2014 - ir - alirocumab
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March 31st, 2014
IR Thematic Call on Alirocumab
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Sanofi Forward Looking Statements
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Regeneron Forward Looking Statements
This presentation includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. (“Regeneron” or the “Company”), and actual events or results may differ materially from these forward-looking statements. Words such as “anticipate,” “expect,” “intend,” “plan,” “believe,” “seek,” “estimate,” variations of such words and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of Regeneron's products, product candidates, and research and clinical programs now underway or planned; unforeseen safety issues resulting from the administration of products and product candidates in patients, including serious complications or side effects in connection with the use of Regeneron’s product candidates in clinical trials, including without limitation the Phase 3 ODYSSEY MONO study and the ODYSSEY global Phase 3 trial program for alirocumab; the likelihood and timing of possible regulatory approval and commercial launch of Regeneron's late-stage product candidates and new indications for marketed products, including without limitation alirocumab; ongoing regulatory obligations and oversight impacting Regeneron’s research and clinical programs and business, including those relating to patient privacy; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron's ability to continue to develop or commercialize Regeneron's products and product candidates; competing drugs and product candidates that may be superior to Regeneron's products and product candidates; uncertainties relating to market acceptance, competitive position, and commercial success of Regeneron's products and product candidates, such as alirocumab; the ability of Regeneron to manufacture and manage supply chains for multiple products and product candidates; coverage and reimbursement determinations by third-party payers, including Medicare and Medicaid; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its sales or other financial projections or guidance and changes to the assumptions underlying those projections or guidance; the potential for any license or collaboration agreement, including Regeneron's agreements with Sanofi and Bayer HealthCare, to be cancelled or terminated without any further product success; and risks associated with third party intellectual property and pending or future litigation relating thereto. These statements are made based on management’s current beliefs and judgment, and you are cautioned not to rely on any such statements. In evaluating such statements, shareholders and potential investors should specifically consider the various factors identified under Part I, Item 1A. “Risk Factors” of Regeneron’s Annual Report on Form 10-K for the fiscal year ended December 31, 2013 filed with the Securities and Exchange Commission on February 13, 2014, which could cause actual events and results to differ materially from those indicated by such forward-looking statements. Regeneron does not undertake any obligation to update publicly any forward-looking statement, including without limitation any financial or other projection or guidance, whether as a result of new information, future events, or otherwise.
Agenda
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PCSK9 Inhibitor Potential Market Opportunity ● Robert Terifay, Senior VP, Commercial, Regeneron
Alirocumab Clinical Development
● Jay Edelberg, M.D., Ph.D. VP, Head of the PCSK9 Development & Launch Unit, Sanofi
Q&A Session
● Robert Terifay, Jay Edelberg and Bill Sasiela, VP, Program Direction, Regeneron
PCSK9 INHIBITOR POTENTIAL MARKET OPPORTUNITY
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Robert Terifay
Senior Vice President, Commercial Regeneron
Despite Current Therapies, There Exists a Significant Population of Patients at High Cardiovascular Risk
6
