/60.3%/36.5%
IGA Response
1.6%
29.7%
33.3%
Pruritus NRS
11.4%
52.9%
59.7%
5-D Pruritus
Score
8.2%
35.4%
43.6%
p<0.0001 vs placebo for all parameters
300mg qw and 300mg q2w dose regimens selected for Phase III program
(1)
(2)
(3)
(4)
(5)
Mean percent change in EASI (Eczema Area Severity Index)
Proportion of patients achieving EASI-50/70/90
Proportion of patients achieving IGA ≤ 1 (Investigator’s Global Assessment score of 0 “clear” or 1 “almost clear”)
Mean percent change in pruritus NRS (Numeric Rating Scale) weekly averaged
Mean percent change 5-D Pruritus Score
140
Safety Findings in Moderate-to-Severe Atopic Dermatitis
Phase IIb Study in Moderate-to-Severe Atopic Dermatitis - Safety Data
Nasopharyngitis
Headache
Injection site
reactions
21%
23%
15%
18.5%
12%
8%
9.5%
5%
Dupilumab
Placebo
Dupilumab
Placebo
3%
Dupilumab
Placebo
● Nasopharyngitis, the most common adverse event, balanced across dupilumab
treatment groups vs. placebo
● Headache and injection site reactions more frequent with dupilumab
Ongoing follow-up period of 16 weeks after treatment
141
Dupilumab Leads Development of Biologics
in AD with Recent Start of Phase III Program
LIBERTY - Phase III Clinical Program of Dupilumab in Moderate-to-Severe AD
CHRONOS
Combination with
topical corticosteroids
in adults(1)
SOLO 1
SOLO 2
Monotherapy
in adults(2)
OLE
Open-label
extension study
in adults(3)
(1) CHRONOS study will assess efficacy of dupilumab in combination with topical corticosteroids through 16 weeks and long-term safety and
efficacy of dupilumab up to 52 weeks, using 2 dosing regimens of dupilumab or placebo in 700 adult patients
(2) SOLO 1 and 2 studies will assess efficacy and safety of dupilumab as monotherapy in adults through 16 weeks using 2 dosing regimens
of dupilumab and matching placebo in 600 adult patients each
(3) The Open-Label Extension (OLE) study will assess long-term safety and efficacy of repeat doses of dupilumab in adults who have previously
participated in controlled studies of dupilumab
142
Moderate-to-Severe Asthma Negatively Impacts the Lives
of Patients and Is Associated with High Burden to Society
Moderate-to-Severe Asthma
●
235-300m people worldwide
estimated to be affected by asthma(1)
● ~25m people in the U.S. alone
● 10 to 20% of patients uncontrolled despite
existing therapies
● Chronic inflammatory disease leading to
acute and chronic narrowing of the airway
and increased mucus production
● Patients with asthma experience
wheezing, shortness of breath, cough
and chest tightness
(1) WHO, http://www.who.int/mediacentre/factsheets/fs307/en/
143
143
Dupilumab Shows Improvement in Lung Function
in Phase IIb in Moderate-to-Severe Asthma
Phase IIb - Mean Improvement in FEV1 (mL and % Change from Baseline)
mL
500
400
25.9%(1)
(2)
25.8%
(1)
18.0%
300
200
(1)
17.7%
Placebo
200mg Q2W
10.4%
6.2%
300mg Q2W
100
0
(1) p<0.001 vs placebo
High Eosinophils Population
Overall population
(2) p<0.01 vs placebo
FEV1=forced expiratory volume over one second
During the treatment period, patients continue their stable medium- or high-dose inhaled corticosteroid and long-acting beta agonist (ICS/LABA)
combination product
This result was based on a pre-specified interim analysis, which occurred when all patients had reached Week 12 of the 24-week treatment period
144
Dupilumab Shows a 64-75% Reduction in Exacerbations
in Phase IIb in Moderate-to-Severe Asthma
Phase IIb: Annualized Rate of Severe Exacerbation Events
0,9
0.9
0,8
0.8
0,7
0.7
0,6
0.6
0,5
0.5
0,4
0.4
(1)
Placebo
(2)
-64%
-67%
(1)
-75%
(3)
-67%
200mg Q2W
300mg Q2W
0.3
0,3
0.2
0,2
0,1
0.1
(1) p<0.05 vs placebo
0
(2) p<0.01 vs placebo
High Eosinophils Population
Overall population
(3) p<0.001 vs placebo
