27ISSN 1479-6678Future Cardiol. (2015) 11(1), 27–37

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10.2217/FCA.14.82 © 2015 Future Medicine Ltd

CliniCal Trial reporT

ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks

Eli M Roth*,1 & James M McKenney2

1University of Cincinnati & Sterling Research Group, 375 Glensprings Drive, 2nd Floor, Cincinnati, OH 45246, USA 2Virginia Commonwealth University & National Clinical Research, Inc., 2809 Emerywood Parkway, Suite 140, Richmond, VA 23294, USA

*Author for correspondence: Tel.: +1 513 671 8080; Fax: +1 513 671 8090; eroth@sterlingresearch.org

January2015January 2015

AbstrAct Alirocumab is a fully human monoclonal antibody to PCSK9. The ODYSSEY MONO study was the first alirocumab Phase III study to test a previously unused dose of 75 mg subcutaneously every 2 weeks in a population on no lipid-lowering therapy. A total of 103 patients were randomly assigned to alirocumab starting at 75 mg subcutaneously every 2 weeks or ezetimibe 10 mg per os every day with alirocumab dose uptitration at 12 weeks based on achieved LDL-cholesterol level at week 8 and followed to week 24. At the week-24 primary end point, the alirocumab intent-to-treat group showed a 47.2% (least square [LS] mean) reduction in LDL-cholesterol compared with a 15.6% (LS mean) reduction with ezetimibe (LS mean difference of 31.6%; p < 0.0001). Safety parameters and adverse events were similar between the two groups.

Keywords • alirocumab • ezetimibe • hypercholesterolemia • LDL-C • PCSK9 • SAR236553/REGN727

LDL-cholesterol (LDL-C) is considered to be a major modifiable risk factor for the development of atherosclerosis and cardiovascular disease (CVD) [1], the leading cause of death worldwide [2]. LDL-C is identified as the primary target of cholesterol-lowering therapy by North American [3,4] and European [5] guidelines. Statins are the recommended first-line therapy for lowering LDL-C. Despite LDL-C-lowering therapies, there are still many patients who cannot achieve a LDL-C level low enough to optimally prevent primary or recurrent cardiovascular (CV) events [6]. In addition, there is currently a greater recognition of the prevalence of heterozygous familial hypercholester-olemia as the most common genetic disorder in humans, and new data suggest an actual occurrence of approximately 1:200, suggesting a US adult population of 1 million and worldwide estimates of 14–34 million [7]. There is a need for additional lipid-lowering therapies (LLT) that can be used with a statin or instead of a statin for those who cannot tolerate statin therapy at any dose [8].

PCSK9 was first reported to have a significant role in the regulation of LDL-C in 2003 [9,10]. LDL receptors (LDLr) typically bind an LDL particle, become internalized and then return to the cell surface after releasing the LDL particle to a lysosome for degradation. This LDLr recycling is esti-mated to occur over 100 times per LDLr [11]. PCSK9 binds to the LDLr and prevents LDLr recycling by preventing release of the LDL particle, causing degradation of both the LDL particle and LDLr. Inhibiting PCSK9 causes increased LDLr numbers because of increased recycling and decreased destruction, with a resultant decrease in LDL-C. Several monoclonal antibodies (mAbs) to PCSK9 have now entered Phase III testing and promising Phase I and II results have been reported [12].

Alirocumab (formerly SAR236553/REGN727) is a fully human mAb to PCSK9 being developed jointly by Sanofi (France) and Regeneron (NY, USA). Phase I and II studies have been completed and previously described [13–16]. The Phase II studies utilized 150 mg of alirocumab as the most common dose and provided limited data in patients not receiving statin therapy. Computer modeling based on Phase II

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Treatment period (24 weeks)Follow-up period

(8 weeks)

n = 50

n = 50

Alirocumab 75 mg Q2W + placebo EZE daily

Alirocumab placebo Q2W + EZE 10 mg daily

Alirocumab 75 or 150 mg Q2W + placebo EZE daily

Up-titration ifLDL-C at W8 ≥70 mg/dl

R

W-2 W-1 W0 W4 W8 W12 W16 W24 W32

Primary end pointEOT visit

Randomization

Due to an error in IVRS, uptitration at week 12 occurred if LDL-C at W8 was ≥70 mg/dl not the protocol specified ≥100 mg/dl)

