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The

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Original Article

Factor VIIIMimetic Function of Humanized


Bispecific Antibody in Hemophilia A
Midori Shima, M.D., Ph.D., Hideji Hanabusa, M.D., Ph.D.,
Masashi Taki, M.D., Ph.D., Tadashi Matsushita, M.D., Ph.D., Tetsuji Sato, M.D.,
Katsuyuki Fukutake, M.D., Ph.D., Naoki Fukazawa, B.Sc.,
Koichiro Yoneyama, M.Sc., Hiroki Yoshida, M.Sc., and Keiji Nogami, M.D., Ph.D.

A BS T R AC T
BACKGROUND
From Nara Medical University, Kashihara
(M.S., K.N.), Ogikubo Hospital (H.H.),
Tokyo Medical University (K.F.), and Chugai
Pharmaceutical (N.F., K.Y., H.Y.), Tokyo,
St. Marianna University School of Medicine, Kawasaki (M.T.), Nagoya University,
Nagoya (T.M.), and University of Occupational and Environmental Health, Kitakyushu (T.S.) all in Japan. Address reprint
requests to Dr. Shima at the Department
of Pediatrics, Nara Medical University,
840 Shijo-cho, Kashihara, Nara 634-8522,
Japan, or at mshima@naramed-u.ac.jp.
N Engl J Med 2016;374:2044-53.
DOI: 10.1056/NEJMoa1511769
Copyright 2016 Massachusetts Medical Society.

In patients with severe hemophilia A, standard treatment is regular prophylactic


and episodic intravenous infusions of factor VIII. However, these treatments are
burdensome, especially for children, and may lead to the formation of antifactor
VIII alloantibodies (factor VIII inhibitors). Emicizumab (ACE910), a humanized
bispecific antibody mimicking the cofactor function of factor VIII, was developed
to abate these problems.
METHODS

We enrolled 18 Japanese patients with severe hemophilia A (with or without factor


VIII inhibitors) in an open-label, nonrandomized, interindividual dose-escalation
study of emicizumab. The patients received subcutaneous emicizumab weekly for
12 weeks at a dose of 0.3, 1.0, or 3.0 mg per kilogram of body weight (cohorts 1, 2,
and 3, respectively). The end points were safety and pharmacokinetic and pharmacodynamic profiles. An additional, exploratory end point was the annualized bleeding rate, calculated as 365.25 times the number of bleeding episodes, divided by
the number of days in the treatment period as compared with the 6 months before
enrollment.
RESULTS

Emicizumab was associated with neither serious adverse events nor clinically relevant coagulation abnormalities. Plasma concentrations of emicizumab increased
in a dose-dependent manner. Activated partial-thromboplastin times remained
short throughout the study. The median annualized bleeding rates in cohorts 1, 2,
and 3 decreased from 32.5 to 4.4, 18.3 to 0.0, and 15.2 to 0.0, respectively. There
was no bleeding in 8 of 11 patients with factor VIII inhibitors (73%) and in 5 of 7
patients without factor VIII inhibitors (71%). Episodic use of clotting factors to
control bleeding was reduced. Antibodies to emicizumab did not develop.
CONCLUSIONS

Once-weekly subcutaneous administration of emicizumab markedly decreased the


bleeding rate in patients who had hemophilia A with or without factor VIII inhibitors. (Funded by Chugai Pharmaceutical; JapicCTI number, 121934.)

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Humanized Bispecific Antibody in Hemophilia A

