Efficacy and Safety of Alirocumab in High Cardiovascular Risk Patients with Suboptimally

Controlled Hypercholesterolemia on Maximally Tolerated Doses of Statins:

The ODYSSEY COMBO I Study

Dean J. Kereiakes1, Jennifer G. Robinson2, Christopher P. Cannon3, Christelle Lorenzato4, Robert Pordy5, Umesh Chaudhari6,

Helen M. Colhoun7

1The Christ Hospital, Heart and Vascular Center/The Lindner Research Center, Cincinnati, OH, USA; 2University of Iowa, Iowa City, IA, USA; 3Harvard Clinical Research Institute, Boston, MA, USA; 4Sanofi, Chilly-Mazarin, France; 5Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 6Sanofi, Bridgewater, NJ, USA; 7University of Dundee, Dundee,

Scotland, UK

This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.

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Primary objective:– Evaluate reduction of LDL-C by alirocumab as add-on to stable maximally

tolerated statin therapy with or without other lipid lowering therapy (LLT) vs placebo after 24 weeks of treatment in high CV risk patients with hypercholesterolemia (ITT analysis)

Secondary objectives include:– Effect of alirocumab 75mg vs placebo on LDL-C after 12 weeks– Effect of alirocumab on other lipid parameters

(Apo B, non-HDL-C, Total-C, Lp (a),HDL-C, TG, and Apo A-1 levels)– Long-term effect of alirocumab on LDL-C– Safety and tolerability of alirocumab– Assessment of possible development of anti-alirocumab antibodies (ADAs)

Methodology:– Multicenter, double-blind, placebo-controlled, parallel group, randomized

(2:1 alirocumab vs. placebo) trial – 45 subjects provide 95% power to detect 30% change in LDL-C from

baseline (0.05 2-sided significance level; assumes common SD of 25%)– 316 subjects randomized to accommodate dropout (estimate 30% at 1 year)

and provide greater safety data

ODYSSEY COMBO I

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ODYSSEY COMBO I: Study Design

Clinicaltrials.gov identifier: NCT01644175**Stratified by Hx MI or ischemic stroke, intensity of statin Rx (high vs not high)

Double-blind treatment period (52 weeks)

High CV risk on maximally tolerated statin ± other LLT

I. LDL-C ≥70 mg/dL(manifest CVD)

orII. LDL-C ≥100 mg/dL

(DM+Other Risk Factors/CKD)

R**

N=209

N=107

AssessmentsW0

W4 W8

W12

W16

W24 W36 W52

Primary endpoint

W60

Dose ↑ if LDL-C ≥70 mg/dL

at W8

Follow-up(8 weeks)

Alirocumab 75 mg with potential ↑ to 150 mg Q2W SC (single 1 mL injection using prefilled pen for self-administration)

Placebo Q2W SC

End of treatment visit

3

All patients on background maximally tolerated statin ±other LLT

Alirocumab (N=209)

Placebo(N=107)

P-value vs placebo†

Age, years, mean (SD) 63.0 (9.5) 63.0 (8.8) 0.77

Male, % (n) 62.7% (131) 72.0% (77) 0.11

Race, white, % (n) 81.3% (170) 82.2% (88) 0.61

BMI, kg/m2, mean (SD) 32.6 (6.3) 32.0 (7.1) 0.23

CHD history, % (n) 78.5% (164) 77.6% (83) 0.97

Hypertension, % (n) 88.5% (185) 88.8% (95) 0.91

Type 2 diabetes, % (n) 45.0% (94) 39.3% (42) 0.39

Baseline Characteristics

†p-values comparing baseline data between treatment groups are provided for descriptive purpose, as a screening tool, using Fisher exact test for qualitative data and the asymptotic one-way ANOVA test for Wilcoxon scores (Kruskal-Wallis test) for continuous data.4

Any statin†,% (n) 99.5% (208) 100% (107) 1.00High dose statin at screening††, % (n) 61.7% (129) 64.5% (69) 0.71Other LLT‡, % (n) 38.3% (80) 49.5% (53) 0.07

Ezetimibe, % (n) 7.2% (15) 10.3% (11) 0.46

All patients on background maximally tolerated statin ± other LLT

Alirocumab (N=209)

Placebo(N=107)

P-value vs placebo*

*p-values comparing baseline data between treatment groups are provided for descriptive purpose. †Patients should receive either rosuvastatin 20–40 mg, atorvastatin 40–80 mg daily, or simvastatin 80 mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the investigator. †† High dose statin: atorvastatin 40–80 mg or rosuvastatin 20–40 mg or simvastatin 80 mg daily. ‡LLT: bile acid sequestrant, cholesterol absorption inhibitor [ezetimibe], niacin, fenofibrate, omega 3 >1000 mg/d, stable nutraceuticals. ‡‡LDL-C measured by beta-quantification for 138 alirocumab-treated and 70 placebo-treated patients.

