Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: lipid modifying agents, other lipid modifying agents. ATC code: C10AX13 
Mechanism of action

Evolocumab binds selectively to PCSK9 and prevents circulating PCSK9 from binding to the low density lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation.
Increasing liver LDLR levels results in associated reductions in serum LDL-cholesterol (LDL-C).

Pharmacodynamic effects

In clinical trials, evolocumab reduced unbound PCSK9, LDL-C, TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a), and increased HDL-C and ApoA1 in patients with primary hypercholesterolemia and mixed dyslipidemia.

A single subcutaneous administration of 140 mg or 420 mg evolocumab resulted in maximum suppression of circulating unbound PCSK9 by 4 hours followed by a reduction in LDL-C reaching a mean nadir in response by 14 and 21 days, respectively. Changes in unbound PCSK9 and serum lipoproteins were reversible upon discontinuation of evolocumab. No increase in unbound PCSK9 or LDL-C above baseline was observed during the washout of evolocumab suggesting that compensatory mechanisms to increase production of PCSK9 and LDL-C do not occur during treatment.

Subcutaneous regimens of 140 mg every 2 weeks and 420 mg once monthly were equivalent in average LDL-C lowering (mean of weeks 10 and 12) resulting in -72% to -57% from baseline compared with placebo. Treatment with evolocumab resulted in a similar reduction of LDL-C when used alone or in combination with other lipid-lowering therapies.

Clinical efficacy in primary hypercholesterolemia and mixed dyslipidemia 
LDL-C reduction of approximately 55% to 75% was achieved with evolocumab as early as week 1 and maintained during long-term therapy. Maximal response was generally achieved within 1 to 2 weeks after dosing with 140 mg every 2 weeks and 420 mg once monthly. Evolocumab was effective in all subgroups relative to placebo and ezetimibe, with no notable differences observed between subgroups, such as age, race, gender, region, body-mass index, National Cholesterol Education Program risk, current smoking status, baseline coronary heart disease (CHD) risk factors, family history of premature CHD, glucose tolerance status, (i.e. diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, statin dose and intensity, unbound baseline PCSK9, baseline LDL-C and baseline TG.

In 80-85% of all primary hyperlipidemia patients treated with either dose, evolocumab demonstrated a ≥ 50% reduction in LDL-C at the mean of weeks 10 and 12. Up to 99% of patients treated with either dose of evolocumab achieved an LDL-C of < 2.6 mmol/L and up to 95% achieved an LDL-C < 1.8 mmol/L at the mean of weeks 10 and 12.

Combination with a statin and statin with other lipid-lowering therapies 
LAPLACE-2 was an international, multicenter, double-blind, randomized, 12-week study in 1,896 patients with primary hypercholesterolemia or mixed dyslipidemia who were randomized to receive evolocumab in combination with statins (rosuvastatin, simvastatin or atorvastatin). Evolocumab was compared to placebo for the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe for the atorvastatin group.

Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with placebo for the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe for the atorvastatin group (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a) and increased HDL-C from baseline to mean of weeks 10 and 12 as compared to placebo for the rosuvastatin and simvastatin groups (p < 0.05) and significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1 and Lp(a), compared with placebo and ezetimibe for the atorvastatin group (p < 0.001) (see tables 2 and 3).

RUTHERFORD-2 was an international, multicenter, double-blind, randomized, placebo-controlled, 12-week study in 329 patients with heterozygous familial hypercholesterolemia on lipid-lowering therapies. Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with placebo (p < 0.001).
Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a) and increased HDL-C and ApoA1 from baseline to mean of weeks 10 and 12 compared to placebo (p < 0.05) (see table 2).

Table 2. Treatment effects of evolocumab compared with placebo in patients with primary hypercholesterolemia and mixed dyslipidemia - mean percent change from baseline to average of weeks 10 and 12 (%, 95% CI)

Study             Dose LDL-C Non- ApoB                       TC       Lp(a) VLDL- HDL-              TG      ApoA1 TC/ ApoB/ regime (%) HDL-C (%)                        (%)       (%)    C     C               (%)      (%) HDL- ApoA1 n        (%)                                             (%)   (%)                           C ratio ratio %      %
LAPLACE-2             140 mg
-72b       -60b       -56b       -41b       -30b       -18b      6b      -17b      3b      -45b       -56b (HMD)            Q2W (-75, -69) (-63, -58) (-58, -53) (-43, -39) (-35, -25) (-23, -14) (4, 8) (-22, -13) (1, 5) (-47, -42) (-59, -53) (combined         (N = 555) rosuvastatin,      420 mg simvastatin, &               -69b       -60b       -56b       -40b       -27b       -22b       8b      -23b      5b      -46b       -58b QM    (-73, -65) (-63, -57) (-58, -53) (-42, -37) (-31, -24) (-28, -17) (6, 10) (-28, -17) (3, 7) (-48, -43) (-60, -55) atorvastatin groups)   (N = 562)
140 mg
-61b       -56b       -49b       -42b       -31b       -22b       8b      -22b       7a      -47b        -53 Q2W
RUTHERFORD- (N = 110) (-67, -55) (-61, -51) (-54, -44) (-46, -38) (-38, -24) (-29, -16) (4, 12) (-29, -15) (3, 12) (-51, -42) (-58, -48) 2
420 mg
(HeFH)               -66b       -60b       -55b       -44b       -31b       -16b       9b      -17b       5a      -49b       -56b QM (-72, -61) (-65, -55) (-60, -50) (-48, -40) (-38, -24) (-23, -8) (5, 14) (-24, -9) (1, 9) (-54, -44) (-61, -50) (N = 110)
Key: Q2W = once every 2 weeks, QM = once monthly, HMD = Primary hypercholesterolemia and mixed dyslipidemia, HeFH = Heterozygous familial hypercholesterolemia, a p value < 0.05 when compared with placebo, b p value < 0.001 when compared with placebo.