Diet (NCEP-ATPIII therapeutic lifestlye changes or equivalent diet)

Screening periodup to 2 weeks

Screeningvisit

Injectiontraining

visit

Figure 1. Study protocol. Due to an error in the interactive voice responsive system, uptitration at week 12 occurred if LDL-C at W8 was ≥70 mg/dl, not the protocol-specified ≥100 mg/dl. EOT: End of treatment; EZE: Ezetimibe; LDL-C: LDL-cholesterol, NCEP-ATP III: National Cholesterol Education Program Adult Treatment Panel III; Q2W: Every 2 weeks; R: Randomization; W: Week. Adapted with permission from [18].

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data suggested that a 75-mg dose of alirocumab subcutaneously (sc.) every 2 weeks (Q2W) should yield an approximate 50% reduction in LDL-C as a monotherapy [17]. The first completed Phase III study, entitled ODYSSEY MONO, tested the new lower 75-mg dose of alirocumab sc. Q2W as a monotherapy versus ezetimibe 10 mg per os (po.) every day (q.d.) as a control [18].

Study designODYSSEY MONO was a randomized, dou-ble-blind, double-dummy, active-controlled (ezetimibe), parallel-group study to investi-gate the efficacy and safety of alirocumab over 24 weeks in 100 patients with hypercholester-olemia on no LLT. Inclusion criteria included patients with an LDL-C between 100 mg/dl (≥2.6 mmol/l) and 190 mg/dl (<4.9 mmol/l; inclusive) and not on LLT. In addition, patients needed to have moderate CV risk defined as a 10-year risk of fatal CV events ≥1% and <5% based on the European Systematic Coronary Risk Estimation (SCORE) [19]. Key exclu-sion criteria were established coronary heart

disease or coronary heart disease risk equiva-lents defined as manifestations of noncoronary forms of atherosclerotic disease (peripheral arte-rial disease, abdominal aortic aneurysm and carotid artery disease), use of any LLT within 4 weeks or a fibrate within 6 weeks of the screen-ing visit, fasting serum triglycerides >400 mg/dl (>4.52 mmol/l) during the screening period and systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening (week -2) or randomization (week 0) visits [18].

Institutional Review Boards or Ethics Boards approved the study protocol at all participating research sites. The study complied with the International Conference on Harmonization Good Clinical Practice Guidelines and all appli-cable local regulations. All patients provided written informed consent.

Patients were randomized in a 1:1 ratio to alirocumab 75 mg sc. Q2W plus ezetimibe pla-cebo po. q.d. (alirocumab group) or alirocumab placebo sc. Q2W plus ezetimibe 10 mg po. q.d. (ezetimibe group). The alirocumab dosing was continued from week 0 through to week

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Figure 2. least square mean lDl-cholesterol values for weeks 0–24. ITT: Intent to treat; LS: Least square; Q2W: Every 2 weeks; SE: Standard error.

242016

Week12840

0

20

40

LS

mea

n (

SE

) L

DL-

C, m

g/d

l

60

80

100

120

140

160

ITT: -19.2 (2.6)%

ITT: -48.1 (2.6)%

ITT Alirocumab 75/150 mg Q2W

ITT Ezetimibe 10 mg QD

ITT: -15.6 (3.1)%

ITT: -47.2 (3.0)%

Difference vs ezetimibeITT: -31.6 (4.32) %p < 0.0001

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24 unless the week-8 LDL-C was ≥100 mg/dl (≥2.5 mmol/l), in which case the alirocumab dose was to be increased to 150 mg sc. Q2W from week 12 to week 24 (last injection at week 22 in both cases). Due to an administrative error, blinded uptitration actually occurred if week-8 LDL-C was ≥70 mg/dl (≥1.8 mmol/l). Both doses of alirocumab were self-administered by autoinjector. Blood samples for multiple param-eters were obtained at weeks 0, 4, 8, 12, 16, 24 and 32 (Figure 1). The primary end point was the percentage change in LDL-C from base-line to week 24 and major secondary end points included the percentage change in LDL-C from baseline to week 12, the percentage change in ApoB, ApoA1, Lp(a), non-HDL-cholesterol (non-HDL-C), total cholesterol, HDL-C, tri-glycerides and HbA1c from baseline to weeks 12 and 24. Safety end points were adverse events (AEs; including adjudicated CV events), labora-tory data, injection site reactions and vital signs assessed throughout the study. Other end points included serum alirocumab concentrations and antialirocumab antibodies also assessed through-out the study. Fifty-two patients were enrolled in the alirocumab group and 51 into the ezetimibe group at eight centers worldwide (USA, Belgium, Finland and The Netherlands). A total sample