Sources: 1) Universe & population growth = US NHANES & Decision Resources 2012; 2) HeFH: Adult prevalence = 1/500 ; 25% of them are diagnosed, 80% are above 70mg/dl; 3) Statin Intolerant: IPSOS Chart Audit, Sept 2012; 4) High Risk: EVD Analysis, Dec 2012; 5) Diabetes Only: EVD Analysis, Dec 2012
31.9 (EU5)
30.2 (US)
5.8
7.6
11.1
11.0
2.7 7.6
11.1
62.1
Statin Intolerant
Diabetics 0/1 Risk Factor
35.7
Total Population
Adults >70mg/dL On Statins +
Statin Intolerant
21.6 Diabetes + 2 Risk
Factors with or w/o CV events
Secondary Prevention w/o Diabetes
Statin Intolerant High CHD Risk
HeFH (200K)
HeFH (250K)
Patient Flow Projections for 2016 (Million Patients)
US & EU5(1)
Very High CV Risk Increasing CV Risk
57%
Secondary Prevention w/o Diabetes
Diabetes + 2 Risk Factors with or w/o CV events
Very High CV
Risk
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11.0M
11.1M
~22M Diabetes Patients With LDL-C >70 mg/dL on Statins
Projections for 2016 (Million Patients) US & EU5(1)
(1) US (NHANES, OPTUM, IPSOS SI); EU (NHANES, Decision Resources, Cegedim, IPSOS SI) Besides Diabetes and LDL-C: UA, MI, Stroke, PAD, bypass surgery, PCI w/wo stent, diagnostic non-invasive evidence of chronic heart disease such as angiogram, stress echocardiogram or exercise electrocardiogram, chronic kidney disease (CKD), hypertension, retinopathy, neuropathy, microalbuminuria, family history of chronic heart disease (CHD)
Diabetes + 0/1 Risk Factors
Diabetes + 2 Risk Factors
with or w/o CV Events
● 52 year-old male
● Diagnosis: Primary Hypercholesterolemia
● Patient history: Type II diabetes & CHD (stented 2 years ago)
● Current LDL-C: 98mg/dL
● Current treatment: atorvastatin 40mg
Illustrative Example
Diabetics Represent a Significant Portion of The Population Who Are at High Risk
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7.6M Secondary Prevention Patients w/o Diabetes And Not at Goal on Statins
Projections for 2016 (Million Patients) US & EU5(1)
(1) US (NHANES, OPTUM for PAD); EU (NHANES, Cegedim for PAD) PAD = Peripheral arterial diseases ACS = Acute coronary syndrome
Secondary Prevention Patients Are at Higher Risk of Cardiovascular Events
● 58 year-old male
● Diagnosis: Primary Hypercholesterolemia
● Patient history: established coronary heart disease (CHD) and acute coronary syndrome (ACS), hypertension, previous myocardial infarction (MI) at age 46
● Current LDL-C: 140mg/dL
● Current treatment: rosuvastatin 40mg, ezetimibe 10mg
Illustrative Example
44% 31%
16% 9%
7.6M Patients With Very High CV Risk
History of CHD
Diagnosed PAD
History of Stroke
History of ACS
250K
200K
Significant Number of HeFH Patients Remain Undiagnosed or Far From Desired LDL-C Goals
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Heterozygous Familial Hypercholesterolemia (HeFH) Number of patients - Projections for 2016
US & EU5(1)
(1) PijlmanAH et al. Atherosclerosis 209 (2010) 189–194; Ned RM at al. PLOS Currents Evidence on Genomic Tests. 2011 Jul 1. Edition 1. doi: 10.1371/currents.RRN1238, PCK9 team assumptions, Optum & Cegedim
HeFH Patients
750K
Treated HeFH Patients
● 44 year-old female
● Diagnosis: Primary Hypercholesterolemia
● Family history of cardiovascular disease
● Sustained LDL-C >190mg/dL
● Current treatment: simvastatin 40mg, ezetimibe 10mg
Illustrative Example
Diagnosed
Undiagnosed
~80% of treated patients are unable achieve LDL-C goal
A Large Number of Statin-Intolerant Patients Are at High Risk For Cardiovascular Diseases
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3.1M
Statin Intolerant High CHD
Risk
5.8M Patients Intolerant to Statins Projections for 2016 (Million Patients)
US & EU5(1)
(1) US: NHANES, OPTUM, IPSOS SI, EU: NHANES, Decision Resources, Cegedim, IPSOS SI
Statin Intolerant Patients
2.7M
● 58 year-old male
● Diagnosis: Primary Hypercholesterolemia
● Patient history: Myocardial Infarction two years ago
● Current LDL-C: 125mg/dL
● History of statin intolerance: experienced muscle pains with simvastatin 20mg, and recently had upper back and bilateral leg pains with atorvastatin 10mg
● Current treatment: ezetimibe 10mg
