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Plenary Paper
CLINICAL TRIALS AND OBSERVATIONS
A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic
bispecific antibody, in healthy subjects
Naoki Uchida,1,2 Takehiko Sambe,1,2 Koichiro Yoneyama,3 Naoki Fukazawa,3 Takehiko Kawanishi,3 Shinichi Kobayashi,1
and Midori Shima4
1
Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, Japan; 2Department of Pharmacology, School of
Medicine, Showa University, Tokyo, Japan; 3Translational Clinical Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan; and 4Department
of Pediatrics, Nara Medical University, Nara, Japan
ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and
factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study
examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of
• Single subcutaneous dosing
ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were
of ACE910 has a linear PK
randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1,
profile, a half-life of 4 to 5
0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n 5 6 per dose group) or placebo (n 5 2 per dose
weeks, and FVIII-mimetic
group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIIIprocoagulant activity in
neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased
humans.
peak height of thrombin generation in a dose-dependent manner. All adverse events were
• ACE910 at doses up to 1 mg/kg nonserious and did not lead to any subject’s withdrawal. Neither clinical findings nor
is well tolerated and has no
laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects
notable adverse hypercoagulable receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (antieffect in healthy Japanese and drug antibodies [ADAs]). One subject tested positive for ADAs both before and after ACE910
white adults.
administration, whereas the other became ADA positive after receiving ACE910. The PK and
PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that
ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as
#JapicCTI-121934. (Blood. 2016;127(13):1633-1641)
Key Points
Introduction
Patients with severe hemophilia A (,1% residual factor VIII coagulant
activity [FVIII:C]) have a much higher risk of bleeding complications
than patients with moderate (1% to 5%) or mild (.5% to ,40%)
hemophilia A. An important goal of hemophilia A treatment is maintenance of FVIII:C $1%,1,2 which reduces bleeding risk, particularly
at joints.3 To achieve this, intravenous recombinant or plasmaderived FVIII agents with short half-lives (8-12 hours1) must be
administered frequently as prophylactic therapy. However, this current
standard treatment of hemophilia A4 incurs a considerable physical
and mental burden on patients and their families.3,5
The use of FVIII agents is complicated by interindividual variability
in FVIII pharmacokinetics (PK)1,6 and requires dose or dosing frequency adjustment to maintain FVIII:C $1%. Further, 20% to 30%
of patients with severe hemophilia A develop FVIII inhibitors
(alloantibodies against FVIII) in response to therapy.1 Patients who
develop FVIII inhibitors are treated with bypassing agents, including
recombinant activated factor VII (rFVIIa)7 or activated prothrombin
complex concentrate (aPCC).8 Frequent intravenous administration of
these agents is required because of their unstable hemostatic efficacy
caused by short half-lives (rFVIIa: 2.3-6.0 hours9-12; aPCC: 4-7 hours
[thrombin generation (TG)–based half-life]13). New treatments with more
convenient administration routes, lower administration frequency,
and less immunogenicity against coagulation factors are needed.
To overcome the shortfall in the current standard of care, bispecific
antibodies14 that recognize both activated factor IX (FIXa) and factor X
(FX) have been developed. One of these, hBS23, demonstrated FVIIImimetic cofactor activity in vitro in both the presence and absence of
FVIII inhibitors and hemostatic activity in a nonhuman primate model
of acquired hemophilia A.15 Notably, hBS23 has high subcutaneous bioavailability and a 2-week half-life in cynomolgus monkeys,
suggesting that hBS23 may have a more convenient administration
route with lower dosing frequency.15
Although the pharmacological concept was clearly demonstrated
by hBS23, further optimization to improve FVIII-mimetic cofactor
activity, PK, immunogenicity, physicochemical stability, and manufacturability resulted in ACE910, a humanized bispecific antibody with
multidimensionally optimized properties.16 The hemostatic activity of
ACE910 was demonstrated in a primate model of acquired hemophilia
A,17 and weekly subcutaneous doses of ACE910 at 1 mg/kg in a longterm primate model significantly reduced spontaneous joint bleeds,
Submitted June 10, 2015; accepted October 27, 2015. Prepublished online as
Blood First Edition paper, December 1, 2015; DOI 10.1182/blood-2015-06650226.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
The online version of this article contains a data supplement.