size of 90 patients (45 in each group) was calcu-lated to have 95% power to detect a difference in mean percentage change in LDL-C of 20% with a 0.05 two-sided significance level assuming a common standard deviation of 25% and a 5% nonevaluable primary end point.

●● Data analysisThe primary efficacy analysis population was the intent-to-treat (ITT) population, defined as the randomized population that actually received at least one dose or partial dose of investigational medicinal product (IMP) and had both the base-line and at least one subsequent LDL-C value. The ITT population included all patients and laboratory assessments regardless of whether the patient was on or off double-blind IMP or regard-less of the timing of laboratory samples. The safety population consisted of the randomized popula-tion who actually received at least one dose or partial dose of IMP analyzed according to the treatment actually received. Safety analysis (AEs [including adjudicated CV events], laboratory parameters, injection site reactions and vital signs) was descriptive, based on the safety population. The safety analysis focused on the treatment-emergent AE (TEAE) period, defined as the time from the first double-blind dose of the IMP

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to the last double-blind dose of the IMP injec-tion plus 70 days (10 weeks). The modified ITT (mITT) or ‘on-treatment’ population included all subjects with a baseline and postbaseline LDL-C that occurred within a prespecified time window of having received the study IMP.

results●● Study population

A total of 204 subjects were screened and 103 were randomized, 52 to the alirocumab group and 51 to the ezetimibe group. All 103 randomized subjects received study treatment

Table 1. patient disposition: randomized population.

Group/outcome ezetimibe 10 mg q.d. (n = 51) alirocumab 75/150 mg sc. Q2W (n = 52)

Randomized and treated 51 (100%) 52 (100%)Completed the study treatment period 44 (86.3%) 44 (84.6%)Did not complete the study treatment period 7 (13.7%) 8 (15.4%)

Reason for treatment discontinuation

Adverse event 4 (7.8%) 5 (9.6%)Poor compliance 1 (2.0%) 0Patient moved 0 1 (1.9%)Patient withdrew consent 0 1 (1.9%)Other 2 (3.9%) 1 (1.9%)

Efficacy populations

Intent-to-treat 51 (100%) 52 (100%)Modified intent-to-treat or ‘on treatment’ 50 (98.0%) 51 (98.1%)Safety population 51 (100%) 52 (100%)Pharmacokinetic/pharmacodynamic population 51 (100%) 52 (100%)Antialirocumab antibody population 49 (96.1%) 51 (98.1%)

Alirocumab patients having a week-12 visit

Non-uptitrated – 32 (61.5%)Uptitrated – 14 (26.9%)Q2W: Every 2 weeks; q.d.: Every day; sc.: Subcutaneously.Adapted with permission from [18].

Table 2. Baseline demographics and lipid values.

Characteristic alirocumab group ezetimibe group

Age (years) 60.8 (4.6) 59.6 (5.3)Male gender, n (%) 28 (53.8%) 27 (52.9%)Race, white, n (%) 46 (88.5%) 47 (92.2%)BMI (kg/m2) 30.1 (5.9) 28.4 (6.7)HbA1c 5.7 (0.5) 5.6 (0.4)Fasting blood glucose (mg/dl) 101.4 (14.3) 97.4 (9.0)Fasting blood glucose (mmol/l) 5.63 (0.8) 5.41 (0.5)Diabetes mellitus, n (%) 3 (5.8) 1 (2.0)SCORE (%) 2.97 (1.29) 2.68 (1.14)