Statin-intolerant patients

GAUSS-2 was an international, multicenter, double-blind, randomized, ezetimibe-controlled, 12-week study in 307 patients who were statin-intolerant or unable to tolerate an effective dose of a statin. Repatha significantly reduced LDL-C compared with ezetimibe (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1 and Lp(a), from baseline to mean of weeks 10 and 12 compared to ezetimibe (p < 0.001) (see table 3).

Treatment in the absence of a statin

MENDEL-2 was an international, multicenter, double-blind, randomized, placebo and ezetimibe-controlled, 12-week study of Repatha in 614 patients with primary hypercholesterolemia and mixed dyslipidemia.
Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with both placebo and ezetimibe (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1 and Lp(a), from baseline to mean of weeks 10 and 12 compared with both placebo and ezetimibe (p < 0.001) (see table 3).

Table 3. Treatment effects of evolocumab compared with ezetimibe in patients with primary hypercholesterolemia and mixed dyslipidemia - mean percent change from baseline to average of weeks 10 and 12 (%, 95% CI)

Study              Dose  LDL-C Non- ApoB                        TC        Lp(a) VLDL- HDL-C TG                        ApoA1 TC/ ApoB/ regimen  (%) HDL-C (%)                         (%)        (%)    C    (%)  (%)                        (%) HDL-C ApoA1 (%)                                               (%)                                        ratio ratio %     %
140 mg
LAPLACE-2                          -43c       -34c       -34c       -23c       -30c        -1         7c         -2         7c        -27c       -38c Q2W        (-50, -37) (-39, -30) (-38, -30) (-26, -19) (-35, -25) (-7, 5)     (4, 10)    (-9, 5)     (4, 9)   (-30, -23) (-42, -34) (HMD)            (N = 219)
(combined
420 mg atorvastatin                     -46c       -39c       -40c       -25c       -33c        -7         8c         -8         7c        -30c       -42c groups)           QM         (-51, -40) (-43, -34) (-44, -36) (-29, -22) (-41, -26) (-20, 6)    (5, 12)   (-21, 5)    (2, 11) (-34, -26) (-47, -38) (N = 220)
140 mg
-38b       -32b       -32b       -24b       -24b        -2         5          -3         5a        -27b       -35b Q2W        (-44, -33) (-36, -27) (-37, -27) (-28, -20) (-31, -17) (-10, 7)    (1, 10)   (-11, 6)     (2, 9)   (-32, -23) (-40, -30) GAUSS-2             (N = 103)
(statin-intolerant)   420 mg
-39b       -35b       -35b       -26b       -25b        -4         6          -6          3        -30b       -36b QM         (-44, -35) (-39, -31) (-40, -30) (-30, -23) (-34, -17) (-13, 6)    (1, 10)   (-17, 4)    (-1, 7) (-35, -25) (-42, -31) (N = 102)
140 mg
-40b       -36b       -34b       -25b       -22b        -7         6a         -9          3        -29b       -35b MENDEL-2              Q2W        (-44, -37) (-39, -32) (-37, -30) (-28, -22) (-29, -16) (-14, 1)    (3, 9)    (-16, -1)    (0, 6)   (-32, -26) (-39, -31) (treatment in the    (N = 153) absence of a      420 mg statin)                      -41b       -35b       -35b       -25b       -20b       -10         4          -9         4a        -28b       -37b QM         (-44, -37) (-38, -33) (-38, -31) (-28, -23) (-27, -13) (-19, -1)   (1, 7)    (-18, 0)     (1, 7)   (-31, -24) (-41, -32) (N = 153)
Key: Q2W = once every 2 weeks, QM = once monthly, HMD = Primary hypercholesterolemia and mixed dyslipidemia, a p value < 0.05 when compared with ezetimibe, b p value < 0.001 when compared with ezetimibe, c nominal p value < 0.001 when compared with ezetimibe.

Long-term efficacy in primary hypercholesterolemia and mixed dyslipidemia 
DESCARTES was an international, multicenter, double-blind, randomized, placebo-controlled, 52-week study in 901 patients with hyperlipidemia who received diet alone, atorvastatin, or a combination of atorvastatin and ezetimibe. Repatha 420 mg once monthly significantly reduced LDL-C from baseline at 52 weeks compared with placebo (p < 0.001). Treatment effects were sustained over 1 year as demonstrated by reduction in LDL-C from week 12 to week 52. Reduction in LDL-C from baseline at week 52 compared with placebo was consistent across background lipid-lowering therapies optimized for LDL-C and cardiovascular risk.

Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a), and increased HDL-C and ApoA1 at week 52 compared with placebo (p < 0.001) (see table 4).

Table 4. Treatment effects of evolocumab compared with placebo in patients with primary hypercholesterolemia and mixed dyslipidemia - mean percent change from baseline to week 52 (%, 95% CI)

Study           Dose  LDL-C Non- ApoB                                TC      Lp(a) VLDL- HDL-C TG                            ApoA1 TC/ ApoB/ regimen  (%) HDL-C (%)                                 (%)      (%)    C    (%)  (%)                            (%) HDL-C ApoA1 (%)                                                     (%)                                            ratio ratio %     %
420 mg
DESCARTES                            -59b        -50b       -44b         -33b      -22b       -29b          5b       -12b           3a           -37b      -46b QM              (-64, -55) (-54, -46) (-48, -41) (-36, -31) (-26, -19) (-40, -18)       (3, 8)   (-17, -6)      (1, 5)   (-40, -34) (-50, -43) (N = 599)
Key: QM = once monthly, a nominal p value < 0.001 when compared with placebo, b p value < 0.001 when compared with placebo.

OSLER and OSLER-2 were two randomized, controlled, open-label extension studies to assess the long-term safety and efficacy of Repatha in patients who completed treatment in a ‘parent’ study. In each extension study, patients were randomized 2:1 to receive either Repatha plus standard of care (evolocumab group) or standard of care alone (control group) for the first year of the study. At the end of the first year (week 52 in OSLER and week 48 in OSLER-2), patients entered the all Repatha period in which all patients received open-label Repatha for either another 4 years (OSLER) or 2 years (OSLER-2).

A total of 1,324 patients enrolled in OSLER. Repatha 420 mg once monthly significantly reduced LDL-C from baseline at week 12 and week 52 compared with control (nominal p < 0.001). Treatment effects were maintained over 272 weeks as demonstrated by reduction in LDL-C from week 12 in the parent study to week 260 in the open-label extension. A total of 3,681 patients enrolled in OSLER-2. Repatha significantly reduced LDL-C from baseline at week 12 and week 48 compared with control (nominal p < 0.001).
Treatment effects were maintained as demonstrated by reduction in LDL-C from week 12 to week 104 in the open-label extension. Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a), and increased HDL-C and ApoA1 from baseline to week 52 in OSLER and to week 48 in OSLER-2 compared with control (nominal p < 0.001). LDL-C and other lipid parameters returned to baseline within 12 weeks after discontinuation of Repatha at the beginning of OSLER or OSLER-2 without evidence of rebound.

TAUSSIG was a multicenter, open-label, 5-year extension study to assess the long-term safety and efficacy of Repatha, as an adjunct to other lipid-lowering therapies, in patients with severe familial hypercholesterolemia (FH), including homozygous familial hypercholesterolemia. A total of 194 severe familial hypercholesterolemia (non-HoFH) patients and 106 homozygous familial hypercholesterolemia patients enrolled in TAUSSIG. All patients in the study were initially treated with Repatha 420 mg once monthly, except for those receiving lipid apheresis at enrolment who began with Repatha 420 mg once every 2 weeks. Dose frequency in non-apheresis patients could be titrated up to 420 mg once every 2 weeks based on LDL-C response and PCSK9 levels. Long-term use of Repatha demonstrated a sustained treatment effect as evidenced by reduction of LDL-C in patients with severe familial hypercholesterolemia (non-HoFH) (see table 5).

Changes in other lipid parameters (TC, ApoB, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) also demonstrated a sustained effect of long-term Repatha administration in patients with severe familial hypercholesterolemia (non-HoFH).

Table 5. Effect of evolocumab on LDL-C in patients with severe familial hypercholesterolemia (non- HoFH) – mean percent change from baseline to OLE week 216 (and associated 95% CI) 
Patient           OLE                 OLE               OLE               OLE             OLE                OLE                OLE               OLE population        week 12             week 24           week 36           week 48         week 96           week 144           week 192           week 216 (N)           (n = 191)           (n = 191)         (n = 187)         (n = 187)       (n = 180)          (n = 180)          (n = 147)          (n = 96) Severe FH
-54.9               -54.1             -54.7            -56.9            -53.3               -53.5             -48.3                -47.2 (non-HoFH)
(N = 194)       (-57.4, -52.4)     (-57.0, -51.3)     (-57.4, -52.0)   (-59.7, -54.1)   (-56.9, -49.7)    (-56.7, -50.2)      (-52.9, -43.7)     (-52.8, -41.5) Key: OLE = open-label extension, N (n) = Number of evaluable patients (N) and patients with observed LDL-C values at specific scheduled visit (n) in the severe familial hypercholesterolemia (non-HoFH) final analysis set.
Treatment of heterozygous familial hypercholesterolemia in pediatric patients 
HAUSER-RCT was a randomized, multicenter, placebo-controlled, double-blind, parallel-group, 24-week trial in 158 pediatric patients aged 10 to < 18 years with heterozygous familial hypercholesterolemia.
Patients were required to be on a low-fat diet and must have been receiving optimized background lipid-lowering therapy (statin at optimal dose, not requiring up titration). Enrolled patients were randomized in a 2:1 ratio to receive 24 weeks of subcutaneous once monthly 420 mg Repatha or placebo.