Lipid Medication and Lipid Levels at Baseline

LDL-C, calculated, mean (SD), mg/dL 100.2 (29.5) 106.0 (35.3) 0.42Median (Q1:Q3) 98.0 (81.0:114.0) 97.0 (86.0:120.0)

Non-HDL-C, mean (SD), mg/dL 130.0 (34.0) 133.4 (39.8) 0.72Apo B, mean (SD), mg/dL 90.8 (21.4) 91.4 (24.1) 0.98Lp(a), median (Q1:Q3, mg/dL) 31.0 (8:81) 38.0 (10:70) 0.70Fasting TGs, median (Q1:Q3), mg/dL 130.0 (92:189) 123.0 (95:177) 0.57HDL-C, mean (SD), mg/dL 48.3 (14.4) 48.8 (12.7) 0.46

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LS m

ean

(SE)

% c

hang

e fr

om

base

line

to W

eek

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LS mean % difference (SE) vs placebo:

All patients on background of maximally tolerated statin ± other LLT

Placebo

Alirocumab

−45.9 (3.3)* −49.9 (3.2)*

ITT On-treatment analysisn=204 n=105n=205 n=106

Primary Endpoint Analysis: % Reduction in LDL-Cfrom Baseline to Week 24 (vs Placebo)

*P<0.0001

16.8% received 150 mg Q2W at

W12

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LDL-

C, L

S m

ean

(SE)

, mg/

dL

All patients on background of maximally tolerated statin ± other LLT

Placebo (n = 106)

Week

97.8 mg/dL

51.4 mg/dL

Alirocumab (n = 205)

99.9 mg/dL

57.2 mg/dL

ITT analysis.

Per-protocol dose increase (n=32, 16.8%)

−2.3%

−48.2%

+0.5%

−42.5%

LDL-C Levels Over Time by Treatment (ITT)

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Dose increase to alirocumab 150 mg Q2W at Week 12 (n = 32)Dose of alirocumab 75 mg Q2W throughout (n = 159)

Mea

n (S

D)

calc

ulat

ed L

DL-

C, m

g/dL

–50%

–25%

–42%

–52% –50%–43%

Per protocol dose increase (n=32 ; 16.8%)

ITT analysis; % values indicated at Weeks 12, 24 and 52 show % change from baseline.

Week

LDL-C Levels Over Time for Alirocumab-treated Patients with/without Dose Increase at Week 12 (ITT)

Proportion of High CV Risk Patients Achieving LDL-C <70 mg/dL at Week 24

% p

atie

nts Placebo

Alirocumab

All patients on background of maximally tolerated statin ± other LLT

*P<0.0001

ITT* On Treatment Analysis*

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Secondary Endpoints: % Reduction from Baseline to Week 24 in Other Lipid Parameters

Apo B

Placebo + max tolerated statin ± LLTAlirocumab + max tolerated statin ± LLT

−37.5 (3.1)*

Non-HDL-C

LS m

ean

(SE)

% c

hang

e fr

om

base

line

to W

eek

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Adjusted mean (SE) shown for Lp(a)

Lp(a)

−35.8 (2.8)* −14.6 (3.4)*LS mean %difference (SE) vs placebo:

Apo BNon-HDL-C Lp(a)

−40.4 (3.0)* −37.5 (2.8)* −17.3 (3.6)*

ITT On-treatment analysis

-39.1%-36.7%

-40.9%

-22.0%

-37.9%

-4.7%

-0.4%-0.5%

-5.9%

-0.9%-1.6%

*P<0.000110

Safety AnalysisIncluding All Data Collected Until Last Patient Visit at Week 52

% (n) of patientsAll patients on background maximally tolerated statin ± other LLT

Alirocumab (N=207)

Placebo(N=107)

TEAEs 75.8% (157) 75.7% (81)

Treatment-emergent SAEs 12.6% (26) 13.1% (14)

TEAE leading to death* 1.0% (2) 2.8% (3)

TEAEs leading to discontinuation 6.3% (13) 7.5% (8)

Adverse Events of Interest

Injection-site reactions 5.3% (11) 2.8% (3)

Adjudicated CV events 2.9% (6) 2.8% (3)

Neurocognitive disorders 0 0.9% (1)

ALT >3 x ULN 1.5% (3/206) 0.9% (1/106)