During the treatment period, patients continue their stable medium- or high-dose inhaled corticosteroid and long-acting beta agonist (ICS/LABA)
combination product
This result was based on a pre-specified interim analysis, which occurred when all patients had reached Week 12 of the 24-week treatment period
145
Safety Profile in Moderate-to-Severe Asthma
Phase IIb Study in Moderate-to-Severe Asthma - Safety Data
Infections
Severe AEs
46%
45%
42%
Injection site
reactions
25%
7%
5%
12%
13%
3%
Dupilumab
Placebo
Dupilumab
Placebo
Dupilumab
Placebo
●
Injection site reaction was the most common adverse event and was more frequent with dupilumab
●
Other common adverse events in the study included upper respiratory tract infection, headache,
nasopharyngitis and bronchitis
●
Incidence of infections of serious adverse events was balanced across treatment groups
Phase III start in moderate-to-severe uncontrolled asthma expected in 2015
146
Prevalence of Chronic Sinusitis with Nasal Polyps
Is Estimated at 3% to 5% in EU and the U.S.(1)
Chronic Sinusitis with Nasal Polyps (CSwNP)
● CSwNP causes mucosal inflammation and polyps
in the nasal cavity and sinuses
● Long-term symptoms of nasal obstruction and congestion
● Reduction in or loss of sense of smell
● Facial pain
● Many patients do not respond to intranasal
corticosteroids
● In the U.S. alone, approximately 200,000 CSwNP
patients have sinus surgery(2)
(1) Adapted from White Book on Allergy published in 2011: http://www.worldallergy.org/definingthespecialty/white_book.php
(2) Bhattacharyya 2010 otolaryngology head and neck surgery (2010) 143,147-151
147
147
Dupilumab Delivers Positive Results in PoC Study in Patients
with Nasal Polyposis and Chronic Symptoms of Sinusitis
● Strong efficacy of dupilumab 300mg qw
vs. placebo, on top of Nasonex®
Chronic
Sinusitis
with Nasal
Polyps(3)
● Rapid, clinically and significant reduction
size of nasal polyposis(1)
Nasal Polyp Score (NPS)
Mean change +/- SE
0.5
0.0
-0.5
● Consistent improvement in measures
of sinusitis by CT scan, nasal air flow
and patient-reported symptoms(2)
● Most common AEs were injection site
reactions, nasopharyngitis, oropharyngeal
pain, epistaxis, headache and dizziness
(1) From baseline to week 16 / p<0.0001
(2) Sense of smell, congestion, postnasal drip, runny nose and sleep disturbance
(3) Who do not respond to intra-nasal corticosteroids
-1.0
-1.5
-2.0
Placebo
-2.5
-3.0
Dupilumab
Baseline
4
8
12
16
Week
148
Dupilumab Has the Potential to Change Management
of Patients Severely Affected by Various Allergic Diseases(1)
1● Execute Phase III program in Atopic Dermatitis as first-in-class biologic
2● Design Phase III program in Asthma to potentially position as best-in-class biologic
3● Accelerate development in Chronic Sinusitis with Nasal Polyps
4● Expand development program with new indications
(1) Atopic Dermatitis, Asthma, Nasal Polyposis
149
Agenda
● Elias Zerhouni, MD, President, Global R&D
Sarilumab
Dupilumab
Wrap-up and Q&A Session
150
New R&D Strategy Expected to Continue to Lead to
Innovative New Medicines and Vaccines Reaching Market
Multiple new product launches
underway or imminent
High potential late stage projects
Promising early stage development
pipeline
151
Q&A
152
APPENDICES
R&D Pipeline
153
Late Stage Pipeline – Pharma & Vaccines
Registration
Phase III
LixiLan
alirocumab
lixisenatide + insulin glargine
Fixed-Ratio / Type 2 diabetes
Anti-PCSK-9 mAb
Hypercholesterolemia
Lyxumia® (lixisenatide)
N
GLP-1 agonist
Type 2 diabetes, U.S.
sarilumab
Toujeo® (U300)
Mild-to-severe
dengue fever vaccine
Insulin glargine
Type 1+2 diabetes, U.S., EU
Metastatic prostate cancer (1L)
N
N
Lemtrada® (alemtuzumab)
Clostridium difficile
Jevtana® (cabazitaxel)
Anti-IL4Rα mAb
Atopic dermatitis
patisiran
Kynamro® (mipomersen)
Apolipoprotein B-100 antisense
Severe HeFH, U.S.
