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Drug Trials Snapshots: REPATHA

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the REPATHA Prescribing Information for complete information.

REPATHA (evolocumab)
ri-Path-a
Amgen Inc.
Approval date: August 27, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

REPATHA is a drug for the treatment of high LDL cholesterol, which is sometimes referred to as “bad cholesterol”.

REPATHA is to be used in the following groups of patients: 1) patients with an inherited condition called heterozygous familial hypercholesterolemia (HeFH) or 2) patients who have had complications of having too much cholesterol, such as heart attacks and strokes. For these patients, it is approved to be used in addition to diet and the highest dose of a statin (another drug commonly used to lower cholesterol) that a patient can tolerate, and only when LDL cholesterol needs to be lowered further.

REPATHA is also to be used in patients with an inherited condition called homozygous familial hypercholesterolemia (HoFH). For these patients, it is approved to be used in addition to diet and other drugs and treatment that lower LDL cholesterol, and only when LDL cholesterol needs to be lowered further.

How is this drug used?

REPATHA is an injection that is given under the skin in the thigh, abdomen, or upper arm.

What are the benefits of this drug?

REPATHA lowers LDL cholesterol.

What are the benefits of this drug (results of trials used to assess efficacy)?

The efficacy of REPATHA was investigated in three double-blind, placebo-controlled trials that included 764 patients with atherosclerotic cardiovascular disease (ASCVD) and HeFH and one that evaluated 49 patients with HoFH. Table 3 below summarizes the results for the primary efficacy endpoint, the mean percent change in LDL-C from baseline for REPATHA compared with placebo, for each trial.

Table 3. Percent (%) Change in LDL-C at Week 12 (Week 52 for Trial 2) by trial

 LS Mean:
% Change
Difference:
Repatha-Placebo (95% CI)
Trial 1
Repatha 140mg every 2 weeks  (n=105)-64%-71% (-81, -61)
Placebo every 2 weeks(n=42)7% 
Repatha 420 mg once monthly (n=105)-58%-63% (-76, -50)
Placebo once monthly (n=44)5% 
Trial 2
Repatha 420 mg once monthly (n=95)-52%-54% (-65, -42)
Placebo once monthly (n=44)2% 
Trial 3 (HeFH only)
Repatha 140 mg every 2 weeks (n=110)-62%-61% (-67, -55)
Placebo every 2 weeks (n=54)-1% 
Repatha 420 mg once monthly (n=110)-56%-60% (-68, -52)
Placebo once monthly (n=55)4% 
Trial 4 (HoFH only)
Repatha 420 mg once monthly (n=33)-22% 
Placebo once monthly (n=16)9%-31% (-44, -18)

Statistical Review

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: REPATHA worked similarly in men and women.
  • Race: The majority of patients in the trials were white. Differences in response to REPATHA among races could not be determined.
  • Age: REPATHA worked similarly in all age groups studied.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Figure 7 summarizes the primary efficacy endpoint, the mean percent change in LDL-C from baseline to week 12 (week 52 in Trial 2), by sex, age, race, and ethnicity.

Data are provided combining Trials 1 and 2 in ASCVD patients and Trial 3 in HeFH patients to allow for the largest possible sample sizes in each subgroup and since comparisons of the treatment effect across subgroups were consistent across trials. Statistical tests assessing whether the treatment effect varied across subgroups are provided.

Figure 7. Difference (95% Confidence Interval) in Average Percent Change in LDL-C (Repatha minus placebo); Trials 1 to 3 Combined (ASCVD and HeFH)

Figure summarizes the primary efficacy endpoint, the mean percent change in LDL-C from baseline to week 12 (week 52 in Trial 2), by sex, age, race, and ethnicity.  Data are provided combining Trials 1 and 2 in ASCVD patients and Trial 3 in HeFH patients to allow for the largest possible sample sizes in each subgroup and since comparisons of the treatment effect across subgroups were consistent across trials.  Statistical tests assessing whether the treatment effect varied across subgroups are provided.

Statistical Review

Figure 8 summarizes the primary efficacy endpoint, the mean percent change in LDL-C from baseline to week 12, for Trial 4 in HoFH patients, by sex, age, race, and ethnicity. Statistical tests assessing whether the treatment effect varied across subgroups are provided.

Figure 8. Difference (95% Confidence Interval) in Average Percent Change in LDL-C (Repatha minus placebo); Trial 4 (HoFH)

Figure summarizes the primary efficacy endpoint, the mean percent change in LDL-C from baseline to week 12, for Trial 4 in HoFH patients, by sex, age, race, and ethnicity.  Statistical tests assessing whether the treatment effect varied across subgroups are provided.