Baseline lipid parameters of all randomized patients

LDL-C 141.1 (27.1) mg/dl; 3.65 (0.7) mmol/l 138.3 (24.5) mg/dl; 3.58 (0.6) mmol/lTC 221.7 (33.7) mg/dl; 5.74 (0.9) mmol/l 223.9 (30.2) mg/dl; 5.80 (0.8) mmol/lNon-HDL-C 167.4 (30.3) mg/dl; 4.34 (0.8) mmol/l 164.0 (29.7) mg/dl; 4.25 (0.8) mmol/lTG, median (IQR) 119.0 (89.0–153.0) mg/dl; 1.34 (1.00–1.73) mmol/l 117.0 (87.0–154.0) mg/dl; 1.32 (0.98–1.74) mmol/lHDL-C 54.3 (16.1) mg/dl; 1.41 (0.4) mmol/l 59.9 (19.2) mg/dl; 1.55 (0.5) mmol/lApoB 104.3 (18.4) mg/dl; 1.04 (0.18) g/l 104.3 (19.1) mg/dl; 1.04 (0.19) g/lApo-A1 153.1 (29.2) mg/dl; 1.53 (0.29) g/l 163.8 (33.4) mg/dl; 1.63 (0.33) g/lLp(a), median (IQR) 13.0 (4.0–39.0) mg/dl; 0.13 (0.04–0.39) g/l 16.0 (6.0–34.0) mg/dl; 0.16 (0.06–0.34) g/lData are mean (standard deviation) baseline characteristics of all randomized patients, unless stated otherwise.HDL-C: HDL-cholesterol; IQR: Interquartile range; LDL-C: LDL-cholesterol; SCORE: European Systematic Coronary Risk Estimation; TC: Total cholesterol; TG: Triglyceride.Adapted with permission from [18].

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Figure 3. percentage change from baseline in secondary lipid parameters (intent-to-treat analysis). *p < 0.0001. ApoB: Apolipoprotein B; HDL-C: HDL-cholesterol; ITT: Intent to treat; Lp(a): Lipoprotein (a); LS: Least square; Non-HDL-C: Non-high- density lipoprotein cholesterol; SE: Standard error; TC: Total cholesterol.

ITT

Apo B0

-5

-10

LS

mea

n (

SE

) %

ch

ang

e fr

om

bas

elin

e to

wee

k 24 -15

-20

-25

-30

-35

-40

-45

-50

**

* Alirocumab(n = 52)Ezetimibe(n = 51)

Non-HDL-C TC Lp(a)

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(the safety population), but one patient from each treatment arm withdrew from treatment before any on treatment postrandomization LDL-C measurements were made (but contin-ued in the study and had subsequent LDL-C levels obtained); the remaining 101 subjects constituted the mITT or ‘on-treatment’ popu-lation. Overall, 15 patients did not complete the study treatment period. The percentage of patients who discontinued the IMP during the study was similar in the alirocumab group (eight patients; 15.4%) and the ezetimibe group (seven patients; 13.7%). The percentage of patients who discontinued the IMP due to AEs was also comparable between the two treatment groups (five patients [9.6%] in the alirocumab group and four patients [7.8%] in the ezetimibe group; Table 1).

Demographics and baseline lipid values were well balanced (Table 2). The protocol called for uptitration of the alirocumab dose at week 12 if LDL-C was ≥100 mg/dl at week 8, which was prompted by a blinded interactive voice responsive system. Instead, the interactive voice responsive system was incorrectly programmed to uptitrate subjects if LDL-C was ≥70 mg/dl. This discrepancy was not known until after study database lock. A total of 14 patients were uptitrated, and of these, only one patient had an LDL-C ≥100 mg/dl at week 8.

●● lipid resultsThe LDL-C was reduced in both the ezetimibe and alirocumab groups by week 4; these reduc-tions in LDL-C between the alirocumab and ezetimibe groups were statistically significant at weeks 12 and 24. Despite uptitration of 14 alirocumab patients at week 12 to 150 mg sc. Q2W, the LDL-C values observed at both weeks 12 and 24 were similar (Figure 2). The primary end point – the percentage difference in least square (LS) mean LDL-C between the alirocumab group and the ezetimibe group at 24 weeks was -31.6% for the ITT population and -36.9% for the mITT population (p < 0.0001 for both ITT and mITT populations). LDL-C lowering in the ITT population with alirocumab was 47.2% and with ezetimibe was 15.6%. The LDL-C lowering with alirocumab was approximately 50%, as predicted for the 75-mg dose based on modeling of Phase II data, and the LDL-C lowering with ezetimibe was 17–20%, as reported in previous ezetimibe studies [20]. The changes in lipid values in the