There is an Inside Blood Commentary on this article in this issue.
BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
© 2016 by The American Society of Hematology
1633
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1634
BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
UCHIDA et al
limping, bruises, hematuria, and organ bleeds.18 Based on these preclinical results, ACE910 is expected to be a more effective and convenient
prophylactic treatment of hemophilia A patients, regardless of FVIII
inhibitor status.
Here, we present the first-in-human phase 1 study of ACE910,
which evaluated the safety, tolerability, PK, and pharmacodynamic
(PD) profiles of ACE910 in healthy adults and compared the PK and
PD profiles between Japanese and white subjects.
Methods
We conducted a phase 1, first-in-human, single-center, double-blind, randomized, placebo-controlled, interindividual dose-escalation study. The study was
registered at www.clinicaltrials.jp (#JapicCTI-121934), conducted at the Clinical
Research Institute for Clinical Pharmacology and Therapeutics in Showa
University (Tokyo, Japan) in accordance with the Declaration of Helsinki and
International Conference on Harmonization–Good Clinical Practice and approved
by the institutional review board. All subjects gave written informed consent
before enrollment. All authors had or have access to the primary trial data.
Subjects
Healthy Japanese and white male subjects aged 20 to 44 years, with body mass
index (BMI) of 18.5 to ,25.0 kg/m2 (Japanese subjects) or 18.5 to ,30.0 kg/m2
(white subjects), were included. Subjects with previous or current history of
clinically significant allergy, hypersensitivity associated with globulin preparations, thromboembolic diseases, FVIII:C $120%, or abnormal protein C activity,
protein S activity, antithrombin activity, lupus anticoagulant, or anti-cardiolipinb-2 glycoprotein I complex antibody were excluded.
Study design
In part A, healthy Japanese subjects were randomized to receive a single
subcutaneous injection of ACE910 (0.001, 0.01, 0.1, 0.3, or 1 mg/kg; n 5 6
per dose group) or placebo (n 5 2 per dose group) (Figure 1). The dose of
0.001 mg/kg was selected as the first-in-human dose anticipated to have minimal
biological effect19 to shorten activated partial thromboplastin time (APTT)
in FVIII-deficient human plasma at an ACE910 concentration of 0.01 mg/mL
(data not shown). In part B, healthy white subjects were randomized to receive a
single subcutaneous injection of ACE910 (0.1, 0.3, or 1 mg/kg; n 5 6 per dose
group) or placebo (n 5 2 per dose group) (Figure 1). Subjects were observed for
4 weeks (0.001 or 0.01 mg/kg), 16 weeks (0.1 mg/kg), 20 weeks (0.3 mg/kg), or
24 weeks (1 mg/kg) until the study end. Observation periods for each dose group
were based on PK considerations. Longer-term safety of a single subcutaneous
injection of ACE910 was confirmed in the highest-dose group.
Administration of ACE910 or placebo followed a stepwise dose-escalation
procedure (Figure 1). At each dose step in part A, ACE910 and placebo were
administered to 1 subject each. After confirming vital signs, 12-lead electrocardiography (ECG) results, and adverse events (AEs) for 7 days, ACE910 or
placebo was administered to the remaining 6 subjects (5 for ACE910 and 1 for
placebo). Laboratory tests, vital signs, ECG results, and AEs were monitored for
up to 4 weeks after administration, and PK profiles, PD responses, and serum
cytokine concentrations were monitored for up to 2 weeks after administration.
After tolerability and safety were confirmed, the decision to proceed to the next
dose step was made. Part B was initiated after confirming the tolerability and
safety of the third dose step of part A.
Drug product
ACE910 was produced from a Chinese hamster ovary cell line using recombinant
DNA technology. The drug product is a solution of ACE910 at 80 mg/mL.
Outcome measures
The observation and test schedule is described in supplemental Table 1 (available
on the Blood Web site).