Statistical Review

What are the possible side effects?

The most common side effects are common cold, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising where the injection is given.

Allergic reactions have also been reported in patients treated with REPATHA.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions reported in at least 3% of REPATHA-treated patients and occurred more frequently than in placebo-treated patients in the 52-week trial (referred to as Trial 2) in patients with primary hyperlipidemia.

Table 4. Adverse Reactions Occurring in Greater than or Equal to 3% of REPATHA-Treated Patients and More Frequently than with Placebo in Trial 2

Adverse ReactionPlacebo
(N=302)
%
REPATHA
(N=599)
%
Nasopharyngitis9.610.5
Upper respiratory tract infection6.39.3
Influenza6.37.5
Back pain5.66.2
Injection site reactions†5.05.7
Cough3.64.5
Urinary tract infection3.64.5
Sinusitis3.04.2
Headache3.64.0
Myalgia3.04.0
Dizziness2.63.7
Musculoskeletal pain3.03.3
Hypertension2.33.2
Diarrhea2.63.0
Gastroenteritis2.03.0

† includes erythema, pain, bruising
REPATHA Prescribing Information, Table 1

The table below summarizes adverse reactions in seven pooled 12-week controlled trials.

Table 5. Adverse Reactions Occurring in Greater than 1% of REPATHA-Treated Patients and More Frequently than with Placebo in Pooled 12-Week Studies

Adverse ReactionPlacebo
(N=1224)
%
REPATHA†
(N=2052)
%
Nasopharyngitis3.94.0
Back pain2.22.3
Upper respiratory tract infection2.02.1
Arthralgia1.61.8
Nausea1.21.8
Fatigue1.01.6
Muscle spasms1.21.3
Urinary tract infection1.21.3
Cough0.71.2
Influenza1.11.2
Contusion0.51.0

† 140mg every 2 weeks and 420mg once monthly combined
REPATHA Prescribing Information, Table 2

Prescribing Information for REPATHA includes a summary of adverse effects observed in the 12-week trial of 49 patients with HoFH. The adverse reactions that occurred in at least two REPATHA-treated patients, and more frequently than in placebo-treated patients, included:

  • Upper respiratory tract infection (9.1% versus 6.3%)
  • Influenza (9.1% versus 0%)
  • Gastroenteritis (6.1% versus 0%)
  • Nasopharyngitis (6.1% versus 0%)

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: The risk of side effects was similar in men and women.
  • Race: The majority of subjects were white. Differences in side effects among races could not be determined.
  • Age: The risk of side effects was similar among age groups studied.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes allergic reaction by subgroup in a pool of the 52-week trial and seven 12-week trials. The population represented is the Safety population, which includes any patients who received at least one dose of trial drug (REPATHA or placebo).

Table 6. Subgroup Analysis of Allergic Reactions—Pooled Trials

SubgroupREPATHA
(N=2651)
Placebo
(N=1526)
n (%)Total Nn (%)Total N
All Allergic Reactions136 (5.1)265172 (4.7)1526
Sex
Male47 (3.5)134630 (4.0)752
Female89 (6.8)130542 (5.4)774
Age Group
less than 65 years102 (5.4)190353 (4.8)1114
65 years and older34 (4.5)74819 (4.6)412
Race
White106 (4.7)224055 (4.3)1268
Black or African American7 (4.5)1554 (5.5)73
Asian17 (8.3)20411 (7.1)155
American Indian or Alaska Native0 (0.0)60 (0.0)2
Native Hawaiian or Other Pacific Islander0 (0.0)20 (0.0)5
Other6 (13.6)442 (8.7)23

Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved REPATHA based on evidence including that from 9 clinical trials of 4,226 patients. This includes two trials that specifically enrolled patients with HeFH and one that enrolled patients with HoFH.

Figure 1 summarizes how many men and women were enrolled in the 8 clinical trials used to evaluate the side effects of REPATHA in the trials that evaluated patients with clinical atherosclerotic cardiovascular disease and those with heterozygous familial hypercholesterolemia (HeFH). MORE INFO includes a table outlining the demographics of 3 trials that evaluated the benefit of the drug.

Figure 1. Baseline Demographics by Sex—Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

Pie chart summarizing how many men and women were enrolled in the clinical trials used to evaluate efficacy of the drug REPATHA for HeFH.  In total, 2098 men (50%) and 2079 women (50%) participated in the clinical trials used to evaluate efficacy of the drug REPATHA for HeFH.

