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  1. Development & Approval Process | Drugs

Drug Trials Snapshots: HEMLIBRA

 

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 HEMLIBRA Package Insert for complete information.

HEMLIBRA (emicizumab)
hem-lee-bruh
Genentech, Inc.
Approval date: November 16, 2017


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

HEMLIBRA is a drug used to prevent or reduce frequency of bleeding episodes in children and adult patients with hemophilia A. It is to be used in patients who have developed an immune response known as a FVIII inhibitor or antibody.

Hemophilia A is an inherited blood-clotting disorder that affects primarily males. It is caused by missing or abnormal clotting protein (Factor VIII) making it more difficult to stop bleeding.

How is this drug used?

HEMLIBRA is a preventative (prophylactic) treatment injected under the skin (subcutaneous) once a week. The amount of drug used depends on patient’s weight.

What are the benefits of this drug?

Patients treated with HEMLIBRA experienced fewer bleeding episodes in comparison to patients who received no preventative treatment.

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

The table below summarizes efficacy results for the randomized portion of Trial 1. The primary endpoint was annualized bleed rate (ABR) for treated bleeds.

Table 2. Annualized Bleed Rate with HEMLIBRA Prophylaxis Arm versus No Prophylaxis Arm in Patients ≥ 12 Years of Age

EndpointHEMLIBRA Prophylaxis (N=35)No Prophylaxis (N=18)
Treated Bleeds
ABR (95% CI) a2.9 (1.7, 5.0)23.3 (12.3, 43.9)
% reduction (95% CI), p-value87% (72.3%, 94.3%), <>
% patients with 0 bleeds (95% CI)62.9 (44.9, 78.5)5.6 (0.1, 27.3)
Median ABR (IQR)0 (0, 3.7)18.8 (13.0, 35.1)
All Bleeds
ABR (95% CI)a5.5 (3.6, 8.6)28.3 (16.8, 47.8)
% reduction (95% CI), p-value80% (62.5%, 89.8%), <>
% patients with 0 bleeds (95% CI)37.1 (21.5, 55.1)5.6 (0.1, 27.3)
Treated Spontaneous Bleeds
ABR (95% CI)a1.3 (0.7, 2.2)16.8 (9.9, 28.3)
% reduction (95% CI), p-value92% (84.6%, 96.3%), <>
% patients with 0 bleeds (95% CI)68.6 (50.7, 83.1)11.1 (1.4, 34.7)
Treated Joint Bleeds
ABR (95% CI)a0.8 (0.3, 2.2)6.7 (2.0, 22.4)
% reduction (95% CI), p-value89% (48%, 97.5%), 0.0050
% patients with 0 bleeds (95% CI)85.7 (69.7, 95.2)50.0 (26.0, 74.0)
Treated Target Joint Bleeds
ABR (95% CI)a0.1 (0.03, 0.6)3.0 (1.0, 9.1)
% reduction (95% CI), p-value95% (77.3%, 99.1%), 0.0002
% patients with 0 bleeds (95% CI)94.3 (80.8, 99.3)50.0 (26.0, 74.0)

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile

a Based on negative binomial regression.

HEMLIBRA Prescribing Information

Table 3. Annualized Bleed Rate with HEMLIBRA Prophylaxis in Pediatric Patients ≥ 12 Years of Age (Interim Analysis)

EndpointABRa (95% CI)
N = 23
Median ABR (IQR)
N = 23
% Zero Bleeds (95% CI)
N = 23
Treated Bleeds0.2 (0.1, 0.6)0 (0, 0)87 (66.4, 97.2)
All Bleeds2.9 (1.8, 4.9)1.5 (0, 4.5)34.8 (16.4, 57.3)
Treated Spontaneous Bleeds0.1 (0, 0.5)0 (0, 0)95.7 (78.1, 99.9)
Treated Joint Bleeds0.1 (0, 0.5)0 (0, 0)95.7 (78.1, 99.9)
Treated Target Joint BleedsNot Estimable*0 (0, 0)100 (85.2, 100)

ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile

* No treated target joint bleeds reported

a Based on negative binomial regression

HEMLIBRA Prescribing Information

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

• Sex: All patients were males; therefore, differences in response among sexes could not be determined.

• Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in response among races could not be determined.

• Age: HEMLIBRA worked similarly in patients younger than and older than 18 years of age.

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

The table below presents efficacy results for the randomized portion of Trial 1 by age and race subgroups. Analysis by sex was not performed because all patients were males. Because Trial 2 was not randomized, no subgroup analyses were performed.

Table 4. Subgroup Analyses of Annualized Bleed Rate (ABR) for treated bleeds by Age and Race-Trial 1

 HEMLIBRA Prophylaxis
(N=35)
No prophylaxis
(N=18)
ABR ratio (95% CI)
# subjectsABR# subjectsABR
Age (years)<>40.4210.90.04 (0.005, 0.314)
≥ 18313.61628.10.13 (0.055, 0.301)
<>343.21726.70.12 (0.051, 0.286)
≥ 6513.4118.30.18 (0.008, 4.376)
RaceWhite214.71031.90.15 (0.052, 0.407)
Asian101.6336.80.04 (0.011, 0.164)
Black/African American40.547.10.07 (0.008, 0.600)
Other0NE1NENE
NE=not evaluable

Adapted from FDA Review

What are the possible side effects?

