14 CLINICAL STUDIES

Adult Patients with Established Cardiovascular Disease

Study 1 (FOURIER, NCT01764633) was a double-blind, randomized, placebo-controlled, event-driven trial in 27,564 (13,784 REPATHA, 13,780 placebo) adult patients with established cardiovascular disease and with LDL-C ≥ 70 mg/dL and/or non-HDL-C ≥ 100 mg/dL despite high- or moderate-intensity statin therapy. Patients were randomly assigned 1:1 to receive either subcutaneous injections of REPATHA (140 mg every 2 weeks or 420 mg once monthly) or placebo; 86% used the every-2-week regimen throughout the trial. The median follow-up duration was 26 months. Overall, 99.2% of patients were followed until the end of the trial or death.

The mean (SD) age at baseline was 63 (9) years, with 45% being at least 65 years old; 25% were women. The trial population was 85% White, 2% Black, and 10% Asian; 8% identified as Hispanic ethnicity. Regarding prior diagnoses of cardiovascular disease, 81% had prior myocardial infarction, 19% prior non-hemorrhagic stroke, and 13% had symptomatic peripheral arterial disease. Selected additional baseline risk factors included hypertension (80%), diabetes mellitus (1% type 1; 36% type 2), current daily cigarette smoking (28%), New York Heart Association class I or II congestive heart failure (23%), and eGFR < 60 mL/min per 1.73 m2 (6%). Most patients were on a high- (69%) or moderate-intensity (30%) statin therapy at baseline, and 5% were also taking ezetimibe. Most patients were taking at least one other cardiovascular medication including anti-platelet agents (93%), beta blockers (76%), angiotensin converting enzyme (ACE) inhibitors (56%), or angiotensin receptor blockers (23%). On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 92 [80, 109] mg/dL; the mean (SD) was 98 (28) mg/dL.

REPATHA significantly reduced the risk for the primary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; p < 0.0001) and the key secondary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, or stroke; p < 0.0001). The Kaplan-Meier estimates of the cumulative incidence of the primary and key secondary composite endpoints over time are shown in Figure 1 and Figure 2 below.

The results of primary and secondary efficacy endpoints are shown in Table 3 below.

Table 3. Effect of REPATHA on Cardiovascular Events in Patients with Established Cardiovascular Disease in FOURIER
	Placebo		REPATHA		REPATHA vs. Placebo
	N = 13780 n (%)	Incidence Rate (per 100 patient years)	N = 13784 n (%)	Incidence Rate (per 100 patient years)	Hazard Ratio (95% CI)
* Time to death by any cause is not a component of either the primary composite endpoint or key secondary composite endpoint. † Not a prespecified endpoint; an ad hoc analysis was performed to ensure results are provided for each individual component of the primary endpoint.
Primary composite endpoint
Time to first occurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina	1563 (11.3)	5.2	1344 (9.8)	4.5	0.85 (0.79, 0.92)
Key secondary composite endpoint
Time to first occurrence of cardiovascular death, myocardial infarction, stroke	1013 (7.4)	3.4	816 (5.9)	2.7	0.80 (0.73, 0.88)
Other secondary endpoints
Time to cardiovascular death	240 (1.7)	0.8	251 (1.8)	0.8	1.05 (0.88, 1.25)
Time to death by any cause*	426 (3.1)	1.4	444 (3.2)	1.5	1.04 (0.91, 1.19)
Time to first fatal or non-fatal myocardial infarction	639 (4.6)	2.1	468 (3.4)	1.6	0.73 (0.65, 0.82)
Time to first fatal or non-fatal stroke	262 (1.9)	0.9	207 (1.5)	0.7	0.79 (0.66, 0.95)
Time to first coronary revascularization	965 (7.0)	3.2	759 (5.5)	2.5	0.78 (0.71, 0.86)
Time to first hospitalization for unstable angina†	239 (1.7)	0.8	236 (1.7)	0.8	0.99 (0.82, 1.18)

Figure 1. Estimated Cumulative Incidence of Primary Composite Endpoint Over 3 Years in FOURIER

Figure 2. Estimated Cumulative Incidence of Key Secondary Composite Endpoint Over 3 Years in FOURIER

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −63% (95% CI: −63%, −62%) and from baseline to Week 72 was −57% (95% CI: −58%, −56%). At Week 48, the median [Q1, Q3] LDL-C was 26 [15, 46] mg/dL in the REPATHA group, with 47% of patients having LDL-C < 25 mg/dL.

In EBBINGHAUS (NCT02207634), a substudy of 1974 patients enrolled in the FOURIER trial, REPATHA was non-inferior to placebo on selected cognitive function domains as assessed with the use of neuropsychological function tests over a median follow-up of 19 months.

