ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every

Clinical Trial Report
For reprint orders, please contact: [email protected]
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
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 week24 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.
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 hypercholesterolemia 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 estimated 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
Keywords • alirocumab • ezetimibe
• hypercholesterolemia
• LDL-C • PCSK9
• SAR236553/REGN727
University of Cincinnati & Sterling Research Group, 375 Glensprings Drive, 2nd Floor, Cincinnati, OH 45246, USA
Virginia 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; [email protected]
1
2
10.2217/FCA.14.82 © 2015 Future Medicine Ltd
Future Cardiol. (2015) 11(1), 27–37
part of
ISSN 1479-6678
27
Clinical Trial Report Roth & McKenney
Follow-up period
(8 weeks)
Treatment period (24 weeks)
n = 50 Alirocumab 75 mg Q2W Alirocumab 75 or 150 mg
+ placebo EZE daily
Q2W + placebo EZE daily
Screening period
up to 2 weeks
Screening Injection
visit
training
visit
Up-titration if
LDL-C at W8
≥70 mg/dl
R
n = 50
Alirocumab placebo Q2W + EZE 10 mg daily
Diet (NCEP-ATPIII therapeutic lifestlye changes or equivalent diet)
W-2
W-1
W0
W4
W8
Randomization
W12
W16
W24
W32
Primary end point
EOT visit
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)
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].
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 design
ODYSSEY MONO was a randomized, double-blind, double-dummy, active-controlled
(ezetimibe), parallel-group study to investigate the efficacy and safety of alirocumab over
24 weeks in 100 patients with hypercholesterolemia 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 exclusion criteria were established coronary heart
28
Future Cardiol. (2015) 11(1)
disease or coronary heart disease risk equivalents defined as manifestations of noncoronary
forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm and
carotid artery disease), use of any LLT within 4
weeks or a fibrate within 6 weeks of the screening 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 applicable local regulations. All patients provided
written informed consent.
Patients were randomized in a 1:1 ratio to
alirocumab 75 mg sc. Q2W plus ezetimibe placebo 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
future science group
ODYSSEY MONO 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 parameters 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 baseline 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, triglycerides and HbA1c from baseline to weeks 12
and 24. Safety end points were adverse events
(AEs; including adjudicated CV events), laboratory data, injection site reactions and vital signs
assessed throughout the study. Other end points
included serum alirocumab concentrations and
antialirocumab antibodies also assessed throughout 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
Clinical Trial Report
size of 90 patients (45 in each group) was calculated 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 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 (IMP) and had both the baseline 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 regardless of the timing of laboratory samples. The safety
population consisted of the randomized population 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 treatmentemergent AE (TEAE) period, defined as the
time from the first double-blind dose of the IMP
160
140
LS mean (SE) LDL-C, mg/dl
ITT: -19.2 (2.6)%
ITT: -15.6 (3.1)%
120
100
ITT: -48.1 (2.6)%
80
ITT: -47.2 (3.0)%
60
40
Difference vs ezetimibe
ITT: -31.6 (4.32) %
p < 0.0001
ITT Alirocumab 75/150 mg Q2W
ITT Ezetimibe 10 mg QD
20
0
0
4
8
12
Week
16
20
24
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.
future science group
www.futuremedicine.com
29
Clinical Trial Report Roth & McKenney
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
Completed the study treatment period
Did not complete the study treatment period
51 (100%)
44 (86.3%)
7 (13.7%)
52 (100%)
44 (84.6%)
8 (15.4%)
4 (7.8%)
1 (2.0%)
0
0
2 (3.9%)
5 (9.6%)
0
1 (1.9%)
1 (1.9%)
1 (1.9%)
51 (100%)
50 (98.0%)
51 (100%)
51 (100%)
49 (96.1%)
52 (100%)
51 (98.1%)
52 (100%)
52 (100%)
51 (98.1%)
–
–
32 (61.5%)
14 (26.9%)
Reason for treatment discontinuation
Adverse event
Poor compliance
Patient moved
Patient withdrew consent
Other
Efficacy populations
Intent-to-treat
Modified intent-to-treat or ‘on treatment’
Safety population
Pharmacokinetic/pharmacodynamic population
Antialirocumab antibody population
Alirocumab patients having a week-12 visit
Non-uptitrated
Uptitrated
Q2W: Every 2 weeks; q.d.: Every day; sc.: Subcutaneously.
Adapted with permission from [18].
to the last double-blind dose of the IMP injection 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 2. Baseline demographics and lipid values.