emophilia A is a serious bleeding


disorder caused by a deficiency of clotting factor VIII. Approximately 50% of
patients have severe hemophilia A,1 defined as
less than 1% residual factor VIII activity (<1 IU
per deciliter).2 Such patients have severe bleeding
from early childhood, and without appropriate
treatment, recurrent bleeding into joints can lead
to irreversible hemoarthropathy.3,4
Standard treatment for hemophilia A includes
regular prophylaxis and episodic treatment with
recombinant or plasma-derived factor VIII. The
goals of prophylaxis with factor VIII are to increase factor VIII activity to at least a moderate
level (1 to 5 IU per deciliter)5 and to reduce
bleeding episodes and joint damage.6 However,
there are significant barriers to this treatment.
The standard regimen, which consists of intravenous administration of factor VIII three times
per week or every other day,6,7 can impose a
substantial burden on patients, particularly children and patients with poor venous access.8-11
Furthermore, despite large improvements in hemo
static activity with regular prophylaxis, the primary aim of this treatment is to achieve factor
VIII activity of at least 1 IU per deciliter at trough
drug levels, yet the level of activity required to
minimize the risk of joint bleeding is 10 to 15 IU
per deciliter.12 Moreover, induction of antifactor
VIII alloantibodies (factor VIII inhibitors), which
occurs in 30% of patients with severe hemophilia A, renders treatment with factor VIII ineffective.13
The main treatment for patients in whom
factor VIII inhibitors develop is episodic treatment or regular prophylaxis with bypassing
agents, including recombinant activated factor
VII (factor VIIa) or activated prothrombin complex concentrates, which provide imperfect control of bleeding.14,15 Another option is induction
of immune tolerance, an approach that aims to
eradicate factor VIII inhibitors. Immune tolerance induction is successful in approximately
70% of patients,16 but it is intensive, requiring
frequent and long-term administration of factor
concentrate,17-19 and many patients with a high
factor VIII inhibitor titer are not eligible for this
treatment.19
A more effective, less burdensome treatment
is needed for patients with hemophilia A. Emici-

zumab (ACE910), developed to help meet this


need, is a humanized bispecific antibody that
binds to and bridges activated factor IX (factor
IXa) and factor X, thereby acting as a factor VIII
mimetic agent (see Fig. S1 in the Supplementary
Appendix, available with the full text of this article at NEJM.org).20,21 Because of its unique structure, emicizumab is not expected to induce or be
affected by factor VIII inhibitors. It has good
subcutaneous bioavailability in nonhuman primates and a long half-life (4 to 5 weeks) in
healthy volunteers.22,23 Emicizumab has been
shown to have in vivo hemostatic activity in a
nonhuman primate model of acquired hemophilia A22,24; it also has been shown to have
limited adverse effects in healthy volunteers after
a single subcutaneous administration of 1 mg or
less per kilogram of body weight.23
In this study, we evaluated the safety, pharmacokinetics, and pharmacodynamics of weekly
subcutaneous administration of emicizumab in
patients who had severe hemophilia A with or
without factor VIII inhibitors. We also performed
an exploratory analysis to determine whether
emicizumab can prevent bleeding and maintain
acceptable hemostatic activity.25

A Quick Take is
available at
NEJM.org

Me thods
Study Oversight

This was a 12-week, open-label, nonrandomized,


interindividual dose-escalation study involving
Japanese patients with severe hemophilia A at
six hemophilia treatment centers in Japan. The
study was conducted from May 2013 through
August 2014 in accordance with the International Conference on Harmonisation Guidelines
for Good Clinical Practice; it was approved by the
institutional review board at each participating
center and was registered before initiation. All
patients gave written informed consent before
enrollment. The protocol, which was developed
by the sponsor, Chugai Pharmaceutical, is available at NEJM.org.
The first author, along with three authors
employed by the sponsor, designed the study.
Two authors employed by the sponsor analyzed
the data and vouch for the accuracy and completeness of the data and for the adherence of
the study to the protocol. The sponsor had the

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2045

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right to review the manuscript, and all authors


had access to the data and made the decision to
submit the manuscript for publication. The first
author and one author employed by the sponsor
prepared the first draft with writing assistance
provided by an employee of the sponsor; assistance with subsequent drafts was provided by
ProScribe, part of Envision Pharma Group, under
contract with Chugai Pharmaceutical.