The primary efficacy endpoint in this trial was percent change from baseline to week 24 in LDL-C. The difference between Repatha and placebo in mean percent change in LDL-C from baseline to week 24 was 38% (95% CI: 45%, 31%; p < 0.0001). The least squares mean Standard Error (SE) reduction (p < 0.0001) in LDL-C from baseline at week 24 was 44% (2%) in the Repatha group and 6% (3%) in the placebo group.
Mean absolute LDL-C values at week 24 were 104 mg/dL in the Repatha group and 172 mg/dL in the placebo group. Reductions in LDL-C were observed by the first post-baseline assessment at the week 12 time point and were maintained throughout the trial.

The secondary endpoint of this trial was mean percent change from baseline to weeks 22 and 24 in LDL-C, where week 22 reflects the peak and week 24 the trough of the subcutaneous once monthly dosing interval, and provides information about the time-averaged effect of Repatha therapy over the entire dosing interval.
The least squares mean treatment difference between Repatha and placebo in mean percent change in LDL-C from baseline to the mean of week 22 and week 24 was 42% (95% CI: 48%, 36%; p < 0.0001). For additional results, see table 6.

Table 6. Treatment effects of Repatha compared with placebo in pediatric patients with heterozygous familial hypercholesterolemia – mean percent change from baseline to week 24 (%, 95% CI) 
TC/             ApoB/
Dose           LDL-C         Non-HDL-C          ApoB            HDL-C            ApoA1 Study regimen           (%)             (%)              (%)             Ratio           Ratio (%)              (%)
HAUSER-RCT
(HeFH            420 mg QM           -38.3            -35.0          -32.5          -30.3              -36.4 Pediatric          (N = 104)      (-45.5, -31.1)   (-41.8, -28.3) (-38.8, -26.1) (-36.4, -24.2)     (-43.0, -29.8) Patients)
QM = monthly (subcutaneous); CI = Confidence Interval; LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; ApoB = apolipoprotein B; ApoA1 = apolipoprotein A1; TC = total cholesterol All adjusted p-values <0.0001
N = number of patients randomized and dosed in the full analysis set.

HAUSER-OLE was an open-label, single-arm, multicenter, 80 week study of Repatha in 150 pediatric patients aged 10 to 17 years with HeFH that rolled-over from HAUSER-RCT and enrolled 13 de novo pediatric HoFH patients. Patients had to be on a low-fat diet and receiving background lipid-lowering therapy. All HeFH patients in this study received 420 mg Repatha subcutaneously once monthly (median exposure duration: 18.4 months). The mean (SE) percent changes in calculated LDL-C from baseline were: -44.4% (1.7%) at week 12, -41.0% (2.1%) at week 48, and -35.2% (2.5%) at week 80.
The mean (SE) percent change from baseline to week 80 in other lipid endpoints were: -32.1% (2.3%) non-HDL-C, -25.1% (2.3%) ApoB, -28.5% (2.0%) TC/HDL-C ratio, -30.3% (2.2%) ApoB/ApoA1 ratio, and -24.9% (1.9%) TC.

Treatment of homozygous familial hypercholesterolemia

TESLA was an international, multicenter, double-blind, randomized, placebo-controlled 12-week study in 49 homozygous familial hypercholesterolemia patients aged 12 to 65 years. Repatha 420 mg once monthly,
as an adjunct to other lipid-lowering therapies (e.g., statins, bile-acid sequestrants), significantly reduced LDL-C and ApoB at week 12 compared with placebo (p < 0.001) (see table 7). Changes in other lipid 
parameters (TC, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) also demonstrated a treatment effect of Repatha administration in patients with homozygous familial hypercholesterolemia.

Table 7. Treatment effects of evolocumab compared with placebo in patients with homozygous familial hypercholesterolemia - mean percent change from baseline to week 12 (%, 95% CI) 
Study          Dose        LDL-C Non-             ApoB          TC        Lp(a)      VLDL- HDL-C               TG         TC/   ApoB/ regimen        (%) HDL-C              (%)          (%)        (%)         C    (%)                (%)       HDL-C ApoA1 (%)                                                  (%)                                 ratio ratio %     %
420 mg
TESLA                         -32b       -30a       -23b         -27a       -12          -44       -0.1         0.3         -26a       -28a (HoFH)         QM          (-45, -19) (-42, -18) (-35, -11) (-38, -16)    (-25, 2)   (-128, 40)   (-9, 9)    (-15, 16)   (-38, -14) (-39, -17) (N = 33)
Key: HoFH = homozygous familial hypercholesterolemia, QM = once monthly, a nominal p value < 0.001 when compared with placebo, b p value < 0.001 when compared with placebo.