Characteristic
Alirocumab group
Ezetimibe group
Age (years)
Male gender, n (%)
Race, white, n (%)
BMI (kg/m2)
HbA1c
Fasting blood glucose (mg/dl)
Fasting blood glucose (mmol/l)
Diabetes mellitus, n (%)
SCORE (%)
60.8 (4.6)
28 (53.8%)
46 (88.5%)
30.1 (5.9)
5.7 (0.5)
101.4 (14.3)
5.63 (0.8)
3 (5.8)
2.97 (1.29)
59.6 (5.3)
27 (52.9%)
47 (92.2%)
28.4 (6.7)
5.6 (0.4)
97.4 (9.0)
5.41 (0.5)
1 (2.0)
2.68 (1.14)
Baseline lipid parameters of all randomized patients
LDL-C
TC
Non-HDL-C
TG, median (IQR)
HDL-C
ApoB
Apo-A1
Lp(a), median (IQR)
141.1 (27.1) mg/dl; 3.65 (0.7) mmol/l
221.7 (33.7) mg/dl; 5.74 (0.9) mmol/l
167.4 (30.3) mg/dl; 4.34 (0.8) mmol/l
119.0 (89.0–153.0) mg/dl; 1.34 (1.00–1.73) mmol/l
54.3 (16.1) mg/dl; 1.41 (0.4) mmol/l
104.3 (18.4) mg/dl; 1.04 (0.18) g/l
153.1 (29.2) mg/dl; 1.53 (0.29) g/l
13.0 (4.0–39.0) mg/dl; 0.13 (0.04–0.39) g/l
138.3 (24.5) mg/dl; 3.58 (0.6) mmol/l
223.9 (30.2) mg/dl; 5.80 (0.8) mmol/l
164.0 (29.7) mg/dl; 4.25 (0.8) mmol/l
117.0 (87.0–154.0) mg/dl; 1.32 (0.98–1.74) mmol/l
59.9 (19.2) mg/dl; 1.55 (0.5) mmol/l
104.3 (19.1) mg/dl; 1.04 (0.19) g/l
163.8 (33.4) mg/dl; 1.63 (0.33) g/l
16.0 (6.0–34.0) mg/dl; 0.16 (0.06–0.34) g/l
Data 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].
30
Future Cardiol. (2015) 11(1)
future science group
ODYSSEY MONO ●●Lipid results
The LDL-C was reduced in both the ezetimibe
and alirocumab groups by week 4; these reductions 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
future science group
ITT
NonHDL-C
Apo B
TC
Lp(a)
0
LS mean (SE) % change from
baseline to week 24
(the safety population), but one patient from
each treatment arm withdrew from treatment
before any on treatment postrandomization
LDL-C measurements were made (but continued in the study and had subsequent LDL-C
levels obtained); the remaining 101 subjects
constituted the mITT or ‘on-treatment’ population. 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.
Clinical Trial Report
-5
-10
-15
-20
-25
-30
*
-35
-40
-45
*
*
Alirocumab
(n = 52)
Ezetimibe
(n = 51)
-50
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.
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 cholesterol (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 groups
Fourteen 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 injection); however, only one of these patients should
www.futuremedicine.com
31
Clinical Trial Report Roth & McKenney
LDL-C mean % change from baseline
10
Uptitrated
0
Non-uptitrated
-10
-20
-30
-40
-50
-60
-70
-80
Baseline
W4
W8
W12
W16
W24
Time point
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.
have been uptitrated by the protocol. Thirtytwo 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 inappropriately uptitrated patients. Alirocumab
blood levels were equivalent at week 12 prior to
study drug injection but, at week 24, the uptitrated 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 nonuptitrated group. LDL-C levels from baseline
to week 24 can be seen in Figure 4. To determine whether the nonprotocol uptitration of
the 13 patients with LDL-C levels between 70
and 100 mg/dl affected the results, a recalculation 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; alirocumab: -44.3% change in LDL-C). In addition, the week-12 data for LDL-C before uptitration 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.
32
Future Cardiol. (2015) 11(1)
●●Safety
TEAEs 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 frequently reported TEAEs in the alirocumab
group versus the ezetimibe group were not
considered clinically significant. Muscle disorders (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 treatmentemergent 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 prematurely 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
future science group
ODYSSEY MONO 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 alirocumab 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
Clinical Trial Report
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 continued to decline to very low levels or become ADA
negative from week 12 to the week-32 followup 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-Clowering efficacy of alirocumab.