mITT or ‘on-treatment’ group were better than the ITT group because mITT only included those patients and visits where the study drug was taken and laboratory work was performed within the appropriate time window for the visits. There were also statistically significant differences between alirocumab and ezetimibe changes for ApoB, non-HDL-C and total cho-lesterol (Figure 3). A hierarchical approach was used for analyzing the data, which resulted in statistical testing being stopped when Lp(a) did not prove statistically significant. Lp(a) was lowered 18% by alirocumab, consistent with what would be expected based on Phase II data, but was lowered 10% with ezetimibe, a result that was not expected and had not been previously reported. The cause of this decrease is unknown.

●● Uptitrated versus non-uptitrated groupsFourteen patients were uptitrated from 75 to 150 mg of alirocumab sc. Q2W at week 12 based on week 8 LDL-C being ≥70 mg/dL and continued this dose until week 22 (last injec-tion); however, only one of these patients should

Future Cardiol. (2015) 11(1)32

Figure 4. percentage change in lDl-cholesterol over time according to uptitration status in the alirocumab group intent-to-treat population, with dose uptitrated at week 12. LDL-C: LDL-cholesterol; W: Week.

10

-10

-20

-30

-40

-50

-60

-70

-80

Baseline W4 W8 W12

Time point

W16 W24

Uptitrated

Non-uptitrated

LD

L-C

mea

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have been uptitrated by the protocol. Thirty-two patients were not uptitrated and received alirocumab 75 mg sc. Q2W from baseline to week 22 (last injection). Only the 46 patients who achieved a week-12 visit were included in the following analysis, including the 13 inap-propriately uptitrated patients. Alirocumab blood levels were equivalent at week 12 prior to study drug injection but, at week 24, the upti-trated group showed approximately double the alirocumab blood level of the non-uptitrated group. The uptitrated group had a baseline LS mean LDL-C level of 153 mg/dl (3.95 mmol/l) versus 135 mg/dl (3.49 mmol/l) for the non-uptitrated group. LDL-C levels from baseline to week 24 can be seen in Figure 4. To deter-mine whether the nonprotocol uptitration of the 13 patients with LDL-C levels between 70 and 100 mg/dl affected the results, a recalcula-tion of the primary end point excluding these 13 patients’ data after week 12 was performed and did not yield a significantly different result (ezetimibe: -15.6% change in LDL-C; ali-rocumab: -44.3% change in LDL-C). In addi-tion, the week-12 data for LDL-C before upti-tration occurred showed a 19.6% decrease for ezetimibe and a 48.1% decrease for alirocumab; neither value is statistically different from the week-24 data with or without the 13 patients being inappropriately uptitrated.

●● SafetyTEAEs were reported in 36 of 52 patients (69.2%) in the alirocumab group compared with 40 of 51 patients (78.4%) in the ezetimibe group (Table 3). The differences in the most fre-quently reported TEAEs in the alirocumab group versus the ezetimibe group were not considered clinically significant. Muscle dis-orders (myalgia and muscle spasms) occurred in a similar frequency within both treatment groups (3.8% in the alirocumab group and 3.9% in the ezetimibe group). Two treatment-emergent serious AEs were reported in two patients: pulmonary embolism in one patient of the alirocumab group and bone erosion in one patient of the ezetimibe group. Neither of the serious AEs was considered to be related to the IMPs by the investigator. Nine patients prema-turely discontinued treatment due to a TEAE: five patients (9.6%) in the alirocumab group and four patients (7.8%) in the ezetimibe group. Six patients (11.5%) in the alirocumab group and five patients (9.8%) in the ezetimibe group had at least one allergic TEAE. One patient in the alirocumab group discontinued treatment permanently due to a potential allergic TEAE (flushing and other concomitant symptoms of fatigue, nausea and headache). One patient (1.9%) in the alirocumab group and two patients (3.9%) in the ezetimibe group had