Primary Hyperlipidemia

Study 2 (LAPLACE-2, NCT01763866) was a multicenter, double-blind, randomized controlled 12-week trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. The trial included 1896 patients with hyperlipidemia who received REPATHA, placebo, or ezetimibe as add-on therapy to daily doses of statins (atorvastatin, rosuvastatin, or simvastatin). Ezetimibe was also included as an active control only among those assigned to background atorvastatin. Overall, the mean age at baseline was 60 years (range: 20 to 80 years), 35% were ≥ 65 years old, 46% women, 94% White, 4% were Black, and 1% Asian; 5% identified as Hispanic or Latino ethnicity. After 4 weeks of background statin therapy, the mean baseline LDL-C ranged between 77 and 127 mg/dL across the five background therapy arms.

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −71% (95% CI: −74%, −67%; p < 0.0001) and −63% (95% CI: −68%, −57%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. The difference between REPATHA and ezetimibe in mean percent change in LDL-C from baseline to Week 12 was −45% (95% CI: −52%, −39%; p < 0.0001) and −41% (95% CI: −47%, −35%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results, see Table 4 and Figure 3.

Table 4. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia on Background Statin Regimens (Mean % Change from Baseline to Week 12 in LAPLACE-2)
Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Estimates based on a multiple imputation model that accounts for treatment adherence
* 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C
REPATHA every 2 weeks vs. Placebo every 2 weeks (Background statin: atorvastatin 10 mg or 80 mg; rosuvastatin 5 mg or 40 mg; simvastatin 40 mg)
Placebo every 2 weeks (n = 281)	8	6	5	4
REPATHA 140 mg every 2 weeks* (n = 555)	-63	-53	-49	-36
Mean difference from placebo (95% CI)	-71 (-74, -67)	-59 (-62, -55)	-55 (-58, -52)	-40 (-43, -38)
REPATHA once monthly vs. Placebo once monthly (Background statin: atorvastatin 10 mg or 80 mg; rosuvastatin 5 mg or 40 mg; simvastatin 40 mg)
Placebo once monthly (n = 277)	4	5	3	2
REPATHA 420 mg once monthly (n = 562)	-59	-50	-46	-34
Mean difference from placebo (95% CI)	-63 (-68, -57)	-54 (-58, -50)	-50 (-53, -47)	-36 (-39, -33)
REPATHA every 2 weeks vs. Ezetimibe 10 mg daily (Background statin: atorvastatin 10 mg or 80 mg)
Ezetimibe 10 mg daily (n = 112)	-17	-16	-14	-12
REPATHA 140 mg every 2 weeks* (n = 219)	-63	-52	-49	-36
Mean difference from Ezetimibe (95% CI)	-45 (-52, -39)	-36 (-41, -31)	-35 (-40, -31)	-24 (-28, -20)
REPATHA once monthly vs. Ezetimibe 10 mg daily (Background statin: atorvastatin 10 mg or 80 mg)
Ezetimibe 10 mg daily (n = 109)	-19	-16	-11	-12
REPATHA 420 mg once monthly (n = 220)	-59	-50	-46	-34
Mean difference from Ezetimibe (95% CI)	-41 (-47, -35)	-35 (-40, -29)	-34 (-39, -30)	-22 (-26, -19)

Figure 3. Effect of REPATHA on LDL-C in Patients with Hyperlipidemia when Combined with Statins (Mean % Change from Baseline to Week 12 in LAPLACE-2)

Estimates based on a multiple imputation model that accounts for treatment adherence
Error bars indicate 95% confidence intervals

Study 3 (DESCARTES, NCT01516879) was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 901 patients with hyperlipidemia who received protocol-determined background lipid-lowering therapy of a cholesterol-lowering diet either alone or in addition to atorvastatin (10 mg or 80 mg daily) or the combination of atorvastatin 80 mg daily with ezetimibe. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or REPATHA 420 mg administered subcutaneously once monthly. Overall, the mean age at baseline was 56 years (range: 25 to 75 years), 23% were ≥ 65 years, 52% women, 80% White, 8% Black, and 6% Asian; 6% identified as Hispanic or Latino ethnicity. After stabilization on the assigned background therapy, the mean baseline LDL-C ranged between 90 and 117 mg/dL across the four background therapy groups.

In these patients with hyperlipidemia on a protocol-determined background therapy, the difference between REPATHA 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was −55% (95% CI: −60%, −50%; p < 0.0001) (Table 5 and Figure 4). For additional results, see Table 5.