Figure 1. Study design and stepwise dose-escalation scheme. Stepwise doseescalation scheme for healthy male Japanese subjects (part A) and white subjects (part B)
is shown. A total of 40 Japanese subjects were recruited to part A, and a total of 24 white
subjects were recruited to part B. Part A: Japanese subjects were randomized to receive a
single subcutaneous dose of ACE910 (n 5 6 for each dose group) or placebo (n 5 2 for
each dose group). The Japanese subjects were observed for 4 weeks at each dose, and
data were reviewed prior to dose escalation. Part B: white subjects were randomized to
receive a single subcutaneous injection of ACE910 (n 5 6 for each dose group) or placebo
(n 5 2 for each dose group). The white subjects were observed for 4 weeks at each dose,
and data were reviewed prior to dose escalation.
PK
Plasma ACE910 concentrations were determined by a validated sandwich
enzyme-linked immunosorbent assay. In brief, ACE910 was captured by a
rabbitized anti-idiotype monoclonal antibody against FX-binding antigenbinding fragment17 and detected by a mouse anti-idiotype monoclonal antibody
against FIXa-binding antigen-binding fragment,17 followed by a horseradish
peroxidase–conjugated goat anti-mouse immunoglobulin G (Southern Biotechnology Associates Inc., Birmingham, AL). The lower limit of quantification
was 0.05 mg/mL. Plasma concentrations of ACE910 target antigens (FIX and FX,
including activated forms) were determined using commercially available sandwich
enzyme-linked immunosorbent assay kits (Assaypro LLC, St. Charles, MO).
PD
APTT and peak height of TG were measured in plasma both with and without
neutralization of endogenous plasma FVIII. The strategy of artificially depleting
endogenous FVIII activity in plasma of healthy subjects using a dual anti-FVIII
neutralizing antibody cocktail (300 mg/mL of VIII-9222 and VIII-223615)
ex vivo was designed to mimic FVIII deficiency observed in patients with
hemophilia A and to allow assessment of the PD profile of ACE910 in healthy
subjects without a coagulation defect. The APTT and peak height of TG
measured in plasma with neutralization of endogenous FVIII reproduced those in
FVIII-deficient plasma (supplemental Figure 1).
APTT was assessed using the Thrombocheck APTT-SLA kit (Sysmex
Corporation, Hyogo, Japan) and a CA-7000 (Sysmex Corporation) automated
blood coagulation analyzer. Peak height of TG in plasma was measured by the
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BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
FIRST-IN-HUMAN STUDY OF ACE910 IN HEALTHY SUBJECTS
1635
Table 1. Demographic and baseline characteristics of subjects
ACE910 (mg/kg)
Placebo
0.001
0.01
0.1
0.3
1
Japanese
N
Age (y)
10
6
6
6
6
6
28.1 6 7.45
33.0 6 7.56
33.0 6 7.97
29.7 6 7.66
34.2 6 4.36
29.8 6 7.78
Body weight (kg)
60.2 6 5.47
62.9 6 4.21
62.9 6 4.24
61.3 6 6.04
59.0 6 3.28
61.2 6 5.04
BMI (kg/m2)
20.9 6 1.77
21.6 6 1.68
21.3 6 1.55
21.6 6 1.24
20.7 6 0.77
21.1 6 1.48
6
NA
NA
6
6
6
30.5 6 3.27
NA
NA
30.3 6 6.06
29.7 6 5.65
32.2 6 9.47
White
N
Age (y)
Body weight (kg)
72.1 6 8.93
NA
NA
69.4 6 6.65
69.9 6 7.06
74.8 6 9.21
BMI (kg/m2)
22.7 6 2.55
NA
NA
22.3 6 2.39
21.4 6 1.34
22.3 6 1.79
Data are presented as mean 6 standard deviation.
NA, not applicable.
calibrated automated thrombogram method using the TG fluorescence assay
analysis system (Thermo Fisher Scientific, Uppsala, Sweden), with 0.47 nM
human activated factor XI (Enzyme Research Laboratories, South Bend, IN) and
20 mM phospholipid as triggers.15,16 The endogenous thrombin potential was
also derived from the thrombogram.
Safety
Safety was assessed by physical examination, AEs (categorized by the Medical
Dictionary for Regulatory Activities code), vital signs, ECG, and laboratory tests.