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at least one local injection site reaction TEAE during the 24-week study. These reactions were mild in severity. Laboratory, ECG and vital sign abnormalities were unremarkable between the two groups. Elevated glucose (≥126 mg/dl [7 mmol/l]) was present in six of the alirocumab patients (Table 4) and one ezetimibe patients at some visit during the study. All seven patients had elevated glucose (≥100 mg/dl [5.5 mmol/l]) or HbA1c levels (≥6.5%) at screening or baseline before receiving IMP and three of the six ali-rocumab patients had the diagnosis of diabetes mellitus at screening. There was no pattern of change in glucose or HbA1c from screening to week 24.

Three patients in the alirocumab group treated with 75 mg Q2W had an LDL-C value <25 mg/dl (<0.65 mmol/l) and one had two consecutive LDL-C values <25 mg/dl (<0.65 mmol/l). No particular safety concern was observed in this patient. No patient had

an LDL-C value <15 mg/dl (<0.39 mmol/l) at any time in the study. A total of four patients had a positive antidrug antibody (ADA) status at least once during the 24-week study period (Table 5). All had low ADA titers, which contin-ued to decline to very low levels or become ADA negative from week 12 to the week-32 follow-up visit. There were no differences between the uptitrated and non-uptitrated groups. No safety concerns were observed in these patients; there were no neutralizing antibodies detected and the presence of ADAs did not alter the LDL-C-lowering efficacy of alirocumab.

DiscussionThis was the first study with alirocumab at the 75-mg dose sc. Q2W utilizing self-injection in a population not receiving statin background therapy and also utilizing an uptitration scheme based on LDL-C response. The results demon-strate alirocumab resulted in a highly effective

Table 3. Treatment-emergent adverse events and laboratory parameters (safety population = 100% randomized patients).

Teaes alirocumab (n = 52) ezetimibe (n = 51)

Any TEAE 36 (69.2%) 40 (78.4%)Any treatment-emergent SAE 1 (1.9%) 1 (2.0%)Any TEAE leading to treatment d/c 5 (9.6%) 4 (7.8%)Any TEAE leading to death 0 0

TEAEs occurring in ≥5% of patients in either group

Nasopharyngitis 12 (23.1%) 8 (15.7%)Diarrhea 6 (11.5%) 2 (3.9%)Influenza 6 (11.5%) 3 (5.9%)Arthralgia 3 (5.8%) 2 (3.9%)Headache 3 (5.8%) 2 (3.9%)Nausea 3 (5.8%) 3 (5.9%)Upper respiratory tract infection 2 (3.8%) 5 (9.8%)Back pain 1 (1.9%) 3 (5.9%)Dizziness 1 (1.9%) 3 (5.9%)Urinary tract infection 0 3 (5.9%)

TEAEs of interest

Musculoskeletal and connective tissue disorders 8 (15.4%) 11 (21.6%)Injection site reaction 1 (1.9%) 2 (3.9%)

Laboratory parameters

ALT >3× ULN 0/52 0/51AST >3× ULN 0/52 0/51CK >3× ULN 0/51 1/50 (2.0%)CK >10× ULN 0/51 1/50 (2.0%)Glucose >126 mg/dl (>7 mmol/l)† 6/51 (11.8%) 1/50 (2.0%)†See Table 4.ALT: Alanine transaminase; AST: Aspartate aminotransferase; CK: Creatine kinase; d/c: Discontinuation; SAE: Serious adverse event; TEAE: Treatment-emergent adverse event; ULN: Upper limit of normal.Adapted with permission from [18].

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reduction in LDL-C of approximately 50%, as projected from Phase II study results, and also resulted in 70% (32/46) of patients achiev-ing a LDL-C of <70 mg/dl (<1.8 mmol/l) at week 12 from a baseline LDL-C of 141 mg/dl (3.6 mmol/l; 46 patients had a week-12 visit in the study). Furthermore, the study dem-onstrated that the difference between ali-rocumab and ezetimibe in lowering LDL-C (47.2 vs 15.6%, respectively, after 24 weeks of treatment in the ITT evaluation) is highly sig-nificantly different (p < 0.0001). There were no meaningful differences between alirocumab and ezetimibe in terms of safety parameters. Numerically, more patients receiving ali-rocumab experienced nasopharyngitis and diarrhea and more had glucose levels above 126 mg/dl (>7 mmol/l) than in those receiv-ing ezetimibe. Again, there was no pattern of change in glucose or HbA1c from screening to week 24 as previously described in the safety section. Ongoing Phase III ODYSSEY studies

with much larger numbers of patients will help further document the safety of alirocumab.