Clinical Trial Data

The figure below summarizes how many men and women were enrolled in the trial that enrolled patients with HoFH. These patients are described in separate figures because patients with HoFH are generally younger and have a disease that is very different than the patients represented in Figure 1.

Figure 2. Baseline Demographics by Sex –Trial of Patients with HoFH

Pie chart summarizing how many men and women were enrolled in the clinical trials used to evaluate efficacy of the drug REPATHA for HoFH.  In total, 25 men (51%) and 24 women (49%) participated in the clinical trials used to evaluate efficacy of the drug REPATHA for HoFH.

Clinical Trial Data

Figure 3 and Table 1 summarize the percentage of patients by race enrolled in the clinical trials used to evaluate side effects in the trials that evaluated patients with clinical atherosclerotic cardiovascular disease and those with heterozygous familial hypercholesterolemia (HeFH).

Figure 3. Demographics by Race--Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

Pie chart summarizing the percentage of patients by race enrolled in the REPATHA clinical trial for HeFH. In total, 3508 White (85%), 228 Black (6%), 359 Asian (9%), 7 Native Hawaiian or Other Pacific Islander (<1%), 8 American Indian or Alaskan Native (<1%), and 67 identified as Other (2%) participated in the clinical trial for HeFH.

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Clinical Trial Data

Table 1. Baseline Demographics by Race--Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

RaceNumber of PatientsPercentage

American Indian or Alaska Native

80%

Asian

3599%

Black or African American

2285%

Native Hawaiian or Other Pacific Islander

70%

White

350884%

Other

672%

Clinical Trial Data

Figure 4 and Table 2 summarize how many by race were enrolled in the trial of patients with HoFH.

Figure 4. Baseline Demographics by Race –Trial of Patients with HoFH

Pie chart summarizing the percentage of patients by race enrolled in the REPATHA clinical trial HoFH. In total, 44 White (90%), 2 Asian (4%), and 3 identified as Other (6%) participated in the clinical trial.

Clinical Trial Data

Table 2. Baseline Demographics by Race--Trial of Patients with HoFH

RaceNumber of PatientsPercentage
White4490%
Asian24%
Other36%

Clinical Trial Data

The figure below summarizes how many patients by age were enrolled in the clinical trials used to evaluate side effects in the trials that evaluated patients with clinical atherosclerotic cardiovascular disease and those with heterozygous familial hypercholesterolemia (HeFH).

Figure 5. Baseline Demographics by Age-- Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

Pie chart summarizing how many individuals of certain age groups were enrolled in the REPATHA clinical trial for HeFH.  In total, 3017 were below 65 years (72%) and 1160 were 65 years and older (28%).

Clinical Trial Data

The figure below summarizes how many by race were enrolled in the trial of patients with HoFH.

Figure 6. Baseline Demographics by Race--Trial of Patients with HoFH

Pie chart summarizing how many individuals of certain age groups were enrolled in the REPATHA clinical trial for HoFH.  In total, 49 were below 65 years (100%).

Clinical Trial Data

Who participated in the trials?

The first table below summarizes baseline demographics for a pooled population from 3 trials that supported the efficacy of REPATHA: patients with primary hyperlipidemia and clinical atherosclerotic cardiovascular disease from 2 trials, and patients with heterozygrous familial hypercholersterolemia from 1 trial. These trials and populations are also described in the Prescribing Information for REPATHA.

The second table below summarizes baseline demographics for the pooled population from 8 trials that supported the safety of REPATHA.

Table 7. Baseline Demographics for Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH in 3 Pooled Trials

Demographic ParametersREPATHA 
N=525
n (%)
Placebo
N=239
n (%)
Total
N=764
n (%)
Sex
Male331 (63.0)142 (59.4)473 (61.9)
Female194 (37.0)97 (40.6)291 (38.1)
Age
Mean years (SD)57.6 (11.4)55.5 (12.6)56.9 (11.8)
Median (years)595658
Min, Max (years)20, 8019, 8019, 80
Age Group
below 65 years365 (69.5)183 (76.6)548 (71.7)
65 years and above160 (30.5)56 (23.4)216 (28.3)
Race
White479 (91.2)218 (91.2)697 (91.2)
Black or African American7 (1.3)5 (2.1)12 (1.6)
Asian19 (3.6)5 (2.1)24 (3.1)
American Indian or Alaska Native0 (0.0)0 (0.0)0 (0.0)
Native Hawaiian or Other Pacific Islander0 (0.0)0 (0.0)0 (0.0)
Other20 (3.8)11 (4.6)31 (4.1)
Ethnicity
Hispanic or Latino14 (2.7)8 (3.3)22 (2.9)
Not Hispanic or Latino511 (97.3)231 (96.7)742 (97.1)
Region
United States79 (15.0)38 (15.9)117 (15.3)
Rest of the World446 (85.0)201 (84.1)647 (84.7)
Canada73 (13.9)23 (9.6)96 (12.6)
South America0 (0.0)0 (0.0)0 (0.0)
Europe262 (49.9)132 (55.2)394 (51.6)
Asia43 (8.2)13 (5.4)56 (7.3)
Africa68 (13.0)33 (13.8)101 (13.2)