The severity of AEs was classified by the investigator as mild, moderate, or
severe. Laboratory tests consisted of hematology tests including platelet count,
blood chemistry and coagulation tests, urinalysis, and serum cytokine concentrations (interleukin [IL]-2, interferon-g, tissue necrosis factor-a, IL-6, IL-8).
Blood coagulation tests included D-dimer, thrombin-antithrombin complex
(TAT), prothrombin time–international normalized ratio (PT-INR), FVIII:C,
FIX activity (FIX:C), and FX activity (FX:C). FVIII:C, FIX:C, and FX:C
were measured by one-stage clotting assay methods.
Immunogenicity
Anti-ACE910 antibodies (anti-drug antibodies [ADAs]) in plasma were detected
by an electro-chemiluminescence immunoassay using a validated method according
to US Food and Drug Administration guidance.20 For ADA-positive samples, an
immunoglobulin E (IgE) antibody test was conducted using Phadia ImmunoCAP kit
(Thermo Fisher Scientific Inc.). ADA-positive subjects were defined as any subject
with at least 1 ADA-positive plasma sample.
Statistical analyses
Demographic, PK, PD, and safety data were summarized by race and dose, and
presented as summary statistics. Data for 2 white subjects who discontinued (1 in
Figure 2. Plasma ACE910 concentration after single
subcutaneous injection of ACE910. The time courses
of plasma ACE910 concentration after single subcutaneous
injection of 0.01 mg/kg (pink reverse triangle), 0.1 mg/kg
(green square), 0.3 mg/kg (blue triangle), and 1 mg/kg (red
circle) of ACE910 in Japanese (A) and white (B) healthy
subjects are shown. Plasma ACE910 concentration was
below the lower limit of quantification in all subjects at a dose
of 0.001 mg/kg. Results are presented as mean 6 standard
deviation. Data out of the quantification range were
handled as missing in summary statistics calculation.
Summary statistics were not calculated when a plasma
ACE910 concentration was below the lower limit of
quantification in the majority of subjects at a certain
dose group and time point.
the placebo group, 22 days after administration; 1 in the 0.3 mg/kg group, 58 days
after administration) were included in the analysis.
PK parameters including maximum plasma concentration (Cmax), time
to reach maximum plasma concentration (T max), area under the plasma
concentration-time curve extrapolated to infinity (AUCinf), elimination halflife (t1/2), mean residence time (MRT), apparent total clearance (CL/F), and
apparent volume of distribution (Vd/F) were calculated from each subject’s
ACE910 plasma concentration-time profile by a noncompartmental analysis
using WinNonlin software version 6.2 (Pharsight Corporation, St. Louis,
MO). The quantitative evaluation of racial differences in PK and population
PK analysis is described in supplemental Methods.
Results
Baseline characteristics
A total of 40 Japanese healthy subjects were randomized to receive
a single subcutaneous injection of ACE910 (0.001, 0.01, 0.1, 0.3,
or 1 mg/kg; n 5 6 per group) or placebo (n 5 2 corresponding to
each dose group, total n 5 10). A total of 24 white healthy subjects
were randomized to receive a single injection of ACE910 (0.1, 0.3,
or 1 mg/kg; n 5 6 per group) or placebo (n 5 2 per dose group, total
n 5 6). Within each race, the age, weight, and BMI of subjects
among the ACE910 dose groups and the combined placebo group
were similar (Table 1). The age and BMI of Japanese and white
subjects were also similar; however, white subjects had a higher
body weight.