Creatine kinase >3 x ULN 2.0% (4/205) 4.9% (5/103)

*The two deaths occurring during treatment with alirocumab were due to myocardial infarction and pulmonary embolism. Three deaths in the placebo group were due to sudden cardiac death, esophageal adenocarcinoma and dementia11

18 patients (of the total 296 evaluable patients administered placebo or alirocumab; 6.1% ) were positive in the ADA assay

5 patients randomized to alirocumab (3/197; 1.5%) or placebo (2/99; 2.0%) exhibited positive responses in the ADA assay at baseline

Treatment-emergent and low titer assay positivity was observed in 13/197 (6.6%) alirocumab-treated patients– In seven of these patients, the responses were transient and

resolved despite continued alirocumab treatment 4 of the 13 alirocumab-treated patients positive in the ADA assay

were positive in the neutralizing antibody assay; each of these resolved (became negative) within 24 weeks

The median time to detection of antibodies to alirocumab was 12 weeks

The presence of anti-alirocumab antibodies had no observed effect on safety and efficacy

Anti-Alirocumab Antibodies

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In high CV risk patients with suboptimally controlled LDL-C on maximally tolerated statin therapy with or without other LLT:– Self-administered alirocumab significantly reduced LDL-C

from baseline at W24 (48% vs. 2% placebo; P<0.0001)• LDL-C reduction was maintained through 52 weeks

– The ‘treat-to-target’ approach with alirocumab resulted in:• 83% patients not requiring a dose ↑ to 150 mg (W12)• 75 -77.5% patients achieving LDL-C <70 mg/dL at W24

– TEAEs were generally comparable between alirocumab and placebo arms

– ODYSSEY COMBO I suggests safety and efficacy of a 75mg/150mg Q2W alirocumab treatment algorithm

ODYSSEY COMBO IConclusions

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Thank You to All Principal Investigators!

USA 76 sites

Lawrence Alwine (Dowingtown, PA), Nabil Andrawis (Manassas, VA); Eddie Armas (Hialeah, FL); John Bertsch (Willoughby Hills, OH); William Bestermann (Kingsport, TN); Bradley Block (Oviedo, FL); Cynthia Bowman-Stroud (Paducah, KY); Patricia Buchanan (Eugene, OR);

William Byars (Greer, SC); Christopher Case (Jefferson City, MO); Richard Cherlin (Los Gatos, CA); Bertrand Cole (Newington, NH); Andrew Cox (Norman, OK); Charles Dahl (Orem, UT); Matthew Davis (Rochester, NY); Pratik Desai (Cary, NC); Larry Dobkin (Pittsburgh, PA); Timothy Dow (Jonesboro, AR); Daniel Duprez (Minneapolis, MN); Mitchell Feller (Mount Pleasant, SC); Raul Gaona,Sr. (San Antonio,

TX); Jeffrey Geohas (Evanston, IL); William Graettinger (Sparks, NV); Alan Graff (Ft. Lauderdale, FL); Terry Haas (Vista, CA); Yehuda Handelsman (Tarzana, CA); David Headley (Port Gibson, MS); Laura Helman (Mishawaka, IN); Donald Hurley (Charleston, SC); Giovanni

Infusino (Chicago, IL); Rebecca Jordan (Sacramento, CA); Dean Kereiakes (Cincinnati, OH); Stanley Koch (Morton, IL); James Kopp (Anderson, SC); Larry Kotek (Edina, MN); Michael Ledet (Mobile, AL); Steven Leichter (Columbus, GA); Andrew Lewin (Los Angeles, CA);

Tad Lowdermilk (Winston-Salem, NC); Sean Lynd (Cincinnati, OH); Abe Marcadis (Palm Beach, FL); Sashi Makam (New Windsor, NY); Mustafa Mandviwala (Tomball, TX); Carolyn Maldonado-Garcia (Boca Raton, FL); Gregory McCarroll (San Antonio, TX); Michael McCartney

(Methuen, MA); Barry McLean (Homewood, AL); Randall Miller (Eunice, LA); Minesh Patel (Michigan City, IN); Naynesh Patel (Kettering, OH); Marina Raikhel (Lomita, CA); Jackson Rhudy (Salt Lake City, UT); Jeffrey Rosen (Coral Gables, FL); Milroy Samuel (Columbus, OH); Jon Shapiro (Philadelphia, PA); Teresa Sligh (Burbank, CA); Phillip Toth (Indianapolis, IN); Pamela Tuck (Montgomery, AL); Ramon Vargas

(New Orleans, LA); Krishnamoorthy Vivekananthan (Houston, TX); Ralph Wade (Bountiful, UT); Franklin Wefald (Smithfield, NC); Debra Weinstein (Boynton Beach, FL); Alexander White (Port Orange, FL); Jonathan Wilson (Winstom Salem, NC).