Long-term efficacy in homozygous familial hypercholesterolemia

In TAUSSIG, long-term use of Repatha demonstrated a sustained treatment effect as evidenced by reduction of LDL-C of approximately 20% to 30% in patients with homozygous familial hypercholesterolemia not on apheresis and approximately 10% to 30% in patients with homozygous familial hypercholesterolemia on apheresis (see table 8). Changes in other lipid parameters (TC, ApoB, non-HDL-C, TC/HDL-C, and ApoB/ApoA1) also demonstrated a sustained effect of long-term Repatha administration in patients with homozygous familial hypercholesterolemia. Reductions in LDL-C and changes in other lipid parameters in 14 adolescent patients (aged ≥ 12 to < 18 years) with homozygous familial hypercholesterolemia are comparable to those in the overall population of patients with homozygous familial hypercholesterolemia.

Table 8. Effect of evolocumab on LDL-C in patients with homozygous familial hypercholesterolemia - mean percent change from baseline to OLE week 216 (and associated 95% CI) 
Patient           OLE week OLE week OLE week OLE week OLE week OLE week OLE week OLE week population (N)         12       24       36       48       96       144      192      216 -21.2         -21.4          -27.0            -24.8          -25.0          -27.7           -27.4           -24.0 HoFH              (-26.0, -       (-27.8, -      (-32.1, -      (-31.4, -         (-31.2, -     (-34.9, -       (-36.9, -       (-34.0, - (N = 106)            16.3)           15.0)          21.9)          18.3)             18.8)         20.5)           17.8)           14.0) (n = 104)        (n = 99)       (n = 94)       (n = 93)          (n = 82)      (n = 79)        (n = 74)        (n = 68) -22.7         -25.8          -30.5            -27.6          -23.5          -27.1           -30.1           -23.4 Non-apheresis         (-28.1, -       (-33.1, -      (-36.4, -      (-35.8, -         (-31.0, -     (-35.9, -       (-37.9, -       (-32.5, - (N = 72)             17.2)           18.5)          24.7)          19.4)             16.0)         18.3)           22.2)           14.2) (n = 70)        (n = 69)       (n = 65)       (n = 64)          (n = 62)      (n = 60)        (n = 55)        (n = 50) -29.7          -29.6
-18.1         -11.2          -19.1            -18.7                                     -19.6        -25.9 Apheresis                                                                           (-40.6, -     (-42.1, - (-28.1, -8.1) (-24.0, 1.7) (-28.9, -9.3) (-29.5, -7.9)                                    (-51.2, 12.1) (-56.4, 4.6) (N = 34)                                                                             18.8)         17.1) (n = 34)      (n = 30)     (n = 29)      (n = 29)                                         (n = 19)      (n = 18) (n = 20)      (n = 19)
Key: OLE = open-label extension, N (n) = Number of evaluable patients (N) and patients with observed LDL values at specific schedule visit (n) in the HoFH final analysis set.

HAUSER-OLE was an open-label, single-arm, multicenter, 80-week trial in 12 HoFH subjects to evaluate the safety, tolerability and efficacy of Repatha for LDL-C reduction in pediatric patients from aged ≥ 10 to < 18 years of age with homozygous familial hypercholesterolemia. Patients had to be on a low-fat diet and receiving background lipid-lowering therapy. All patients in the study received 420 mg Repatha subcutaneously once monthly. Median (Q1, Q3) LDL-C at baseline was 398 (343, 475) mg/dL. The median (Q1, Q3) percent change in LDL-C from baseline to week 80 was -14% (-41, 4). Reductions in LDL-C were observed by the first assessment at week 12 and was maintained throughout the trial, median (Q1, Q3) reductions ranging between 12% (-3, 32) and 15% (-4, 39). For additional results, please see table 9.


Table 9. Treatment effects of evolocumab compared with placebo in patients with homozygous familial hypercholesterolemia – median (Q1, Q3) percent change from baseline to week 80 
TC/            ApoB/
Dose          LDL-C        Non-HDL-C           ApoB           HDL-C           ApoA1 Study regimen          (%)            (%)               (%)            Ratio          Ratio (%)             (%)
HAUSER-
OLE (HoFH       420 mg QM           -14.3            -13             -19.1          -3.7           -3 Pediatric        (N = 12)       (-40.6, 3.5)   (-40.7, 2.7)    (-33.3, 11.6)   (-41.6, 7.6)  (-35.7, 9.3) Patients)
QM = monthly (subcutaneous); LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; ApoB = apolipoprotein B; ApoA1 = apolipoprotein A1, TC = total cholesterol N = number of patients randomized and dosed in the interim analysis set.

Effect on atherosclerotic disease burden

The effects of Repatha 420 mg once monthly on atherosclerotic disease burden, as measured by intravascular ultrasound (IVUS), were evaluated in a 78-week double-blind, randomized, placebo-controlled study in 968 patients with coronary artery disease on a stable background of optimal statin therapy. Repatha reduced both percent atheroma volume (PAV; 1.01% [95% CI 0.64, 1.38], p < 0.0001) and total atheroma volume (TAV; 4.89 mm3 [95% CI 2.53, 7.25], p < 0.0001) compared with placebo. Atherosclerotic regression was observed in 64.3% (95% CI 59.6, 68.7) and 47.3% (95% CI 42.6, 52.0) of patients who received Repatha or placebo respectively, when measured by PAV. When measured by TAV, atherosclerotic regression was observed in 61.5% (95% CI 56.7, 66.0) and 48.9% (95% CI 44.2, 53.7) of patients who received Repatha or placebo respectively. The study did not investigate the correlation between atherosclerotic disease regression and cardiovascular events.