The group receiving an uptitration of ali-rocumab to 150 mg sc. Q2W had higher LDL-C baseline levels, as may be expected. Alirocumab levels rose to approximately double the blood concentration and PCSK9 levels declined fur-ther. However, LS mean LDL-C levels at week 24 were not appreciably different between the uptitrated and non-uptitrated alirocumab groups. This may have been because the sup-pression in PCSK9 was already substantial when the dose was increased but some (albeit small) additional reduction would have been expected. In the Phase II dose-ranging study, 100 mg sc. Q2W and 150 mg sc. Q2W resulted in LS mean LDL-C reductions of 64 and 72%, respectively, after 12 weeks of treatment [14]. However, the dose-ranging study was conducted on the background of statin therapy, which is known to increase PCSK9 levels by 35–45%, and this may accentuate the LDL-C lowering

Table 4. Blood glucose levels for patients in the alirocumab arm with blood glucose ≥126 mg/dl or Hba1c ≥6.5% at any time during the study (n = 6).

patient number Time point Fasting blood glucose; mg/dl (mmol/l) Hba1c (%)

1 (known DM)  Screening (week -2) 126 (7.0) 6.2Week 24 112 (6.2) 5.9

2 (known DM) Screening (week -2)Baseline (week 0)Week 24

105 (5.8) 97 (5.4) 70 (3.9)

7.0 –6.2

3 (known DM) Screening (week -2) Baseline (week 0) Week 24

164 (9.1) 142 (7.9) 183 (10.2)

7.5 –7.7

4 Screening (week -2) Baseline (week 0) Week 24

121 (6.7) 115 (6.4) 112 (6.2)

5.7 –5.9

5 Screening (week -2) Baseline (week 0) Week 24

128 (7.1) 119 (6.6) 121 (6.7)

6.2 –6.5

6 Screening (week -2) Baseline (week 0) Week 12

125 (6.9) 129 (7.2) 135 (7.5)

6.7 – 6.3

All six patients had abnormal fasting blood glucose (≥100 mg/dl) or HbA1c ≥6.5% at screening or baseline.DM: Diabetes mellitus.Adapted with permission from [18].

Table 5. anti-alirocumab antibodies versus time for the alirocumab group.

Week aDa-positive patients (n)/measured patients (n) Titer range

Baseline 0/52 NAWeek 12 4/48 30–120Week 24 1/49 120Follow-up week 32 1/48 60ADA: Antidrug antibody; NA: Not applicable.

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achieved when the PCSK9 mAb is adminis-tered [21]. A doubling of the PCSK9 mAb dose is an approach to enhancing the duration of the LDL-C lowering, especially in patients receiving no background lipid-modifying therapy, as more mAbs would be available to neutralize newly synthesized PCSK9. Based on this considera-tion, once-monthly administration of the 150-mg alirocumab dose is currently being tested in the ODYSSEY CHOICE II study.

ConclusionThese data suggest that the 75-mg dose of alirocumab sc. Q2W may be appropriate for adequate lowering of LDL-C in a large portion of patients with primary hypercholesterolemia at moderate CV risk who are not receiving sta-tin therapy. In addition, the safety profile con-tinues to show good tolerability and appears comparable to that of ezetimibe in this study. Alirocumab self-injected sc. Q2W appears to be a viable option for lowering LDL-C in patients unable or unwilling to utilize statin therapy. An uptitration plan based on LDL-C response appears to be feasible and may be useful in future clinical practice. Alirocumab

significantly lowers LDL-C to a much greater degree than ezetimibe, which is a commonly prescribed lipid-lowering medicine.

DisclaimerIn addition to the peer-review process, with the author(s) consent, the manufacturer of the product(s) discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made at the discretion of the author(s) and based on scientific or editorial merit only.