Table 5. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia* (Mean % Change from Baseline to Week 52 in DESCARTES)
Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Estimates based on a multiple imputation model that accounts for treatment adherence
* Prior to randomization, patients were stabilized on background therapy consisting of a cholesterol-lowering diet either alone or in addition to atorvastatin (10 mg or 80 mg daily) or the combination of atorvastatin 80 mg daily with ezetimibe.
Placebo once monthly (n = 302)	8	8	2	5
REPATHA 420 mg once monthly (n = 599)	-47	-39	-38	-26
Mean difference from placebo (95% CI)	-55 (-60, -50)	-46 (-50, -42)	-40 (-44, -37)	-31 (-34, -28)

Figure 4. Effect of REPATHA 420 mg Once Monthly on LDL-C in Patients with Hyperlipidemia in DESCARTES

Estimates based on a multiple imputation model that accounts for treatment adherence
Error bars indicate 95% confidence intervals

Study 4 (MENDEL-2, NCT01763827) was a multicenter, double-blind, randomized, placebo- and active-controlled, 12-week trial that included 614 patients with hyperlipidemia who were not taking lipid-lowering therapy at baseline. Patients were randomly assigned to receive subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. Blinded administration of ezetimibe was also included as an active control. Overall, the mean age at baseline was 53 years (range: 20 to 80 years), 18% were ≥ 65 years old, 66% were women, 83% White, 7% Black, and 9% Asian; 11% identified as Hispanic or Latino ethnicity. The mean baseline LDL-C was 143 mg/dL.

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −55% (95% CI: −60%, −50%; p < 0.0001) and −57% (95% CI: −61%, −52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. The difference between REPATHA and ezetimibe in mean percent change in LDL-C from baseline to Week 12 was −37% (95% CI: −42%, −32%; p < 0.0001) and −38% (95% CI: −42%, −34%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results, see Table 6.

Table 6. Effect of REPATHA on Lipid Parameters in Patients with Hyperlipidemia (Mean % Change from Baseline to Week 12 in MENDEL-2)
Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Estimates based on a multiple imputation model that accounts for treatment adherence
* 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C
Placebo every 2 weeks (n = 76)	1	0	1	0
Ezetimibe 10 mg daily (n = 77)	-17	-14	-13	-10
REPATHA 140 mg every 2 weeks* (n = 153)	-54	-47	-44	-34
Mean difference from placebo (95% CI)	-55 (-60, -50)	-47 (-52, -43)	-45 (-50, -41)	-34 (-37, -30)
Mean difference from Ezetimibe (95% CI)	-37 (-42, -32)	-33 (-37, -29)	-32 (-36, -27)	-23 (-27, -20)

Placebo once monthly (n = 78)	1	2	2	0
Ezetimibe 10 mg daily (n = 77)	-18	-16	-13	-12
REPATHA 420 mg once monthly (n = 153)	-56	-49	-46	-35
Mean difference from placebo (95% CI)	-57 (-61, -52)	-51 (-54, -47)	-48 (-52, -44)	-35 (-38, -32)
Mean difference from Ezetimibe (95% CI)	-38 (-42, -34)	-32 (-36, -29)	-33 (-36, -29)	-23 (-26, -20)

Study 5 (RUTHERFORD-2, NCT01763918) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with HeFH on statins with or without other lipid-lowering therapies. Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome criteria (1991). In Study 5, 38% of patients had clinical atherosclerotic cardiovascular disease. The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were ≥ 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black. The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high-intensity statin therapy.

The differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −61% (95% CI: −67%, −55%; p < 0.0001) and −60% (95% CI: −68%, −52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results, see Table 7 and Figure 5.

Table 7. Effect of REPATHA on Lipid Parameters in Patients with HeFH (Mean % Change from Baseline to Week 12 in RUTHERFORD-2)
Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Estimates based on a multiple imputation model that accounts for treatment adherence
* 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C
Placebo every 2 weeks (n = 54)	-1	-1	-1	-2
REPATHA 140 mg every 2 weeks* (n = 110)	-62	-56	-49	-42
Mean difference from placebo (95% CI)	-61 (-67, -55)	-54 (-60, -49)	-49 (-54, -43)	-40 (-45, -36)

Placebo once monthly (n = 55)	4	4	4	2
REPATHA 420 mg once monthly (n = 110)	-56	-49	-44	-37
Mean difference from placebo (95% CI)	-60 (-68, -52)	-53 (-60, -46)	-48 (-55, -41)	-39 (-45, -33)

Figure 5. Effect of REPATHA on LDL-C in Patients with HeFH (Mean % Change from Baseline to Week 12 in RUTHERFORD-2)

N = number of patients randomized and dosed in the full analysis set
Estimates based on a multiple imputation model that accounts for treatment adherence
Error bars indicate 95% confidence intervals