Illustrative Example Very High CV
Risk
Lipid-Lowering Market Sales Are ~$30 Billion
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(1) Worldwide MAT sales in €bn of dyslipidemia market, IMS MIDAS (2) Niacin, omega-3 therapies FDC = fixed dose combination
● Statins remain the primary treatment option for high LDL-C
● Many hypercholesterolemic patients not at LDL-C goal with statins ● Patients with LDL-C too high at
maximally tolerated statin dose ● Patients unable to tolerate a
recommended statin dose ● Patients completely statin
intolerant
● Approximately 8 million patients worldwide receive ezetimibe(1) (mono/FDC)
Others(2)
Statins Ezetimibe (mono/FDC)
Fibrates
Lipid-Lowering Agents(1) Worldwide Sales 2013
60%
8% 16%
15%
$30 Billion
Economic Burden From CV Disease Remains Substantial
12 (1) O’Sullivan AK et al. Pharmacoeconomics 2011; 29(8): 693-704
$73,300
$36,000
$71,600
Non-Fatal MI Hospitalizations for Angina
Non-Fatal Hemorrhagic
Stroke
Cost Estimation of Cardiovascular Disease Events in The US(1) Attributable Costs Per Patient Over 36 Months Following Event
Alirocumab: Potential Novel Treatment For Patients at High CV Risk With Unmet Needs
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● Fully human monoclonal antibody against PCSK9
● Binds PCSK9 with high affinity
● Up to 70% LDL-C reduction observed in Phase 2 trial
● Being investigated in a broad Phase 3 program to lower LDL-C and to reduce the risk for CV disease
● Dosing flexibility in terms of dose, titration, and interval
● Patient friendly pen being evaluated in Phase 3
Percent of Physicians Aware of PCSK9 Inhibitor Class And Perceiving New Class as Very or Extremely Innovative
High Awareness of PCSK9 Class Among Cardiologists, Endocrinologists, And Subset of PCPs
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Source: Proprietary survey conducted in U.S. (CARDS=150; ENDOS=152, PCPs=306 and in EU5 (CARDS=379, ENDOS=376, PCPs=379), measured in November-December 2013 Q1: Please name and describe all the potential treatments in development for hypercholesterolemia of which you are aware Q2: In your opinion, how innovative are the following classes of medication (PCSK9 inhibitors, CETP inhibitors and statins)
82%
57%
89%
66%
84%
11%
86%
37%
88%
35%
80%
11%
Innovation of Class
Awareness
Endocrinologists
Primary Care Physicians (PCP) Cardiologists
Percent of Physicians Likely or Very Likely to Prescribe For Treating Hypercholesterolemia
High Likelihood to Prescribe a Self Injectable Treatment or a Monoclonal Antibody Treatment
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Source: Proprietary survey conducted in U.S. (CARDS=150; ENDOS=152, PCPs=306 and in EU5 (CARDS=379, ENDOS=376, PCPs=379), measured in November-December 2013 Q1: Based on your experiences and anything you might have heard, how likely would you be to prescribe a self-injected subcutaneous treatment for hypercholesterolemia, if available in the future? Q2: Based on your experiences and anything you might have heard, how likely would you be to prescribe a monoclonal antibody for the treatment of hypercholesterolemia, if available in the future?
52%
52%
51%
53%
27%
29%
40%
50%
41%
48%
29%
31%
Monoclonal Antibody Treatment
Self Injectable Treatment
Endocrinologists
Primary Care Physicians (PCP) Cardiologists
Market Development Activities Underway: Unbranded Education And Awareness Campaigns
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“Looming Threat” of Unmet Need
PCSK9 Role in LDL-C Metabolism
ALIROCUMAB CLINICAL DEVELOPMENT
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Jay Edelberg, M.D., Ph.D.
Vice President, Head of the PCSK9 Development & Launch Unit Sanofi
Blocking PCSK9 Lowers LDL-C Levels
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Sources: (1) Tibolla G et al. Nutr Metab Cardiovasc Dis 2011;21:835-43. (2) Akram ON et al. Arterioscler Thromb Vasc Biol 2010;30:1279-81. (3) Duff CJ et al. Expert Opin Ther Targets 2011;15:157-68. (4) Horton JD et al. J Lipid Res 2009;50 Suppl:S172-7. (5) Cariou B et al. Atherosclerosis 2011;216:258-65.