activity per deciliter was estimated to be approximately 0.3, on the basis of nonclinical data (see
the Description section in the Supplementary
Appendix), these trough levels were expected to
correspond to 3, 10, and 30 IU of equivalent factor VIII activity per deciliter, respectively, and to
be sufficient to prevent bleeding. We evaluated
outcome measures up to week 12 (or at the time
of treatment discontinuation if the regimen was
stopped early) before enrolling patients at the
Study Patients and Study Design
next dose level. Bleeding episodes were treated
Japanese patients (12 to 59 years of age) who had with factor VIII or a bypassing agent, according
severe hemophilia A, with or without factor VIII to standard clinical practice.
inhibitors, were eligible for enrollment in the
study. Before enrollment, patients without factor Outcome Measures
VIII inhibitors had received regular prophylaxis Emicizumab plasma concentrations, activated
with factor VIII; patients with factor VIII inhibi- partial-thromboplastin time, thrombin generators had received episodic therapy or regular tion triggered by activated factor XI (factor XIa),
prophylaxis with a bypassing agent and had had factor IX and factor X plasma concentrations,
a total of six or more bleeding episodes in the and plasma anti-emicizumab antibodies were
previous 6 months. Major exclusion criteria were assessed as previously described.23 Safety outa history of a bleeding disorder other than con- comes included adverse events, laboratory test
genital hemophilia A; clinically significant infec- results, vital signs, and 12-lead electrocardiotion other than infection with hepatitis B virus, grams. The annualized bleeding rate, an exhepatitis C virus, or human immunodeficiency ploratory efficacy end point, was calculated as
virus; and a value for protein C activity, free 365.25 times the number of bleeding episodes,
protein S antigen level, or antithrombin activity divided by the number of days in the treatment
that was below the low end of the normal range period. A bleeding episode was defined as bleedat screening. At least two patients with and two ing or suspected bleeding that required treatment
patients without factor VIII inhibitors were en- with clotting factors. The overall annualized
rolled in each cohort.
bleeding rate and the annualized bleeding rates
Enrolled patients were assigned to cohort 1, at joints and at target joints (i.e., joints at which
cohort 2, or cohort 3 and received subcutaneous 3 spontaneous bleeding episodes had occurred
emicizumab (80 mg per milliliter) at an initial during the 6 months26 before study entry) during
dose of 1.0 mg per kilogram of body weight emicizumab treatment were compared with the
(cohort 1) or 3.0 mg per kilogram (cohorts 2 annualized bleeding rates for the 6 months beand 3) at week 0 (day 1), followed by a once- fore study entry (calculated retrospectively from
weekly subcutaneous dose of 0.3, 1.0, or 3.0 mg medical records).
per kilogram (cohorts 1, 2, and 3, respectively)
from week 1 through week 12. The initial and Statistical Analysis
subsequent doses for cohort 3 were the same. Summary statistics were calculated for demoOn the basis of pharmacokinetic data modeling graphic characteristics and pharmacokinetic,
from a previous nonclinical study,22 these doses pharmacodynamic, and safety outcomes. The
were predicted to result in plasma emicizumab target sample size was not based on hypothesis
concentrations at 1 week after each administra- testing; we planned to enroll at least six patients
tion (trough levels) of 11.2 g per milliliter (co- per cohort to enable exploratory evaluations.
hort 1), 37.3 g per milliliter (cohort 2), and Bleeding episodes during the 6 months before
112 g per milliliter (cohort 3) at steady state. study entry and between the first dose and week
Since the factor for the conversion of micro- 12 (or treatment discontinuation) were summagrams of emicizumab per milliliter to interna- rized. Given the small size of the cohorts, statistional units of equivalent factor VIII hemostatic tical comparisons were not performed.

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Humanized Bispecific Antibody in Hemophilia A

Table 1. Baseline Demographic and Clinical Characteristics of the Study Population.*


Cohort 1
(N=6)

Cohort 2
(N=6)

Cohort 3
(N=6)

Median yr

32

30

33

Range yr

1751

1258

1258

18 yr no. (%)

1 (17)

2 (33)

2 (33)

Median

60

56

66

Range

4181

4882

4978

No no. (%)

2 (33)

2 (33)

3 (50)

Yes no. (%)

4 (67)

4 (67)

3 (50)

Titer range Bethesda units/ml

39111

349

654

2 (33)

2 (33)

3 (50)

3 (50)

4 (67)

4 (67)