Effect on coronary atherosclerotic plaque morphology

The effects of Repatha 420 mg once monthly on coronary atherosclerotic plaques as assessed by optical coherence tomography (OCT), were evaluated in a 52-week double-blind, randomized, placebo-controlled study including adult patients initiated within 7 days of a non-ST-segment elevation acute coronary syndrome (NSTEACS) on maximally tolerated statin therapy. For the primary endpoint of absolute change in minimum FCT (fibrous cap thickness) in a matched segment of artery from baseline, least squares (LS) mean (95% CI) increased from baseline by 42.7 µm (32.4, 53.1) in the Repatha group and 21.5 µm (10.9, 32.1) in the placebo group, an additional 21.2 µm (4.7, 37.7) compared to placebo (p = 0.015; 38% difference (p = 0.041)). The reported secondary findings show treatment differences including change in mean minimum FCT (increase 32.5 µm (12.7, 52.4); p = 0.016) and absolute change in maximum lipid arc (-26° (- 49.6, -2.4); p = 0.041).

Cardiovascular risk reduction in adults with established atherosclerotic cardiovascular disease 
The Repatha Outcomes Study (FOURIER) was a randomized, event-driven, double-blind study of 27,564 subjects, aged between 40 and 86 years (mean age 62.5 years), with established atherosclerotic CV disease; 81% had a prior MI event, 19% had a prior stroke event and 13% had peripheral arterial disease. Over 99% of patients were on moderate to high intensity statin and at least one other cardiovascular medicine such as anti-platelet agents, beta blockers, Angiotensin-Converting Enzyme (ACE) inhibitors, or angiotensin receptor blockers; median (Q1, Q3) baseline LDL-C was 2.4 mmol/L (2.1, 2.8). Absolute CV risk was balanced between treatment groups, in addition to the index event all patients had at least 1 major or 2 minor CV risk factors; 80% had hypertension, 36% had diabetes mellitus, and 28% were daily smokers. Patients were randomized 1:1 to either Repatha (140 mg every two weeks or 420 mg once every month) or matching placebo; the mean duration of patient follow-up was 26 months.

A substantial reduction of LDL-C was observed throughout the study, with achieved median LDL-C ranges of 0.8 to 0.9 mmol/L at each assessment; 25% of patients achieved a LDL-C concentration less than 0.5 mmol/L. Despite the very low levels of LDL-C achieved, no new safety issues were observed (see 
section 4.8); the frequencies of new onset diabetes and cognitive events were comparable in patients who achieved LDL-C levels < 0.65 mmol/L and those with higher LDL-C.

Repatha significantly reduced the risk of cardiovascular events defined as the composite of time to first CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina (see table 10); the Kaplan-Meier curves for the primary and key secondary composite endpoints separated at approximately 5 months (see figure 1 for the MACE three year Kaplan-Meier curve). The relative risk of the MACE composite (CV death, MI, or stroke) was significantly reduced by 20%. The treatment effect was consistent across all subgroups (including age, type of disease, baseline LDL-C, baseline statin intensity, ezetimibe use, and diabetes) and was driven by a reduction in the risk of myocardial infarction, stroke and coronary revascularization; no significant difference was seen on cardiovascular or all-cause mortality however the study was not designed to detect such a difference.

Table 10. Effect of evolocumab on major cardiovascular events

Placebo              Evolocumab
(N = 13,780)            (N = 13,784)            Hazard ratioa n (%)                   n (%)                 (95% CI)               p valueb MACE+ (composite of MACE,                       1,563 (11.34)           1,344 (9.75)           0.85 (0.79, 0.92)       < 0.0001 coronary revascularization, or hospitalization for unstable angina)
MACE (composite of CV death, MI, or              1,013 (7.35)            816 (5.92)            0.80 (0.73, 0.88)       < 0.0001 stroke)
Cardiovascular death                              240 (1.74)             251 (1.82)            1.05 (0.88, 1.25)          0.62 All-cause mortality                               426 (3.09)             444 (3.22)            1.04 (0.91, 1.19)          0.54 Myocardial infarction (fatal/non-fatal)           639 (4.64)             468 (3.40)            0.73 (0.65, 0.82)       < 0.0001c Stroke (fatal/non-fatal) d                        262 (1.90)             207 (1.50)            0.79 (0.66, 0.95)        0.0101c Coronary revascularization                        965 (7.00)             759 (5.51)            0.78 (0.71, 0.86)       < 0.0001c e
Hospitalization for unstable angina               239 (1.7)               236 (1.7)            0.99 (0.82, 1.18)          0.89 a Based on a Cox model stratified by the randomization stratification factors collected via Interactive Voice Response System (IVRS).
b 2-sided log-rank test stratified by randomization stratification factors collected via IVRS.
c Nominal significance.
d The treatment effect on stroke was driven by a reduction in risk of ischemic stroke; there was no effect on hemorrhagic or  undetermined stroke.
e Assessment of time to hospitalization for unstable angina was ad-hoc.