Dengue
Toxoid vaccine
Anti-CD52 mAb
Multiple sclerosis, U.S.
Rotavirus
Cerdelga™ (eliglustat tartrate)
Live attenuated tetravalent
Rotavirus oral vaccine
Glucosylceramide synthetase inhibitor
Gaucher disease, EU
N
Anti-IL-6R mAb
Rheumatoid arthritis
dupilumab
N
SYNVISC-ONE®
VaxiGrip® QIV IM
PR5i
Medical device
Pain in hip OA
Quadrivalent inactivated
influenza vaccine
DTP-HepB-Polio-Hib
Pediatric hexavalent vaccine, U.S.
N
N
Fluzone® QIV ID
mRNA inhibitor
Familial amyloid polyneuropathy
Quadrivalent inactivated
influenza vaccine intradermal
Quadracel®
Diphtheria, tetanus, pertussis
& polio vaccine; 4-6 y of age
N
New Molecular Entity
Oncology
Diabetes Solutions
Rare Diseases
Biosurgery
Immune Mediated Diseases
Infectious Diseases
Cardiovascular / Renal
Diseases
Vaccines
Ophthalmology
Age Related Degenerative
Diseases
154
Early Stage Pipeline – Pharma & Vaccines
Phase II
dupilumab
SAR391786
Anti-IL4Rα mAb
Asthma; Nasal polyposis
Anti-GDF8 mAb
Sarcopenia
vatelizumab
Anti-VLA 2 mAb
Multiple sclerosis
SAR156597
N
N
N
N
Combination
Meningitis ACYW conj.
2nd generation meningococcal
conjugate infant vaccine
N
Maytansin-loaded anti-CD19 mAb
B-cell refractory/relapsed malignancies
Tuberculosis
Recombinant subunit vaccine
N
SAR245409 (XL765) / MSC1936369B
RNAi
Familial amyloid cardiomyopathy
Oral dual inhibitor of PI3K & mTOR / pimasertib
Ovarian cancer
Combination
sarilumab
N
ferroquine / OZ439
Anti-IL-6R mAb
Uveitis
fresolimumab
SAR3419
Rabies VRVg
Purified vero rabies vaccine
Anti-CD38 naked mAb
Multiple myeloma
IL4/IL13 Bi-specific mAb
Idiopathic pulmonary fibrosis
SAR438714 (ALN-TTRsc)
SAR650984
N
Antimalarial
Malaria
N
TGFβ antagonist
Focal segmental glomerulosclerosis
N
New Molecular Entity
Oncology
Diabetes Solutions
Rare Diseases
Biosurgery
Immune Mediated Diseases
Infectious Diseases
Cardiovascular / Renal
Diseases
Vaccines
Ophthalmology
Age Related Degenerative
Diseases
155
Early Stage Pipeline – Pharma & Vaccines
Phase I
N
SAR405838 (MI-773)
N
SAR408701
Anti-CEACAM5 ADC
Solid tumors
HDM2 / p53 antagonist
Solid tumors
N
SAR566658
Maytansin-loaded anti-CA6 mAb
Solid tumors
GZ402663 (sFLT-01)
Gene therapy
N
SAR113244
StarGen®
N
SAR252067
UshStat®
Anti-LIGHT mAb
Crohn’s disease
Solid tumors
N
SAR260301
PI3K β selective inhibitor
PTEN – Deficient tumors
SAR228810
N
Anti-ANG2 mAb
Solid tumors
N
SAR245408 (XL147)
SAR425899
N
GZ402665
HSV-2 vaccine
N
N
(rhASM)
Niemann-Pick type B
N
GZ402671
GLP-1 / GCGR agonist
Diabetes
Oral GCS Inhibitor
Fabry Disease
SAR342434
GZ402666
Oral PI3K inhibitor
Solid tumors
Insulin Lispro
Diabetes
neo GAA
Pompe Disease
Combination
SAR438584 (REGN2222)
SAR405838 / MSC1936369B
Herpes Simplex Virus Type 2
Gene therapy
Usher syndrome 1B
Anti-protofibrillar AB mAb
Alzheimer’s disease
SAR307746
N
Gene therapy
Stargardt disease
N
Streptococcus pneumonia
Meningitis & pneumonia vaccine
Age-related macular degeneration (AMD)