Discussion
This 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 demonstrate 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
Any treatment-emergent SAE
Any TEAE leading to treatment d/c
Any TEAE leading to death
36 (69.2%)
1 (1.9%)
5 (9.6%)
0
40 (78.4%)
1 (2.0%)
4 (7.8%)
0
12 (23.1%)
6 (11.5%)
6 (11.5%)
3 (5.8%)
3 (5.8%)
3 (5.8%)
2 (3.8%)
1 (1.9%)
1 (1.9%)
0
8 (15.7%)
2 (3.9%)
3 (5.9%)
2 (3.9%)
2 (3.9%)
3 (5.9%)
5 (9.8%)
3 (5.9%)
3 (5.9%)
3 (5.9%)
8 (15.4%)
1 (1.9%)
11 (21.6%)
2 (3.9%)
0/52
0/52
0/51
0/51
6/51 (11.8%)
0/51
0/51
1/50 (2.0%)
1/50 (2.0%)
1/50 (2.0%)
TEAEs occurring in ≥5% of patients in either group
Nasopharyngitis
Diarrhea
Influenza
Arthralgia
Headache
Nausea
Upper respiratory tract infection
Back pain
Dizziness
Urinary tract infection
TEAEs of interest
Musculoskeletal and connective tissue disorders
Injection site reaction
Laboratory parameters
ALT >3× ULN
AST >3× ULN
CK >3× ULN
CK >10× ULN
Glucose >126 mg/dl (>7 mmol/l)†
†
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].
future science group
www.futuremedicine.com
33
Clinical Trial Report Roth & McKenney
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)
Week 24
Screening (week -2)
Baseline (week 0)
Week 24
Screening (week -2)
Baseline (week 0)
Week 24
Screening (week -2)
Baseline (week 0)
Week 24
Screening (week -2)
Baseline (week 0)
Week 24
Screening (week -2)
Baseline (week 0)
Week 12
126 (7.0)
112 (6.2)
105 (5.8)
97 (5.4)
70 (3.9)
164 (9.1)
142 (7.9)
183 (10.2)
121 (6.7)
115 (6.4)
112 (6.2)
128 (7.1)
119 (6.6)
121 (6.7)
125 (6.9)
129 (7.2)
135 (7.5)
6.2
5.9
7.0
–
6.2
7.5
–
7.7
5.7
–
5.9
6.2
–
6.5
6.7
–
6.3
2 (known DM)
3 (known DM)
4
5
6
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].
reduction in LDL-C of approximately 50%,
as projected from Phase II study results, and
also resulted in 70% (32/46) of patients achieving 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 demonstrated that the difference between alirocumab and ezetimibe in lowering LDL-C
(47.2 vs 15.6%, respectively, after 24 weeks of
treatment in the ITT evaluation) is highly significantly different (p < 0.0001). There were
no meaningful differences between alirocumab
and ezetimibe in terms of safety parameters.
Numerically, more patients receiving alirocumab experienced nasopharyngitis and
diarrhea and more had glucose levels above
126 mg/dl (>7 mmol/l) than in those receiving 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 alirocumab 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 further. 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 suppression 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 5. Anti-alirocumab antibodies versus time for the alirocumab group.
Week
ADA-positive patients (n)/measured patients (n)
Titer range
Baseline
Week 12
Week 24
Follow-up week 32
0/52
4/48
1/49
1/48
NA
30–120
120
60
ADA: Antidrug antibody; NA: Not applicable.
34
Future Cardiol. (2015) 11(1)
future science group
ODYSSEY MONO achieved when the PCSK9 mAb is administered [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 consideration, once-monthly administration of the 150mg alirocumab dose is currently being tested in
the ODYSSEY CHOICE II study.
Conclusion
These 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 statin therapy. In addition, the safety profile continues 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
Clinical Trial Report
significantly lowers LDL-C to a much greater
degree than ezetimibe, which is a commonly
prescribed lipid-lowering medicine.
Disclaimer
In 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 disclosure
EM 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 currently 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 summary
Background
●●
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 science group
www.futuremedicine.com
35
Clinical Trial Report Roth & McKenney
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.
References
management of dyslipidaemias of the
European Society of Cardiology (ESC) and
the European Atherosclerosis Society (EAS).
Atherosclerosis 217(1), 3–46 (2011).
Papers of special note have been highlighted as:
• of interest; •• of considerable interest
1
2
3
4
5
36
National Cholesterol Education Program,
National Heart, Lung and Blood Institute,
NIH. Detection, evaluation, and treatment of
high blood cholesterol in adults (Adult
Treatment Panel III) final report. NIH
Publication No. 02-5215.
www.nhlbi.nih.gov (2002).
WHO. Leading causes of death.
www.who.int 6
7
Stone NJ, Robinson J, Lichtenstein AH et al.
Cardiovascular risk in adults: a report of the
American College of Cardiology/American
2013 ACC/AHA guideline on the treatment
of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults: a report of the
American College of Cardiology/American
Heart Association Task Force on Practice
Guidelines. Circulation 129(25 Suppl. 2),
S1–S45 (2014).
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).
Catapano AL, Reiner Z, De Backer G et al.