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Treatment during the studyAll patients on background of maximally tolerated statin ± other LLT

*>80% scheduled injections; **12 months double-blind treatment (>50 weeks exposure and visit W52 performed)***Among patients with ≥1 injection after W12; uptitration based on LDL-C on W8 visit if LDL-C≥70mg/dL

Placebo

Alirocumab

n=32

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% (n) of patientsAll patients on background of maximally tolerated statin ±other LLT

ODYSSEY COMBO IPooled alirocumab

Phase 2/3 placebo-controlled studies

Alirocumab(N=207)

Placebo(N=107)

Alirocumab (N=2476)

Placebo (N=1276)

TEAEs 75.8% 75.7% 75.8% 76.4%Treatment-emergent SAEs 12.6% 13.1% 13.7% 14.3%TEAEs leading to death 1.0% 2.8% 0.5% 0.9%TEAEs leading to discontinuation 6.3% 7.5% 5.3% 5.1%

Safety Analysis vs Pooled Data from Placebo-Controlled Studies

Safety analysis from double-blind treatment period

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% (n) of patientsAll patients on background maximally tolerated statin ± other LLT

Alirocumab (N=207)

Placebo(N=107)

Upper respiratory tract infection 7.7% (16) 10.3% (11)

Nasopharyngitis 7.2% (15) 4.7% (5)

Urinary tract infection 6.3% (13) 3.7% (4)

Dizziness 5.3% (11) 5.6% (6)

Sinusitis 5.3% (11) 3.7% (4)

Injection-site reaction 5.3% (11) 2.8% (3)

Arthralgia 3.9% (8) 7.5% (8)

Non-cardiac chest pain 1.0% (2) 6.5% (7)

Safety Analysis TEAEs Occurring in ≥5% of Either Alirocumab or Placebo Patients

Statistical analyses have not been performed. 17

Subgroup n LS mean difference(95% CI)

Interaction p-value

Overall 311 -45.9 (-52.5 to -39.3)Race 0.1859

White 255 -47.9 (-55.1 to -40.8)Black/African American 50 -35.9 (-52.4 to -19.4)

Gender 0.9126Male 205 -46.2 (-54.2 to -38.3)Female 106 -47.0 (-58.7 to -35.3)

Age 0.2044<65 182 -41.5 (-50.1 to -32.9)65 to <75 98 -54.5 (-65.9 to -43.1)≥75 31 -46.5 (-68.6 to -24.4)

Ethnicity 0.0928Not Hispanic/Latino 277 -47.4 (-54.2 to -40.5)Hispanic/Latino 34 -28.1 (-49.6 to -6.6)

BMI 0.2437<30 125 -51.2 (-61.3 to -41.1)≥30 185 -43.4 (-51.9 to -34.8)

Differences vs placebo for % change from baseline in LDL-C at Week 24 by demographic characteristics – ITT analysis

LS mean difference vs. placebo (95% CI)

All patients on background of maximally tolerated statin ± other LLT

Line

of n

o ef

fect

Favors alirocumab

Favors placebo

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Favors placebo

Subgroup n LS mean difference(95% CI)

Interaction p-value

Overall 311 -45.9 (-52.5 to -39.3)Statin treatment 0.8039

High-intensity statin* 183 -46.6 (-55.2 to -38.0No high-intensity statin 128 -44.9 (-55.1 to -34.7)

Other LLT at randomization 0.0122Statin with other LLT 129 -55.1 (-64.9 to -45.2)Statin without other LLT 182 -37.9 (-46.9 to -28.9)

History of MI or ischemic stroke 0.0183Prior history MI or stroke 178 -52.8 (-61.4 to -44.1)No prior MI or stroke 133 -36.9 (-46.8 to -27.0)

Moderate CKD at randomization 0.2207Moderate CKD 60 -37.9 (-52.2 to -23.7)No moderate CKD 251 -48.0 (-55.4 to -40.5)

Diabetes at randomization 0.0841Diabetes 135 -39.6 (-49.7 to -29.5)No diabetes 176 -51.3 (-59.8 to -42.7)

Differences vs placebo for % change from baseline in LDL-C at Week 24 by subgroup – ITT analysis

*High-intensity statin: atorvastatin 40–80 mg or rosuvastatin 20–40 mg dailyLS mean difference vs. placebo (95% CI)

All patients on background of maximally tolerated statin ± other LLT

Line

of n

o ef

fect

Favors alirocumab

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