Key Differentiating Features of The Phase 3 Alirocumab ODYSSEY Program
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● 14 studies with primary endpoint evaluated at 24 weeks
● Double-blind for 6, 12, 18, and 24 months
● Solid long-term double-blind exposure (≥5,000 patient years) at completion of studies ● This will allow for a robust characterization of safety and efficacy prior to the data of
ODYSSEY OUTCOMES
● Dosing flexibility ● Q2W and Q4W dosing regimens ● 75mg and 150mg doses ● Up-titration “treat to target” approach provides physicians the ability to tailor therapy
to suit individual patient needs
● Several key patient populations studied ● Patients with HeFH (largest cohort of such patients) ● Hypercholesterolemic patients at high CV risk and poorly controlled LDL-C
despite standard of care treatment ● First PCSK9 Phase 3 trial in statin intolerant patients with a re-challenge arm
Phase 3 Program
(1) Q2W = Every two weeks dosing (2) Q4W = Every four weeks dosing
ODYSSEY Phase 3 Clinical Trial Program: 14 Studies Including More Than 23,500 Patients
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Statin Intolerant
High CV Risk Recent CV Event
Patients receiving statins
Patients not receiving statins
HeFH FH I (n=471) FH II (n= 250) HIGH FH (n=105)
OLE (Open-Label Extension, n≥1,000)
High CV Risk MI, Stroke, T2D, CKD
COMBO I (n=306) COMBO II (n=660)
OPTIONS I (n=350) OPTIONS II (n=300)
CHOICE I (n=700, 300mg Q4W) LONG TERM(1) (n=2,100)
OUTCOMES (n=18,000)
Monotherapy
CHOICE II(2) (n=200, 150mg Q4W)
MONO (n=100)
ALTERNATIVE (n=250)
Except CHOICE I & II, all studies are investigating Q2W regimens: a dose titration scheme (75mg up-titrated to 150mg, based on LDL-C levels at Week 12) or a continuous treatment with 150mg for patients with LDL-C >160mg/dL (HIGH FH) n = Target enrollment (except for ODYSSEY MONO for which results are already reported). Chronic Kidney Disease (CKD) (1) LONG TERM includes a subset of FH patients (2) CHOICE II includes some patients on additional non-statin lipid-lowering therapy
Lipid-Lowering Trials: Double-Blind for 6, 12, 18, and 24 Months(1)
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Double-Blinded Efficacy and Safety Evaluation
Solid long-term double-blind exposure data (≥5,000 patient years) at completion of studies
MONO (n=100) OPTIONS I (n=350) OPTIONS II (n=300) CHOICE II (n=200)
24 Weeks
COMBO I (n=306) CHOICE I (n=700)
52 Weeks
COMBO II (n=660) 104 Weeks
FH I (n=471) FH II (n= 250) HIGH FH (n=105) ALTERNATIVE (n=250) LONG TERM (n=2,100)
78 Weeks
(1) Does not include ODYSSEY OUTCOMES (event-driven) and ODYSSEY OLE (open label safety study; up to 120 weeks), ODYSSEY ALTERNATIVE will have an indefinite open label extension
Primary Endpoint Evaluation at Week 24
ODYSSEY Program Evaluates Multiple Options to Personalize Dosing Regimen
● Q2W dosing ● 75mg Q2W as the starting dose
• Possibility to titrate up to 150mg Q2W if needed
● Alternatively, 150mg Q2W as a starting dose for patients with high baseline LDL-C
● Q4W dosing ● 150mg Q4W for patients not
receiving statins ● 300mg Q4W for patients receiving
statins
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Flexible Model
Baseline LDL-C Values
Patient CV Risk Profile
Background Lipid-
Lowering Therapy
Patient Preference
Looking to Flexible Dosing Based on Patient Needs
Dosing Regimens Evaluated in Phase 3
ODYSSEY MONO(1): ~50% LDL-C Reduction Achieved With 75mg Q2W at 12 Weeks; Sustained Over 24 Weeks
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LDL-C % Change From Baseline
-70
-60
-50
-40
-30
-20
-10
00 4 8 12 16 20 24
Alirocumab 75/150mg Q2W 86% of patients stayed on 75mg from W12 to W24
Week
–20.4% –17.2%
–53.2% –54.1%
Difference vs. ezetimibe: -36.9%. P<0.0001