ESC/EAS guidelines for the management of
dyslipidaemias the task force for the
8
9
Waters DD, Brotons C, Chiang CW et al.;
Lipid Treatment Assessment Project 2
Investigators. Lipid treatment assessment
project 2: a multinational survey to evaluate
the proportion of patients achieving
low-density lipoprotein cholesterol goals.
Circulation 120, 28–34 (2009).
Nordestgaard BG, Chapman MJ,
Humphries SE et al.; European
Atherosclerosis Society Consensus Panel.
Familial hypercholesterolaemia is
underdiagnosed and undertreated in the
general population: guidance for clinicians
to prevent coronary heart disease: consensus
statement of the European Atherosclerosis
Society. Eur. Heart J. 34(45), 3478a–3490a
(2013).
Bruckert E, Hayem G, Dejager S, Yau C,
Bégaud B. Mild to moderatemuscular
symptomswith high-dosage statin therapy in
hyperlipidemic patients-the PRIMO study.
Cardiovasc. Drugs Ther. 19, 403–414
(2005).
Abifadel M, Varret M, Rabes JP et al.
Mutations in PCSK9 cause autosomal
dominant hypercholesterolemia. Nat. Genet.
34, 154–6 (2003).
Future Cardiol. (2015) 11(1)
•
First report of an association between
PCSK9 and cholesterol levels.
10 Cohen JC, Boerwinkle E, Mosley TH Jr,
Hobbs HH. Sequence variations in PCSK9, low
LDL, and protection against coronary heart
disease. N. Engl. J. Med. 354, 1264–72 (2006).
•• First clinical data associating decreased
PCSK9 levels with lower LDL-cholesterol
and decreased cardiovascular disease event
rates.
11 Goldstein JL, Brown MS. The LDL receptor.
Arterioscler. Thromb. Vasc. Biol. 29, 431–438
(2009).
12 Stein EA, Swergold GD. Potential of proprotein
convertase subtilisin/kexin type 9 based
therapeutics. Curr. Atheroscler. Rep. 15, 310
(2013).
•• Good summary of PCSK9 data in Phase I
and II studies of alirocumab and
evolocumab.
13 Stein EA, Mellis S, Yancopoulos GD et al.
Effect of a monoclonal antibody to PCSK9 on
LDL cholesterol. N. Engl. J. Med. 366,
1108–1118 (2012).
14 McKenney JM, Koren MJ, Kereiakes DJ
et al. Safety and efficacy of a monoclonal
antibody to proprotein convertase
subtilisin/kexin type 9 serine protease,
SAR236553/REGN727, in patients with
primary hypercholesterolemia receiving
future science group
ODYSSEY MONO ongoing stable atorvastatin therapy. J. Am.
Coll. Cardiol. 59, 2344–2353 (2012).
•
17 Pordy R, Lecrops G, Bessac L, Sasiela WG,
Ginsberg H. Alirocumab, a fully human
monoclonal antibody to proprotein convertase
subtilisin/kexin type 9: therapeutic dosing in
Phase 3 studies. J. Clin. Lipidol. 7, 279 (2013).
Phase II dose-ranging study of alirocumab.
15 Roth EM, McKenney JM, Hanotin C, Asset
G, Stein EA. Atorvastatin with or without an
antibody to PCSK9 in primary
hypercholesterolemia. N. Engl. J. Med. 367,
1891–1900 (2012).
18 Roth EM, Taskinen MR, Ginsberg HN
et al. Monotherapy with the PCSK9
inhibitor alirocumab versus ezetimibe in
patients with hypercholesterolemia: results
of a 24 week, double-blind, randomized
Phase 3 trial. Int. J. Cardiol. 176(1), 55–61
(2014).
16 Roth EM, Diller P. Alirocumab for
hyperlipidemia: physiology of PCSK9
inhibition, pharmacodynamics and Phase I
and II clinical trial results of a PCSK9
monoclonal antibody. Future Cardiol. 10(2),
183–99 (2014).
•
Review of alirocumab and PSCK9
inhibition.
future science group
•
Original study report of the ODYSSEY
MONO study.
Clinical Trial Report
cardiovascular disease in Europe: the
SCORE project. Eur. Heart J. 24(11),
987–1003 (2003).
20 Bays HE, Neff D, Tomassini JE, Tershakovec
AM. Ezetimibe: cholesterol lowering and
beyond. Expert Rev. Cardiovasc. Ther. 6(4),
447–470 (2008).
21 Dubuc GA, Chamberland H, Wassef J et al.
Statins upregulate PCSK9, the gene
encoding the proprotein convertase neural
apoptosis-regulated convertase-1 implicated
in familial hypercholesterolemia.
Arterioscler. Thromb. Vasc. Biol. 24,
1454–1459 (2004).
19 Conroy RM, Pyorala K, Fitzgerald AP et al.
Estimation of ten-year risk of fatal
www.futuremedicine.com
37