Figure 1. Time to a MACE event (composite of CV death, MI, or stroke); 3-year Kaplan-Meier 


FOURIER-OLE (study 1 and study 2) consisted of two open-label, single-arm, multicenter, extension studies to evaluate the long-term safety, tolerability, and efficacy of Repatha in patients with established cardiovascular disease who completed the FOURIER study. Enrolled patients received Repatha 140 mg every 2 weeks or 420 mg once monthly for approximately 5 years and continued moderate- (22.2%) or high- intensity (74.8%) background statin therapy. Of the 5,031 patients who received at least one dose of Repatha in study 1, 2499 patients received Repatha and 2,532 patients received placebo in the FOURIER study. Of the 1,599 patients who received at least one dose of Repatha in study 2,854 patients received Repatha and 745 patients received placebo in the FOURIER study. Upon completion of study 1 and study 2, patients randomized to Repatha in the FOURIER study had up to 8.4 years (median 85.4 months) and 8.0 years of total Repatha exposure (median 80.2 months) and patients randomized to placebo had up to 5.25 years (median 60.0 months) and 4.9 years of total Repatha exposure (median 55.1 months), respectively.

In study 1 and 2 combined, 72.4% (n = 4,802) of patients achieved a lowest post-baseline LDL-C < 25 mg/dL (0.65 mmol/L), 87.0% (n = 5,765) of patients achieved an LDL-C < 40 mg/dL (1.03 mmol/L), and 11.9% (n = 792) of patients had an all post-baseline LDL-C ≥ 40 mg/dL (1.03 mmol/L). Of the patients who achieved post-baseline low LDL-C (< 25 mg/dL or < 40 mg/dL), the overall subject incidences of treatment emergent adverse events were 80.0% patients who achieved LDL-C < 25 mg/dL and 82.7% in patients who achieved LDL-C < 40 mg/dL compared to 85.0% in patients with LDL-C ≥ 40 mg/dL. The overall subject incidences of serious treatment emergent adverse events were 37.7% in patients who achieved LDL-C < 25 mg/dL and 40.0% in patients who achieved LDL-C < 40 mg/dL compared to 41.5% in patients with LDL-C ≥ 40 mg/dL.

The mean percent reduction from baseline in LDL-C was stable during the OLE study period and ranged from 53.4% to 59.1% for study 1 and 62.5% to 67.2% for study 2, regardless of the patient’s original randomized treatment group in the FOURIER study. This appears to translate into a numerically lower subject incidence rate of adjudicated exploratory CV endpoints of the composite of CV death, MI and stroke for patients who had received Repatha in both the FOURIER and FOURIER OLE studies compared with patients who had received placebo in the FOURIER study and Repatha in the FOURIER OLE studies.

Overall, no new safety findings were identified in these studies.


Effect on LDL-C during acute phase of Acute Coronary Syndromes (ACS) 
EVOPACS was a single country, multicenter, double-blind, randomized, placebo-controlled, 8-week study on 308 ACS patients with evolocumab initiated in-hospital within 24 to 72 hours of presentation.

If patients were not on a statin or were on statin treatment other than atorvastatin 40 mg prior to screening, this was stopped and atorvastatin 40 mg once daily was initiated. Randomization was stratified by study center and presence of stable statin treatment within ≥ 4 weeks prior to enrolment. Most subjects (241 [78%]) were not on stable statin treatment for ≥ 4 weeks prior to screening and most (235 [76%]) were not taking a statin at baseline. By week 4, 281 (97%) subjects were receiving high-intensity statins. Evolocumab 420 mg once monthly significantly reduced LDL-C from baseline to week 8 compared with placebo
(p < 0.001). The mean (SD) reduction in calculated LDL-C from baseline at week 8 was 77.1% (15.8%) in the evolocumab group and 35.4% (26.6%) in the placebo group with a least squares (LS) mean difference (95% CI) of 40.7% (36.2%, 45.2%). Baseline LDL-C values were 3.61 mmol/L (139.5 mg/dL) in the evolocumab group and 3.42 mmol/L (132.2 mg/dL) in the placebo group. LDL-C reductions in this study were consistent with previous studies where evolocumab was added to stable lipid-lowering therapy as demonstrated by on-treatment LDL-C levels at week 8 in this study (reflecting steady-state effect of high- intensity statin in both treatment arms) of 0.79 mmol/L (30.5 mg/dL) and 2.06 mmol/L (79.7 mg/dL) in the evolocumab plus atorvastatin and the placebo plus atorvastatin groups, respectively.