HEMLIBRA may cause severe blood clots called thrombotic microangiopathy and thromboembolism. Thrombotic microangiopathy is a condition that causes blood clots and injury to small blood vessels in organs. Thromboembolism is a condition that causes blood clots to travel and obstruct blood vessels.

The most common side effects of HEMLIBRA are injection site reactions, headache, and joint pain.

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

Below is the summary of the most common adverse reactions with frequency of 5% or greater that were observed in the safety population.

Table 5. Adverse Reactions Reported in ≥ 5% of Patients from Pooled Clinical Trials with HEMLIBRA (safety population)

Body SystemAdverse ReactionNumber of Patients
n (%)
(N=189)
General Disorders and Administration Site ConditionsInjection site reaction*35 (19%)
Pyrexia13 (7%)
Nervous System DisordersHeadache28 (15%)
Gastrointestinal DisordersDiarrhea12 (6%)
Musculoskeletal and Connective Tissue DisordersArthralgia18 (10%)
Myalgia9 (5%)

* Includes injection site bruising, injection site discomfort, injection site erythema, injection site hematoma, injection site induration, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticarial, and injection site warmth.

HEMLIBRA Prescribing Information

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

• Sex: All patients were male; therefore, differences in side effects among sexes could not be determined.

• Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in side effects among races could not be determined.

• Age: The occurrence of side effects was similar in patients younger and older than 18 years of age.

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

The tables below summarize the frequency of the three most common adverse reactions by race and age for the safety population.

Table 6. Pooled Safety Analysis by Race (safety population)

Adverse ReactionRace
White
N=106
Asian N=48Black or African American
N=21
Other/Unknown
N=14
Injection site reactions, n (%)18 (17%)11 (23%)1 (5%)5 (36%)
Headache, n (%)15 (14%)6 (13%)2 (10%)5 (36%)
Arthralgia, n (%)11 (10%)2 (4%)2 (10%)2 (14%)

Clinical Trial Data

Table 7. Pooled Safety Analysis by Age (safety population)

Adverse ReactionAge
< 18="" years="">
N =95
≥18 years
N=94
Number of Patients
N=189
Injection site reactions, n (%)18 (19%)17 (18%)35 (19%)
Headache, n (%)17 (18%)11 (12%)28 (15%)
Arthralgia, n (%)7 (7%)11 (12%)18 (10%)

Clinical Trial Data

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved HEMLIBRA based on evidence from three clinical trials, Trial 1 (NCT02622321), Trial 2 (NCT02795767), and Trial 3 of 189 patients with hemophilia A.

Trial 1 was conducted at 43 sites in the following 14 countries: Australia, Costa Rica, France, Germany, Italy, Japan, New Zealand, Poland, South Africa, South Korea, Spain, Taiwan, United Kingdom, and the United States.

Trial 2 was conducted at 24 sites in the following 10 countries: Costa Rica, France, Germany, Italy, Japan, South Africa, Spain, Turkey, United Kingdom, and the United States.

Trial 3 was conducted in Japan.

Figures below summarize 189 patients by sex, race and age who were considered in the assessment of HEMLIBRA’s safety (safety population). This population includes all patients who received at least one dose of the drug any time during the drug development.

Patient demographics by trials are presented under MORE INFO.

Figure 1. Baseline Demographics by Sex (safety population)

Pie chart summarizing how many males and females were in the clinical trials. In total, 189 males (100%) and 0 (0%) females participated in the clinical trials.

FDA Review

Figure 2 and Table 1 summarize the percentage of patients by race in clinical trials.

Figure 2. Baseline Demographics by Race (safety population)

Pie chart summarizing the percentage of patients by race enrolled in the clinical trials. In total, 106 White (56%), 48 Asian (26%), 21 Black or African American (11%), 4 Other patients (2%), and 10 patients (5%) where race was not reported participated in the clinical trial.

FDA Review

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage
White10656
Black or African American2111
Asian4826
American Indian or Alaska Native1less than 1
Native Hawaiian or Other Pacific Islander1less than 1
Multiple21
Unknown105

Adapted from FDA Review

Figure 3 summarizes the percentage of patients by age in clinical trials.

Figure 3. Baseline Demographics by Age (safety population)

Pie charts summarizing how many individuals of certain age groups were enrolled in the clinical trials. In total, 57 patients (30%) were less than 12 years old, 38 patients (20%) were 12 – 18 years old, 89 patients were 18 – 65 years old, and 5 patients (3%) were 65 years and older.

FDA Review

Who participated in the trials?