37.925.2

19.69.8

15.911.9

Characteristic
Age

Weight kg

Factor VIII inhibitors

Treatment before enrollment no. (%)


Factor VIII prophylaxis
Prophylaxis with bypassing agents
Episodic treatment with bypassing agents
Annualized bleeding rate during 6 mo before study entry
Mean
Median

32.5

18.3

15.2

Range

8.177.1

10.138.6

0.032.5

6 (100)

6 (100)

3 (50)

Patients with target joints no. (%)


Previous or concomitant disease no. (%)
HIV infection

1 (17)

Hepatitis B

1 (17)

1 (17)

Chronic hepatitis C

4 (67)

4 (67)

3 (50)

* Plusminus values are means SD. HIV denotes human immunodeficiency virus.
All patients without factor VIII inhibitors had received secondary prophylaxis (defined as prophylaxis started after the
onset of joint damage or other clinically significant bleeding27).
The annualized bleeding rate for each patient was calculated as 365.25 times the number of bleeding episodes that required treatment with coagulation-factor products, divided by the number of days in the 6-month period before study
enrollment.
Target joints were defined as joints at which three or more episodes of spontaneous bleeding had occurred during the
6-month period before enrollment.

R e sult s
Study Population

A total of 18 Japanese patients with severe hemophilia A participated in the study, with 6 patients
in each cohort. The patients ages and weights
were similar across the cohorts (Table1, and
Table S1 in the Supplementary Appendix). Each
cohort included 1 or 2 adolescent patients (age
range, 12 to 18 years) and 3 or 4 patients with
factor VIII inhibitors. All patients without factor

VIII inhibitors had received secondary prophylaxis (defined as prophylaxis started after the
onset of joint damage or other clinically significant bleeding27). Over the 6-month period before
study entry, the annualized bleeding rate was
highest in cohort 1. Six patients each in cohorts
1 and 2, and 3 patients in cohort 3, had target
joints at baseline. All patients completed 12 weeks
of emicizumab administration except for 1 patient in cohort 2, who discontinued treatment on
day 29 because of injection-site erythema.

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The

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Pharmacokinetic and Pharmacodynamic


Outcomes

Plasma emicizumab concentrations had a dosedependent increase, as predicted on the basis of


nonclinical pharmacokinetic data. In cohorts 1
and 2, mean (SD) trough levels reached steady
state by week 12 (10.34.54 and 29.96.88 g
per milliliter, respectively) (Fig.1A). In cohort 3,
in which the initial dose and subsequent doses
were the same, the mean trough level gradually
increased to 87.920.0 g per milliliter by week
12 but did not reach steady state. During treatment, the activated partial-thromboplastin time
remained short, and factor XIatriggered thrombin generation was detected at each assessment in
all three cohorts (Fig.1B and 1C, respectively).
Efficacy Outcomes

During prophylactic treatment with emicizumab,


the bleeding rate was reduced markedly from the
rate at baseline in all cohorts. Median annualized bleeding rates decreased from 32.5 (range,
8.1 to 77.1) to 4.4 (range, 0.0 to 59.5) in cohort
1, from 18.3 (range, 10.1 to 38.6) to 0.0 (range,
0.0 to 4.3) in cohort 2, and from 15.2 (range, 0.0
to 32.5) to 0.0 (range, 0.0 to 4.2) in cohort 3; for
joint bleeding, the annualized rates decreased
from 27.4 (range, 8.1 to 69.0) to 4.3 (range, 0.0 to
59.5) in cohort 1, from 15.2 (range, 10.1 to 22.3)
to 0.0 (range, 0.0 to 0.0) in cohort 2, and from
9.1 (range, 0.0 to 32.5) to 0.0 (range, 0.0 to 0.0)
in cohort 3 (Fig. S2 in the Supplementary Appendix). The annualized bleeding rate decreased
among 17 patients regardless of the presence or
absence of factor VIII inhibitors and prior prophylaxis; 1 patient without factor VIII inhibitors
(in cohort 3) had an annualized bleeding rate of
0.0 both at baseline and while receiving emicizumab (Fig.2). Eight of 11 patients with factor
VIII inhibitors (73%) and 5 of 7 patients without
factor VIII inhibitors (71%) had no bleeding episodes. All 21 bleeding episodes were successfully treated with a clotting factor (factor VIII or
a bypassing agent), and 18 of the episodes (86%)
resolved with one or two doses (Table S2 in the
Supplementary Appendix). Episodic use of clotting factors to control bleeding was reduced
from baseline (Table S3 in the Supplementary
Appendix).
One patient without factor VIII inhibitors (in
cohort 1) had an unusually large number of bleed-