Ezetimibe 10mg QD
● Percent of patients reporting TEAEs
● 78.4% with ezetimibe
● 69.2% with alirocumab
● Most common class of AEs
● Infections (39.2% with ezetimibe vs. 42.3% with alirocumab), included nasopharyngitis, influenza, and upper respiratory tract infection
● Injection-site reactions in <2% of patients in both groups
● Muscle-related adverse events (3.9% patients treated with ezetimibe vs. 3.8% with alirocumab)
(1) Roth et al. 2014 ACC Abstract #1183/125 TEAEs = Treatment-emergent adverse events
Up-titration if needed
Clinical Study Supports 150mg Q4W Dosing in Patients Not on Statins ~48% LDL-C Reduction Maintained Over 28-Day Dosing Interval(1)
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(1) Rey et al. 2014 ACC Abstract #1183/131 (2) Patients received placebo, ezetimibe or fenofibrate alone (w/o alirocumab)
-70
-60
-50
-40
-30
-20
-10
0
10
-29 -1 8 15 22 29 57 64 71 78 85 99 120
Alirocumab sc Study Day
Alirocumab 150mg Q4W - Alirocumab + placebo (N=24) - Alirocumab + ezetimibe (N=24) - Alirocumab + fenofibrate (N=24)
Run-in(2) Follow-up(2)
4 W 4 W 4 W
LDL-
C %
Cha
nge
from
D-2
9 B
asel
ine
● Patient-friendly single-use, disposable pen being evaluated ● Small injection volume of 1ml (75 or 150mg) ● Allows quick injection ● Interchangeably injected in the abdomen, upper arm, or thigh(1) ● >90% compliance in Phase 2 open label extension(2)
Delivery Options Evaluated in ODYSSEY Program
25 (1) Lunven et al. 2014 ACC Abstract #1183/132 (2) Stein et al. 2014 ACC Abstract #1183/126
Both options have been included in studies intended for registration
Option 1
● Ready-to-use pre-filled syringe ● Small injection volume of 1ml (75 or 150mg) ● Self-injection at home in clinical studies
Option 2
Alirocumab Generally Well Tolerated in Completed Studies(1)
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● DMC for the lipid program and DMC for the CV outcome trial
● DMCs meet every 3 months to review unblinded data
● Safety assessment includes ● Injection site reactions ● Immunogenicity ● Hypersensitivity reactions ● Neurocognitive disorders
● DMC review of Phase 3 and CVOT data (March 2014) detected no signal for neurocognitive adverse events
● Injection site reactions
● Diarrhea
● Fatigue
● Headache
● All above events were of mild intensity
Most Frequent TEAEs From Pooled Phase 2 Studies
ODYSSEY Program Overseen by Two Data Monitoring Committees (DMC)
(1) Three Phase 2 studies ( Stein EA et al. Lancet 2012;380:29-36; McKenneyJM et al. J Am Coll Cardiol 2012;59:2344-53; Roth EM, N Engl J Med 2012;367:1891-900) and ODYSSEY MONO (Roth et al. 2014 ACC Abstract #1183/125)
ODYSSEY OUTCOMES: Large CV Outcomes Trial Initiated in November 2012
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(1) High intensity statin therapy include atorvastatin 40/80mg or rosuvastatin 20/40mg (2) Patients can also qualify with apoB>80mg/dL or non-HDL-C > 100 mg/dL (3) Primary endpoint is a composite endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), fatal and non-fatal ischemic stroke, and unstable angina requiring hospitalization
N=9,000
Run-in period Randomization must be
4-52 weeks after index event
Screening visit: Initiate high dose statin therapy(1)
Double-blind treatment period (minimum of 2 years)
Qualifying visit: LDL-C must be >70mg/dl(2)
R
Patients with recent ACS
>40 years of age
Alirocumab 75mg SC Q2W Up-titration at Week 12 if needed
Placebo SC Q2W
N=9,000 Primary
Endpoint(3)
A composite of major CV endpoints
+ Diet (NCEP ATP III TLC or equivalent diet) Continued high dose statin
49 countries/ 1,110 sites expected to participate
Primary Endpoint(3)
A composite of major CV endpoints
Q&A
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