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BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
UCHIDA et al
Table 2. PK parameters of ACE910 after single subcutaneous injection of ACE910
Dose of ACE910 (mg/kg)
Japanese
Parameter
N
Cmax (mg/mL)
Tmax (d)
White
0.01
0.1
0.3
1
0.1
0.3
6
6
6
6
6
6
1
6
0.0675 6 0.0120
0.655 6 0.0837
1.72 6 0.377
5.92 6 1.24
0.603 6 0.0825
2.12 6 0.244
5.56 6 0.812
14.1
12.0
10.1
10.1
12.6
7.00
8.53
(5.00-28.0)
(7.00-14.1)
(7.00-11.1)
(4.00-14.2)
(7.00-21.2)
(3.00-14.2)
(7.00-15.2)
AUCinf (d 3 mg/mL)
NC
30.2 6 9.28
86.5 6 17.9
266 6 50.0
34.6 6 12.6
112 6 18.2
304 6 79.3
t1/2 (d)
NC
28.3 6 4.77
30.3 6 4.12
29.0 6 3.26
28.8 6 10.4
34.4 6 6.55
32.2 6 6.68
MRT (d)
NC
44.5 6 6.26
47.3 6 8.25
43.1 6 4.57
47.9 6 14.6
50.8 6 9.26
49.3 6 9.96
CL/F (mL/d/kg)
NC
3.51 6 0.776
3.61 6 0.845
3.91 6 0.840
3.16 6 0.933
2.75 6 0.470
3.49 6 0.931
Vd/F (mL/kg)
NC
140 6 24.1
156 6 28.8
163 6 35.6
121 6 34.8
133 6 14.9
156 6 20.3
Data are presented as mean 6 standard deviation for Cmax, AUCinf, t1/2, MRT, CL/F, Vd/F, or median (range) for Tmax. Summary statistics were not calculated when a PK
parameter was not calculable in the majority of subjects at a certain dose group.
NC, not calculated (N 5 2).
PK
The absorption of ACE910 after subcutaneous administration was
confirmed by determination of plasma ACE910 concentrations, which
peaked 1 to 2 weeks after administration, with the elimination phase of
the concentration-time profile appearing monophasic for both Japanese
and white subjects (Figure 2). Because plasma concentrations of
ACE910 at the 0.001 mg/kg dose were below the lower limit of
quantification for all subjects, PK parameters were calculated for doses
of 0.01 mg/kg and higher (Table 2). ACE910 showed a linear doseexposure profile in both Japanese and white subjects, with Cmax ranging
from 0.0675 to 5.92 mg/mL (0.01-1 mg/kg) and AUCinf ranging from
30.2 to 304 day 3 mg/mL (0.1-1 mg/kg). Notably, the half-life of
ACE910 averaged 28.3 to 34.4 days, in agreement with PK data in
cynomolgus monkeys, in which the half-life averaged 23.6 to 26.5 days
at doses of 0.06, 0.6, and 6 mg/kg.17
The PK profiles of ACE910 in Japanese and white subjects were
similar. The relative differences in Cmax and AUCinf between
Japanese and white subjects were limited to 3.7% and 21.1%,
respectively (supplemental Table 2).
A single subcutaneous injection of ACE910 up to 1 mg/kg did
not affect plasma concentrations of the target antigens, FIX and FX,
in both Japanese (Figure 3; supplemental Figure 2) and white (data
not shown) subjects.
height of TG was not increased by ACE910 up to 1 mg/kg
(Figure 4B; supplemental Figure 3B).
In plasma in which endogenous FVIII was neutralized ex vivo,
ACE910 resulted in a dose-dependent shortening of APTT compared
with baseline in both Japanese and white subjects (Figure 5A-B). An
APTT similar to normal plasma was achieved at 1 mg/kg ACE910.
TG in FVIII-neutralized plasma was undetectable at baseline in
most subjects in each group (data not shown). After ACE910 administration, peak height of TG increased in a dose-dependent
manner in both Japanese and white subjects (Figure 5C-D). A dosedependent increase in endogenous thrombin potential was also
observed (supplemental Figure 4). Maximum peak height of TG
at the maximum ACE910 dose of 1 mg/kg approached mean values
of 192 nM and 186 nM for Japanese and white subjects, respectively.
By comparison, baseline peak height of TG values for normal plasma
without FVIII neutralization were ;385 nM and 405 nM for
Japanese and white subjects, respectively. TG remained undetectable throughout the study in most subjects receiving placebo (data not
shown).