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ing episodes, even with factor VIII prophylaxis at


a dose of 2000 IU three times per week before
the study treatment began. During emicizumab
treatment, this patient had 14 nontraumatic
bleeding episodes (i.e., episodes not caused by any
evident external triggers) at joints, with 13 of the
episodes at target joints. These results were attributed to very high levels of physical activity
and hemophilic arthropathy. Nevertheless, 11 of
14 episodes resolved with one or two doses of
factor VIII.
Safety Outcomes

Weekly administration of emicizumab had an acceptable safety profile over the 12-week treatment
period. A total of 43 adverse events were observed
in 15 of the 18 patients (83%) (Table2), no serious adverse events were reported, and the number
of patients with at least 1 adverse event was similar across the cohorts. All adverse events were
mild, except for 2 moderate events (upper respiratory tract infection in a patient in cohort 2 and
headache in a patient in cohort 3). Nasopharyngitis was the only adverse event reported in 15%
or more of the patients (Table2). Adverse events
thought by the investigators to be possibly related
to emicizumab included malaise, injection-site
erythema, injection-site rash, injection-site pruritus, injection-site discomfort, diarrhea, increased
C-reactive protein level, and increased blood
creatine kinase level. Injection-site erythema,
reported twice in 1 patient (cohort 2), resulted in
treatment discontinuation on day 29; the events
were mild and resolved.
No evidence of clinically relevant coagulation
abnormalities was noted on the basis of reported
adverse events (Table2). No thromboembolic
events were reported, even when factor VIII or a
bypassing agent was administered as episodic
therapy in the presence of emicizumab. Laboratory test results are shown in Figure S3 in the
Supplementary Appendix. Emicizumab did not
affect factor IX or factor X plasma concentrations (Fig.3). Anti-emicizumab antibodies did
not develop during treatment in any of the patients. One patient had a positive test for antiemicizumab antibodies at baseline and had a
transient increase in the C-reactive protein level
on day 3, which did not affect the pharmacokinetics or pharmacodynamics of emicizumab
during treatment (data not shown).

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Humanized Bispecific Antibody in Hemophilia A

Cohort 1

Cohort 2

Cohort 3

A
120

Plasma Emicizumab (g/ml)

Figure 1. Pharmacokinetics and Pharmacodynamics of


Weekly Subcutaneous Administration of Emicizumab.
Patients received a loading dose of 1.0 mg of emicizu
mab per kilogram of body weight, followed by weekly
injections of 0.3 mg per kilogram (cohort 1), or a loading dose of 3.0 mg per kilogram, followed by weekly injections of 1.0 mg per kilogram (cohort 2) or 3.0 mg per
kilogram (cohort 3). Panel A shows plasma emicizumab
concentrations, Panel B activated partial-thromboplastin
time (APTT), and Panel C peak height for thrombin generation (one of the variables derived from the thrombingeneration assay) triggered by activated factor XI. Data
are mean values; I bars represent standard deviations.
Data below the limits of quantification (<0.05 g per
milliliter for the plasma emicizumab concentration and
<2 nmol per liter for peak height for thrombin generation) were not included in the analyses. Summary statistics were not calculated when measured values were out
of the quantification range in the majority of patients
for each cohort and time point. The reference ranges
for APTT and peak height for thrombin generation are
25.4 to 37.2 seconds and 341 to 489 nmol per liter, respectively, which were derived from the mean baseline
values 1.96 SD for 40 healthy Japanese participants
enrolled in the first-in-human study of emicizumab.23