Anti-CXCR5 mAb
Systemic lupus erythematosus
SAR125844
C-MET kinase inhibitor
N
N
N
N
anti-RSV-F protein mAb
Respiratory syncytial virus
Solid tumors
N
New Molecular Entity
Oncology
Diabetes Solutions
Rare Diseases
Biosurgery
Immune Mediated Diseases
Infectious Diseases
Cardiovascular / Renal
Diseases
Vaccines
Ophthalmology
Age Related Degenerative
Diseases
156
R&D Pipeline Summary Table(1)
Phase I
Phase II
Phase III
Registration
TOTAL
Oncology
7
3
0
0
10
Diabetes Solutions
1
0
1
1
3
Cardiovascular / Renal
Diseases
0
1
1
0
2
Immune Mediated
Diseases
2
2
2
0
6
Infectious Diseases
1
1
0
0
2
Ophthalmology
3
0
0
0
3
Rare Diseases
3
1
1
1
6
Age Related
Degenerative Diseases
1
1
0
0
2
Vaccines
2
3
4
3
12
20
12
9
5
TOTAL
32
(1) Excluding life cycle management programs
14
34
46
NMEs & Vaccines
157
Expected R&D Milestones
Product
Event
Timing
New Insulin Lispro (SAR342434)
Expected start of Phase III trial in Diabetes
Q4 2014
Praluent™ (alirocumab)
Expected U.S. and EU regulatory submissions in Hypercholesterolemia
Q4 2014
Fluzone® QIV ID
Expected U.S. regulatory decision
Q4 2014
Fluzone® High Dose
Expected U.S. label upgrade
Q4 2014
Cerdelga™ (eliglustat tartrate)
Expected EU regulatory decision in Gaucher disease
Q1 2015
PR5i (DTP-HepB-Polio-Hib)
Expected EU regulatory submission
Q1 2015
Quadracel®
Expected U.S. regulatory decision
Q1 2015
Toujeo® (U300)
Expected U.S. regulatory decision in Diabetes
Q1 2015
Dengue vaccine
Expected regulatory submission in endemic countries
H1 2015
Toujeo® (U300)
Expected EU regulatory decision in Diabetes
Q2 2015
Lyxumia® (lixisenatide)
Expected ELIXA CV outcome trial top-line results
Q2 2015
Dupilumab
Expected start of Phase III trial in Asthma
Q2 2015
158
Expected R&D Milestones (cont’d)
Product
Event
Timing
Praluent™ (alirocumab)
Expected U.S. regulatory decision in Hypercholesterolemia
Q3 2015
PR5i (DTP-HepB-Polio-Hib)
Expected U.S. regulatory decision
Q3 2015
LixiLan
Expected Phase III top line results in Diabetes
Q3 2015
Lyxumia® (lixisenatide)
Expected U.S. regulatory submission in Diabetes
Q3 2015
Sarilumab
Expected Phase III top line results in Rheumatoid Arthritis
H2 2015
Dengue vaccine
Expected regulatory decision in endemic countries
Q4 2015
LixiLan
Expected U.S. and EU regulatory submissions in Diabetes
Q4 2015
Sarilumab
Expected U.S. regulatory submission in Rheumatoid Arthritis
Q4 2015
Lyxumia® (lixisenatide)
Expected U.S. regulatory submission in Diabetes
Q3 2015
159
APPENDICES
Regeneron Agreement
Financial Terms
160
Antibodies Collaboration Agreement with Regeneron
● In November 2007, Sanofi and Regeneron entered into a global collaboration to
discover, develop and commercialize fully human monoclonal antibodies.
● The collaboration is governed by a Discovery and Preclinical Development
Agreement and a License and Collaboration Agreement (each as amended in
November 2009).