Financial & competing interests disclosureEM Roth is an employee of a research company that receives grants from Sanofi, Regeneron, Pfizer, Esperion and Lilly (those currently developing lipid-modifying drugs) and is a consultant to Regeneron and Sanofi. JM McKenney is an employee of a research company that receives grants from Sanofi, Regeneron, Pfizer, Esperion and Lilly (those cur-rently developing lipid-modifying drugs). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

executive summAryBackground

● Alirocumab (formerly SAR236553/REGN727) is a monoclonal antibody directed at PCSK9 that showed good efficacy in Phase II trials when added to background statin therapy.

● This is the first completed Phase III study in the ODYSSEY development program and is unique (compared with the Phase II studies) in the dose used (starting dose of 75 mg), the population (no background lipid-modifying therapies), the use of disposable autoinjectors for self-administration, the length of the study (24 weeks) and the alirocumab uptitration scheme (75–150 mg at week 12) for LDL-cholesterol (LDL-C) >100 mg/dl at week 8.

Study design

● This was a randomized, double-blind, active-controlled (ezetimibe), parallel-group, double-dummy study. General inclusion criteria were LDL-C between 100 and 190 mg/dL on no lipid-lowering medications in a moderate-risk population with a European Systematic Coronary Risk Estimation (SCORE) of 1–4%. In total, 103 patients were randomized into the study.

Data analysis

● The primary efficacy analysis population was the intent-to-treat (ITT) population, defined as the randomized population that actually received at least one dose or partial dose of investigational medicinal product and had both the baseline and at least one subsequent LDL-C value.

results

● The primary end point – the percentage difference (least square mean) in LDL-C between the alirocumab arm and the ezetimibe arm at 24 weeks – was -31.6% for the ITT population (p < 0.0001). LDL-C lowering with alirocumab was 47.2% and with ezetimibe was 15.6%.

Future Cardiol. (2015) 11(1)36

clinicAl triAl report Roth & McKenney

future science group

referencesPapers of special note have been highlighted as: • of interest; •• of considerable interest

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2 WHO. Leading causes of death. www.who.int

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4 Anderson TJ, Gregoire J, Hegele RA et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can. J. Cardiol. 29(2), 151–167 (2013).

5 Catapano AL, Reiner Z, De Backer G et al. ESC/EAS guidelines for the management of dyslipidaemias the task force for the

management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 217(1), 3–46 (2011).

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• FirstreportofanassociationbetweenPCSK9andcholesterollevels.

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•• FirstclinicaldataassociatingdecreasedPCSK9levelswithlowerLDL-cholesterolanddecreasedcardiovasculardiseaseeventrates.

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•• GoodsummaryofPCSK9datainPhaseIandIIstudiesofalirocumabandevolocumab.

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executive summAry (cont.)results (cont.)

● Thirteen patients were uptitrated in error at week 12 from 75 to 150 mg subcutaneously every 2 weeks due to a programming error in the interactive voice responsive system (LDL-C ≥70 mg/dl instead of ≥100 mg/dl per protocol). Uptitration did not result in a significant decrease in LDL-C compared with the non-uptitrated group, and the primary end point excluding the 13 incorrectly uptitrated patients was not significantly different from the ITT population results.

Safety

● Safety parameters, adverse events and study discontinuation rates were similar between the two groups. No patterns of change in glucose or HbA1c were observed from screening to week 24. LDL-C values of <25 mg/dl were not associated with any particular safety finding. Low levels of antidrug antibodies were present in four of the alirocumab patients and these levels decreased or disappeared from week 12 to week 24, and then to week 34 (the follow-up visit).

Significance

● Alirocumab showed significantly better LDL-C lowering than ezetimibe, with a comparable safety profile to ezetimibe. Uptitrated patients did not show a significant reduction in their LDL-C compared with that achieved with alirocumab 75 mg subcutaneously every 2 weeks; this may have occurred because the PCSK9/LDL receptor system was already saturated in these patients.

Conclusion

● This new lower dose of alirocumab may be adequate to achieve substantial LDL-C lowering for many hypercholesterolemic patients at moderate cardiovascular risk who are not receiving other lipid-modifying therapies.

37future science group www.futuremedicine.com

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