100
80
60
40
20
0

10

12

10

12

10

12

Weeks since First Dose

B
150
125

Discussion

APTT (sec)

100
75

Peak Height for Thrombin Generation


(nmol/liter)

Prophylactic treatment with weekly subcutaneous


50
administration of emicizumab reduced the bleed25
ing rate in patients with severe hemophilia A,
irrespective of the presence or absence of factor
0
VIII inhibitors. Thirteen of the 18 patients (72%)
0
2
4
6
8
had no bleeding episodes and did not require
Weeks since First Dose
clotting factors, including 3 patients with factor
VIII inhibitors who had had frequent bleeding C
episodes, even during prophylaxis with bypassing
400
agents, before receiving emicizumab treatment
(Fig.2). This finding suggests that emicizumab
300
has the potential to maintain high hemostatic
activity in patients with hemophilia A.
Plasma emicizumab trough levels at week 12
200
were approximately 10, 30, and 90 g per milli
liter in cohorts 1, 2, and 3, respectively. On the
basis of nonclinical in vivo data (see the Descrip100
tion section in the Supplementary Appendix),
these levels were expected to result in equivalent
hemostatic activity of approximately 3, 9, and 27 IU
0
0
2
4
6
8
of factor VIII per deciliter in cohorts 1, 2, and 3,
Weeks
since
First
Dose
12
respectively. As reported in a previous study,
the relationship between the annualized bleeding rate at joints and the estimated equivalent was 0.0 at higher doses [i.e., in cohorts 2 and 3]).
factor VIII activity in our study was asymptotic The plasma emicizumab concentrations achieved
(the median annualized bleeding rate at joints in these cohorts were expected to correspond to

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2049

The

No prophylaxis

Emicizumab
prophylaxis

n e w e ng l a n d j o u r na l

Bypassing-agent
prophylaxis

Factor VIII
prophylaxis

A Cohort 1
80

Annualized Bleeding Rate

Without Factor VIII


Inhibitors

With Factor VIII Inhibitors

77.1

36.5

40
28.4
20.3

20

12.9
0.0

1-1

8.7

8.1

0.0
1-2

0.0
1-3

1-4

1-5

1-6

Patient No.

B Cohort 2
Without Factor VIII
Inhibitors

With Factor VIII Inhibitors


38.6

Annualized Bleeding Rate

40

30
Withdrawn
at Day 29
20

18.3

18.3

18.3
14.2
10.1

10
4.3
0.0

2-1

0.0
2-2

2-3

0.0
2-4

0.0
2-5

0.0
2-6

Patient No.

C Cohort 3

Annualized Bleeding Rate

40

With Factor VIII Inhibitors

Without Factor VIII Inhibitors

32.5
30
24.3
20.3

20

10.1

10

8.1
4.2

0.0
3-1

0.0
3-2

0.0
3-3

0.0
3-4

Patient No.

2050

m e dic i n e

Figure 2. Annualized Bleeding Rates during Weekly


Emicizumab Administration in Individual Patients.
The annualized bleeding rates for each patient were
calculated as 365.25 times the number of bleeding episodes that required treatment with coagulation-factor
products, divided by the number of days in the treatment period as compared with the 6 months before
enrollment.

59.5

56.8

60

of

0.0 0.0
3-5

3-6

at least 10 IU of factor VIII activity per deciliter.