The effects of evolocumab in this patient population were consistent with those observed in previous studies in evolocumab clinical development program and no new safety concerns were noted.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption and distribution
Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days. Administration of single subcutaneous dose of 140 mg resulted in a Cmax mean (SD) of 13.0 (10.4) µg/mL and AUClast mean (SD) of 96.5 (78.7) day•µg/mL. Administration of single subcutaneous dose 420 mg resulted in a Cmax mean (SD) of 46.0 (17.2) µg/mL and AUClast mean (SD) of 842 (333) day•µg/mL. Three subcutaneous 140 mg doses were bioequivalent to a single subcutaneous 420 mg dose. The absolute bioavailability after SC dosing was determined to be 72% from pharmacokinetic models.

Following a single 420 mg evolocumab intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L, suggesting evolocumab has limited tissue distribution.

Biotransformation

Evolocumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Elimination

Evolocumab was estimated to have an effective half-life of 11 to 17 days.
In patients with primary hypercholesterolemia or mixed dyslipidemia on high dose statin, the systemic exposure of evolocumab was slightly lower than in subjects on low-to-moderate dose statin (the ratio of AUClast 0.74 [90% CI 0.29, 1.9]). An approximately 20% increase in the clearance is in part mediated by statins increasing the concentration of PCSK9 which did not adversely impact the pharmacodynamic effect of evolocumab on lipids. Population pharmacokinetic analysis indicated no appreciable differences in evolocumab serum concentrations in hypercholesterolemic patients (non-familial hypercholesterolemia or familial hypercholesterolemia) taking concomitant statins.
Linearity/non-linearity

Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr. In clinical studies with repeated subcutaneous dosing over 12 weeks, dose proportional increases in exposure were observed with dose regimens of 140 mg and greater. An approximate two to three-fold accumulation was observed in trough serum concentrations (Cmin (SD) 7.21 (6.6)) following 140 mg doses every 2 weeks or following 420 mg doses administered monthly (Cmin (SD) 11.2 (10.8)), and serum trough concentrations approached steady-state by 12 weeks of dosing.

No time dependent changes were observed in serum concentrations over a period of 124 weeks.

Renal impairment
No dose adjustment is necessary in patients with renal impairment. Data from the evolocumab clinical trials did not reveal a difference in pharmacokinetics of evolocumab in patients with mild or moderate renal impairment relative to non-renally impaired patients.

In a clinical trial of 18 patients with either normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2, n = 6), severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2, n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6), exposure to unbound evolocumab as assessed by Cmax after a single 140 mg subcutaneous dose was decreased by 30% in patients with severe renal impairment and by 45% in patients with ESRD receiving hemodialysis. Exposure as assessed by AUClast was decreased by approximately 24% in patients with severe renal impairment and by approximately 45% in patients with ESRD receiving hemodialysis. The exact mechanism of PK differences is unknown; however, differences in body weight could not explain these differences. Some factors including small sample size and large inter-subject variability should be considered when interpreting the results. The pharmacodynamics and safety of evolocumab in patients with severe renal impairment and ESRD were similar to patients with normal renal function, and there were no clinically meaningful differences in LDL-C lowering. Therefore, no dose adjustments are necessary in patients with severe renal impairment or ESRD receiving hemodialysis.

Hepatic impairment

No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). Single 140 mg subcutaneous doses of evolocumab were studied in 8 patients with mild hepatic impairment, 8 patients with moderate hepatic impairment and 8 healthy subjects. The exposure to evolocumab was found to be approximately 40-50% lower compared to healthy subjects. However, baseline PCSK9 levels and the degree and time course of PCSK9 neutralization were found to be similar between patients with mild or moderate hepatic impairment and healthy volunteers. This resulted in similar time course and extent of absolute LDL-C lowering. Evolocumab has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.4).

Body weight

Body weight was a significant covariate in population PK analysis impacting evolocumab trough concentrations, however there was no impact on LDL-C reduction. Following repeat subcutaneous administration of 140 mg every 2 weeks, the 12-week trough concentrations were 147% higher and 70% lower in patients of 69 kg and 93 kg respectively, than that of the typical 81 kg subject. Less impact from body weight was seen with repeated subcutaneous evolocumab 420 mg monthly doses.

Other special populations

Population pharmacokinetic analyzes suggest that no dose adjustments are necessary for age, race or gender.
The pharmacokinetics of evolocumab were influenced by body weight without having any notable effect on LDL-C lowering. Therefore, no dose adjustments are necessary based on body weight.


The pharmacokinetics of Repatha were evaluated in 103 pediatric patients aged ≥ 10 to < 18 years with heterozygous familial hypercholesterolemia (HAUSER-RCT). Following subcutaneous administration of 420 mg Repatha once monthly, mean (SD) trough serum concentrations were 22.4 (14.7) mcg/mL, 64.9
(34.4) mcg/mL and 25.8 (19.2) mcg/mL over the Week 12, Week 22 and Week 24 time points, respectively.
The pharmacokinetics of Repatha were evaluated in 12 pediatric patients aged ≥ 10 to < 18 years with homozygous familial hypercholesterolemia (HAUSER-OLE). Following subcutaneous administration of 420 mg Repatha once monthly, mean (SD) serum trough concentrations were 20.3 (14.6) mcg/mL and 17.6
(28.6) mcg/mL at Week 12 and Week 80, respectively.