● In January 2014, Sanofi and Regeneron agreed to amend and restate the
original investor agreement. The Amended Investor Agreement was amended
to, among other things, provide Sanofi with the right to nominate a single
independent director to the Regeneron Board of Directors upon reaching 20%
ownership of Regeneron's outstanding Share Capital and to extend the term of
the lock-up obligations.
161
Discovery and Development Activities with Regeneron
Discovery activities
● Regeneron leads the antibody discovery activities to identify and validate potential
drug discovery targets and develop fully human monoclonal antibodies against these
targets.
● In return, Sanofi funded $120 million per year for 2007 through 2009 and will fund up
to $160 million per year of Regeneron’s antibody discovery activities from 2010
through 2017
● Sanofi has an option to extend certain antibody development and preclinical activities
for up to an additional three years after 2017.
Development activities
● For each drug candidate identified through discovery research under the discovery
agreement which advances to an IND filing, Sanofi has the option to license rights to
the candidate under the license agreement. If Sanofi elects to do so, Sanofi codevelops the drug candidate with Regeneron through product approval.
● Development costs for the drug candidate are generally funded up front by Sanofi,
except that following receipt of the first positive Phase III trial results for a codeveloped drug candidate, subsequent Phase III trial-related costs for that drug
candidate are funded 80% by Sanofi and 20% by Regeneron.
Accounting treatment in
Sanofi’s income statements
● The discovery fees as well as
the total development costs
for all collaboration antibody
products are booked under
the “Research and
development expenses” P&L
line.
● The reimbursement to be
received from Regeneron for
half of the total development
costs for all collaboration
antibody products will be
booked under the “Research
and development expenses”
P&L line.
● Regeneron is responsible for reimbursing Sanofi for half of the total development
costs for all collaboration antibody products from their share of profits from
commercialization of collaboration products; limited to 10% of their share of profits
from commercialization of collaboration products in any calendar quarter.
162
Commercial Activities with Regeneron
Commercial activities
●
●
●
Sanofi leads commercialization activities for products developed under the license
agreement, subject to Regeneron’s right to copromote such products.
In the event that Regeneron desires to copromote in a particular country,
Regeneron’s copromotion effort shall be between 25% and 50% of the anticipated
total effort.
Sanofi and Regeneron share profits and losses from sales.
● Within the United States, Sanofi and Regeneron share equally profits and
losses.
● Outside the United States, Sanofi and Regeneron share profits on a sliding
scale based on sales starting at 65% (Sanofi) / 35% (Regeneron) and ending
at 55% (Sanofi) / 45% (Regeneron), and share losses at 55% (Sanofi) / 45%
(Regeneron).
●
In addition to profit sharing, Sanofi is required to pay to Regeneron up to $250
million in sales milestone payments, with milestone payments commencing after
aggregate annual sales outside the United States exceed $1.0 billion on a rolling 12month basis.
●
If Sanofi does not exercise its licensing option for an antibody under development,
Sanofi would be entitled to receive a royalty once the antibody begins to be
marketed.
Accounting treatment in
Sanofi’s income statements
● The sales will be booked by
Sanofi solely and the
commercial costs incurred by
Sanofi are booked under the
“Selling and general
expenses” P&L line.
● Regeneron share of net profit
or loss is recognized under
the “Other operating income
and expenses” P&L line.
163
Record of Sanofi Holding in Regeneron
●
Pursuant to the Amended and Restated Investor Agreement, Sanofi has purchased additional
shares of Common Stock to increase its beneficial ownership to approximately 22% of the
Common Stock outstanding.
Accounting treatment in Sanofi’s income statements
●
Sanofi has recorded under the “Share of profits from associates” P&L line its holding in
Regeneron (approximately 22%) accounted for using the equity method since beginning of
April as follows
●
Segment operating result (BOI) includes the share of Regeneron net profit (IFRS restated) before
•
●
acquisition-related effects (workdown of acquired inventories and intangible assets remeasured at
fair value at the acquisition date) and dilution impact due to stock option exercises
Net income additionally includes:
•
Workdown inventory step-up, after tax
•
Amortization intangible step-up, after tax
•
Dilution impact due to stock option exercises
164
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