Clinical Trial Data

Table 8. Baseline Demographics for 8 Pooled Trials that Included Patients with Clinical Atherosclerotic Cardiovascular Disease or HeFH

  Demographic ParametersREPATHA
(N=2651)
n (%)
Placebo
(N=1526)
n (%)
Total
(N=4177)
n (%)
Sex
Male1346 (50.8)752 (49.3)2098 (50.2)
Female1305 (49.2)774 (50.7)2079 (49.8)
Age
Mean years (SD)57.1 (11.3)57.0 (11.1)57.1 (11.2)
Median (years)585858
Min, Max (years)18, 8019, 8018, 80
Age Group
below 65 years1903 (71.8)1114 (73.0)3017 (72.2)
65 years and above748 (28.2)412 (27.0)1160 (27.8)
Race
American Indian or Alaska Native6 (0.2)2 (0.1)8 (0.2)
Asian204 (7.7)155 (10.2)359 (8.6)
Black or African American155 (5.8)73 (4.8)228 (5.5)
Native Hawaiian or Other Pacific Islander2 (0.1)5 (0.3)7 (0.2)
White2240 (84.5)1268 (83.1)3508 (84.0)
Other44 (1.7)23 (1.5)67 (1.6)
Ethnicity
Hispanic or Latino146 (5.5)81 (5.3)227 (5.4)
Not Hispanic or Latino2505 (94.5)1445 (94.7)3950 (94.6)
Region
United States908 (34.3)506 (33.2)1414 (33.9)
Rest of the World1743 (65.7)1020 (66.8)2763 (66.1)
Canada319 (12.0)172 (11.3)491 (11.8)
South America0 (0.0)0 (0.0)0 (0.0)
Europe1101 (41.5)627 (41.1)1728 (41.4)
Asia205 (7.7)156 (10.2)361 (8.6)
Africa118 (4.5)65 (4.3)183 (4.4)

Clinical Trial Data

The table below summarizes baseline demographics for the trial that enrolled patients with HoFH.

Table 8. Baseline Demographics for the Trial of HoFH Patients

Demographic ParametersREPATHA
N=33
n (%)
Placebo 
N=16
n(%)
Total
N=49
n(%)
Sex
Male17 (51.5)8 (50.0)25 (51.0)
Female16 (48.5)8 (50.0)24 (49.0)
Age
Mean years (SD)30.3 (12.4)32.1 (13.8)30.9 (12.8)
Median (years)313031
Min, Max (years)13, 5114, 5713, 57
Age Group
below 65 years33 (100.0)16 (100.0)49 (100.0)
65 years and above0 (0.0)0 (0.0)0 (0.0)
Race
White29 (87.9)15 (93.8)44 (89.8)
Black or African American0 (0.0)0 (0.0)0 (0.0)
Asian1 (3.0)1 (6.3)2 (4.1)
American Indian or Alaska Native0 (0.0)0 (0.0)0 (0.0)
Native Hawaiian or Other Pacific Islander0 (0.0)0 (0.0)0 (0.0)
Other3 (9.1)0 (0.0)3 (6.1)

Clinical Trial Data

How were the trials designed?

There were nine placebo-controlled trials that contributed to the evaluation of the side effects of REPATHA, including one 52-week placebo-controlled trial and eight 12-week placebo-controlled trials, including two that specifically enrolled participants with HeFH and one that enrolled participants with HoFH. Four of these trials were also central to the evaluation of the benefit of REPATHA. In each of these trials, patients were randomly assigned to receive REPATHA or placebo injections. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed.

The benefit of REPATHA (the percent change in LDL C blood levels) was measured at 12 weeks in all trials except for one in which it was measured at 52 weeks.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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