efficacy and safety of alirocumab in high...
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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.
1
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
2
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
24
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
6
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)
7
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
24
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
15
% (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
16
% (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
18
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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