The safety population of 189 patients includes any patient who received at least one dose of HEMLIBRA across the clinical development program and is presented below.

Table 8. Demographic Characteristics of Safety Population

Demographic ParametersAll patients N=189 n (%)
Sex
Male189 (100%)
Age (years)
Median (Min, Max)17 (1, 75)
Mean (SD)24 (17.7)
Age Group (years)
<>57 (30.2)
12-1838 (20.1)
18-6589 (47.1)
≥655 (2.6)
Race
White106 (56.1)
Black or African American21 (11.1)
Asian48 (25.4)
American Indian or Alaska Native1 (0.5)
Native Hawaiian or Other Pacific Islander1 (0.5)
Multiple2 (1.1)
Unknown10 (5.3)
Ethnicity
Hispanic or Latino23 (12.2)
Not Hispanic or Latino146 (77.2)
Not reported/Unknown20 (10.6)

Clinical Trial Data

The tables below summarize demographics of patients enrolled in Trials 1 and 2.

Table 9. Demographic Characteristics for Trials 1 and 2 (enrolled population)

Demographic ParametersTrial 1
(N=109)
n (%)
Trial 2
(N=60)
n (%)
Sex
Male109 (100%)60 (100%)
Age
Mean years (SD)31.5 (15.8)6.9 (3.3)
Median (years)28.07
Age Group
< 65="">105 (96.3%)60 (100%)
> 65 years4 (3.7%)0
Race
White71 (65.1%)32 (53.3%)
Black or African American11 (10.1%)10 (16.7%)
Asian21 (19.3%)10 (16.7%)
Other/Unknown6 (5.5%)8 (1.3%)
Ethnicity
Hispanic or Latino18 (16.5)5 (8.3)
Not Hispanic or Latino91 (83.5)53 (88.3%)
Unknown02 (3.4)
Region
Africa6 (5.5)6 (10)
Asia17 (15.6)9 (15%)
Australia and Oceania6 (5.5)0
Central America5 (4.6)1(1.6)
North America39 (35.8)17 (28.3)
Europe36 (33.0)27(45%)

Adapted from FDA Review

The table below summarizes demographics of patients enrolled in Trial 3 that provided additional safety data.

Table 10. Demographic Characteristics for Trial 3 (enrolled population in Part C)

Demographic ParametersN = 18
n (%)
Age
Median (Min, Max)30 (12, 58)
Mean32.9 (15.4)
Gender
Male18 (100%)
Race
Asian18 (100%)
Country
Japan18 (100%)

Adapted from FDA Review

How were the trials designed?

Trial 1 enrolled patients 12 years and older with hemophilia A with Factor VIII inhibitors. Approximately half of the patients who were not receiving prophylaxis with a bypassing agent prior to enrollment on the study received, in random order, either HEMLIBRA once a week or no preventative treatment for 24 weeks. These patients were evaluated for benefit and side effects.

Trial 2 enrolled patients younger than 12 years of age with hemophilia A with factor VIII inhibitors. All patients received HEMLIBRA once a week. At the time of data analysis (interim analysis) only patients who completed at least 12 weeks of treatment with HEMLIBRA were evaluated for benefit. All enrolled patients were evaluated for side effects.

In Trial 3, patients 12 years and older received HEMLIBRA subcutaneously once a week for longer than 52 weeks. Patients were evaluated primarily for side effects.

The benefit of HEMLIBRA was assessed in Trial 1 and Trial 2 by counting the number of bleeding episodes during treatment.

How were the trials designed?

FDA approved HEMLIBRA based primarily on data from three, open-label, multicenter trials in male patients with hemophilia A with Factor VIII inhibitors.

In Trial 1, patients 12 years and older with hemophilia A with factor VIII inhibitors were enrolled. In the randomized portion of the trial, patients received either HEMLIBRA treatment or no preventative treatment. Patients, who received treatment, received HEMLIBRA subcutaneously at a dose of 3 mg/kg/week for 4 weeks, followed by 1.5 mg/kg weekly for a total of 24 weeks. To obtain additional efficacy and safety data, all patients could continue their HEMLIBRA dose of 1.5 mg/kg/week after completing 24 weeks of treatment, and patients who were randomized to no preventative treatment could start HEMLIBRA treatment after 24 weeks.

In Trial 2, pediatric patients less than 12 years old, could have been either on prophylaxis or episodic treatment with bypassing agents prior to study enrollment. All patients were treated with HEMLIBRA subcutaneously at a dose of 3 mg/kg/week for 4 weeks, followed by 1.5 mg/kg/week. An interim efficacy analysis was conducted on patients who received at least 12 weeks of treatment. Patients who continued to benefit from HEMLIBRA treatment could continue treatment.

The efficacy outcomes, in both trials, were the annualized bleeding rates.

In Trial 3 which was a dose finding trial, patients 12 years and older with hemophilia A received HEMLIBRA at three different dosing regimens. Trial data was provided for safety analysis only.

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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