The results in cohort 2 suggest that the factor
would be 0.3 or higher for the conversion of
micrograms of emicizumab per milliliter to international units of equivalent factor VIII hemostatic activity per deciliter and that treatment
with emicizumab may convert severe hemophilia A to a moderate phenotype (factor VIII
activity, 1 to 5 IU per deciliter) or even a mild
phenotype (>5 to <40 IU per deciliter).
We hypothesize that 30 to 50 g of emicizu
mab per milliliter would correspond to at least
10 to 15 IU of equivalent factor VIII activity per
deciliter, which is a level of activity associated
with a very low risk of joint bleeding.12 Since the
steady-state trough level in cohort 2 was approximately 30 g per milliliter, doses slightly higher
than 1 mg per kilogram once weekly may be
needed to meet desired factor VIIIequivalent
activity levels. In this study, pharmacodynamic
markers of the activated partial-thromboplastin
time and factor XIatriggered thrombin generation did not clearly discriminate between cohorts 2 and 3 (Figs. S4 and S5 in the Supplementary Appendix). Further investigations are needed
to establish more appropriate pharmacodynamic
markers. For example, thrombin generation triggered by a low level of tissue factor showed a
clear concentration-dependent response when
emicizumab (30 to 300 g per milliliter) was
added in vitro to factor VIIIdeficient plasma
(Fig. S6 in the Supplementary Appendix).28
Neither serious nor thrombotic adverse events
occurred during the study (Table2). Although
adverse events thought to be related to the study
treatment occurred more frequently in cohort 3
than in the other cohorts, we could not draw any
conclusions about a dose-dependent relationship
between emicizumab and adverse events because

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Humanized Bispecific Antibody in Hemophilia A

Table 2. Summary of Adverse Events during Weekly Subcutaneous Administration of Emicizumab.*


Cohort 1
(N=6)

Event

Cohort 2
(N=6)

Cohort 3
(N=6)

no. of patients
Any event

All Patients
(N=18)
no. of patients (%)

15 (83)

Nasopharyngitis

3 (17)

Contusion

2 (11)

Erythema

2 (11)

Excoriation

2 (11)

Myalgia

2 (11)

Tongue injury

2 (11)

Injection-site hematoma

2 (11)

Increase in C-reactive protein

1 (6)

Heat rash

1 (6)

Injection-site discomfort

1 (6)

Stab wound

1 (6)

Thermal burn

1 (6)

Wound

1 (6)

Arthralgia

1 (6)

Back pain

1 (6)

Eyelid folliculitis

1 (6)

Injection-site erythema

1 (6)

Pharyngitis

1 (6)

Procedural-site reaction

1 (6)

Upper respiratory tract infection

1 (6)

Increase in blood creatine kinase

1 (6)

Burns, first-degree

1 (6)

Dermatitis, contact

1 (6)

Diarrhea

1 (6)

Headache

1 (6)

Infected dermal cyst

1 (6)

Injection-site pruritus

1 (6)

Injection-site rash

1 (6)

Insomnia

1 (6)

Laceration

1 (6)

Malaise

1 (6)

Postprocedural hematoma

1 (6)

Pruritus

1 (6)

Rash

1 (6)

* A total of 43 adverse events were reported: 16 in cohort 1, 11 in cohort 2, and 16 in cohort 3.


This event was judged by the investigator to be related to emicizumab administration.
This event was reported twice in this patient and resulted in discontinuation of emicizumab administration.

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2051

The

Cohort 1

Cohort 2

n e w e ng l a n d j o u r na l

Cohort 3

A
12

Plasma Factor IX (g/ml)

10
8
6
4
2
0

10

12

10

12

Weeks since First Dose

B
12

Plasma Factor X (g/ml)

10
8
6
4
2
0

Weeks since First Dose

Figure 3. Plasma Factor IX and Factor X Concentrations during Weekly


Emicizumab Administration.
Panel A shows plasma factor IX concentrations, and Panel B plasma factor X
concentrations. Data are mean values; I bars represent standard deviations.

of the small sample and the low incidence of


treatment-related adverse events in each cohort. In
addition, although some patients had transient
changes in laboratory values, including d-dimer
and thrombinantithrombin complex, no emicizumab-dependent change over time toward hypercoagulation was evident. Treatment of bleeding
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episodes with factor VIII or bypassing agents


was successful, suggesting that emicizumab is
unlikely to disturb the functions of clotting
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the very weak antigen-binding affinity of emicizumab to each factor.28
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Presented in part at the 56th Annual Meeting of the American Society of Hematology, San Francisco, December 69, 2014.
Supported by Chugai Pharmaceutical.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank all the patients and their family members, Dr. Hoyu
Takahashi at Niigata Prefectural Kamo Hospital, investigators
and staff at participating medical institutions, and the project
team members at Chugai Pharmaceutical, especially Takehisa
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