Pediatric Patients with HeFH

Study 6 (HAUSER-RCT, NCT02392559) was a randomized, multicenter, placebo-controlled, double-blind, 24-week trial in 157 pediatric patients aged 10 to 17 years with HeFH [see Use in Specific Populations (8.4)]. HeFH was diagnosed by diagnostic criteria for HeFH [Simon Broome Register Group (1991), the Dutch Lipid Clinic Network (1999), MEDPED (1993)] or by genetic testing. Patients were required to be on a low-fat diet and optimized background lipid-lowering therapy. Patients were randomly assigned 2:1 to receive 24 weeks of subcutaneous once monthly 420 mg REPATHA or placebo; 104 patients received REPATHA and 53 patients received placebo. The mean age was 14 years (range: 10 to 17 years), 56% were female, 85% White, 1% Black, 1% Asian, 13% Other, and 8% Hispanic. The mean LDL-C at baseline was 184 mg/dL; 17% of patients were on high-intensity statin, 62% on moderate-intensity statin, and 13% on ezetimibe.

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). For additional results, see Table 8 and Figure 6.

Figure 6. Effect of REPATHA on LDL-C in Pediatric Patients with HeFH (Mean % Change from Baseline in HAUSER-RCT)

EvoMab = evolocumab; LDL-C = low density lipoprotein cholesterol; QM = monthly (subcutaneous)
N = number of patients randomized and dosed in the full analysis set.
Vertical lines represent the standard error around the mean. Plot is based on observed data and no imputation is used for missing values.

Table 8. Effect of REPATHA on Lipid Parameters in Pediatric Patients with HeFH (Mean % Change from Baseline to Week 24 in HAUSER-RCT)
Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
All adjusted p-values < 0.0001. n = number of patients randomized and dosed in the full analysis set.
Placebo once monthly (n = 53)	-6	-6	-2	-5
REPATHA 420 mg once monthly (n = 104)	-44	-41	-35	-32
Mean difference from placebo (95% CI)	-38 (-45, -31)	-35 (-42, -28)	-32 (-39, -26)	-27 (-32, -21)

Adults and Pediatric Patients with HoFH

Study 7 (TESLA, NCT01588496) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with HoFH. In this trial, 33 patients received subcutaneous injections of 420 mg of REPATHA once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other. The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received REPATHA. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents.

The difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was −31% (95% CI: −44%, −18%; p < 0.0001). For additional results, see Table 9.

Patients known to have two LDL-receptor negative alleles (little to no residual function) did not respond to REPATHA.

Table 9. Effect of REPATHA on Lipid Parameters in Patients with HoFH (Mean % Change from Baseline to Week 12 in TESLA)
Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Estimates based on a multiple imputation model that accounts for treatment adherence
Placebo once monthly (n = 16)	9	8	4	8
REPATHA 420 mg once monthly (n = 33)	-22	-20	-17	-17
Mean difference from placebo (95% CI)	-31 (-44, -18)	-28 (-41, -16)	-21 (-33, -9)	-25 (-36, -14)

Study 8 (TAUSSIG, NCT01624142) was a multicenter, open-label 5-year extension study with REPATHA in 106 patients with HoFH, who were treated with REPATHA as an adjunct to other lipid-lowering therapies. The study included 14 pediatric patients (ages 13 to 17 years). All patients in the study were initially treated with REPATHA 420 mg once monthly except for those receiving lipid apheresis at enrollment, who began with REPATHA 420 mg 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.

A total of 48 patients with HoFH received REPATHA 420 mg once monthly for at least 12 weeks in Study 8 followed by REPATHA 420 mg every 2 weeks for at least 12 weeks. Mean percent change from baseline in LDL-C were −20% at Week 12 of 420 mg once monthly treatment and −30% at Week 12 of 420 mg every 2 weeks treatment, based on available data.

Study 9 (HAUSER-OLE, NCT02624869) was an open-label, single-arm, multicenter, 80-week study to evaluate the safety, tolerability, and efficacy of REPATHA for LDL-C reduction in pediatric patients aged 10 to 17 years with HoFH [see Use in Specific Populations (8.4)]. Patients were on a low-fat diet and receiving background lipid-lowering therapy. Overall, 12 patients with HoFH received 420 mg REPATHA subcutaneously once monthly. The mean age was 12 years (range 11 to 17 years), 17% were female, 75% White, 17% Asian, and 8% Other. Median (Q1, Q3) LDL-C at baseline was 398 (343, 475) mg/dL, and all patients were on statins (atorvastatin or rosuvastatin) and ezetimibe. No patients were receiving lipid apheresis. The diagnosis of HoFH was made by genetic confirmation in all patients but enrollment by a clinical diagnosis was permitted. The median (Q1, Q3) percent change in LDL-C from baseline to Week 80 was −14% (−41, 4). Two of the 3 subjects with < 5% LDLR activity responded to evolocumab treatment.