The enhanced PD response to ACE910 was observed with increased
plasma ACE910 concentration (supplemental Figure 1). Accordingly,
the PD response was maintained in association with the long-lasting
plasma ACE910 concentration (Figure 2). The concentration-response
relationship was similar for both Japanese and white subjects and
reproduced in vitro data.16
PD
In the absence of FVIII neutralization, ACE910 slightly shortened
APTT in a dose-dependent manner in both Japanese (Figure 4A;
supplemental Figure 3A) and white (data not shown) subjects. Peak
Safety
ACE910 was well tolerated up to 1 mg/kg during the study (up to
24 weeks). Fifteen AEs were reported in 13 of 48 (27.1%) subjects
Figure 3. Plasma FIX and FX concentrations after
single subcutaneous injection of ACE910. The time
courses of plasma FIX (A) and FX (B) concentration
after single subcutaneous injection of placebo (black
circle), 0.001 mg/kg (light blue diamond), 0.01 mg/kg
(pink reverse triangle), 0.1 mg/kg (green square),
0.3 mg/kg (blue triangle), and 1 mg/kg (red circle) of
ACE910 in Japanese healthy subjects are shown. The
concentrations of FIX and FX including their activated
forms in plasma were determined. Results are presented as mean 6 standard deviation.
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BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
FIRST-IN-HUMAN STUDY OF ACE910 IN HEALTHY SUBJECTS
1637
Figure 4. PD responses after single subcutaneous
injection of ACE910 without neutralization of the
endogenous FVIII. The time courses of APTT (A) and
peak height of TG (B) after single subcutaneous
injection of placebo (black circle), 0.001 mg/kg (light
blue diamond), 0.01 mg/kg (pink reverse-triangle),
0.1 mg/kg (green square), 0.3 mg/kg (blue triangle), and
1 mg/kg (red circle) of ACE910 in Japanese healthy subjects measured without neutralization of endogenous FVIII
are shown. Results are presented as mean 6 standard
deviation.
receiving ACE910, compared with 6 AEs in 4 of 16 (25.0%)
subjects receiving placebo (Table 3). All AEs were mild, except for
1 moderate AE (nasopharyngitis in 1 white subject, 0.1 mg/kg).
There were no serious AEs or AEs that led to study withdrawal.
Moreover, the incidence of AEs did not increase dose dependently
and did not differ between Japanese and white subjects. Clinically
significant changes of blood pressure, pulse rate, and body
temperature were not reported. No hypersensitivity AE, serum
cytokine concentration abnormality, or injection site reaction was
reported following ACE910 administration.
To evaluate the hypercoagulation risk of ACE910, several
coagulation markers were measured. No clinically relevant abnormal
coagulability resulting from ACE910 administration (from the first-inhuman dose of 0.001 mg/kg to the highest dose of 1 mg/kg) was
indicated by either clinical findings or laboratory tests. Laboratory
values for D-dimer, TAT, PT-INR, and platelet counts did not change
dose dependently in both Japanese (Figure 6A-D; supplemental
Figure 5A-D) and white (data not shown) subjects. In the Japanese
0.3 mg/kg group, D-dimer and TAT transiently increased 112 days after
administration in 1 subject each; both were judged by the investigator
to be a blood collection artifact and not related to ACE910 because
no abnormalities were observed in other coagulation markers. No clear
changes in FVIII:C, FIX:C, or FX:C were observed (data not shown).
Immunogenicity
Two of 48 (4.2%) subjects receiving 0.1 mg/kg ACE910 (1 Japanese,
1 white) were ADA positive. The Japanese subject was ADA positive
Figure 5. PD responses after single subcutaneous
injection of ACE910 with neutralization of the
endogenous FVIII. The time courses of APTT (A-B)
and peak height of TG (C-D) after single subcutaneous
injection of placebo (black circle), 0.001 mg/kg (light
blue diamond), 0.01 mg/kg (pink reverse triangle),
0.1 mg/kg (green square), 0.3 mg/kg (blue triangle),
and 1 mg/kg (red circle) of ACE910 in Japanese (A,C)
and white (B,D) healthy subjects measured with neutralization of endogenous FVIII are shown. TG was undetectable at baseline in the majority of subjects in each dose
group. TG remained undetectable throughout the study
period in the majority of subjects receiving placebo
(data not shown). Results are presented as mean 6
standard deviation. Data out of the quantification range
were handled as missing in summary statistics calculation. Summary statistics were not calculated when TG
was undetectable in the majority of subjects at a certain
dose group and time point. One observed data point of
TG was excluded because of being judged as an outlier,
considering its unlikely time course and drug concentration dependency.
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BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
UCHIDA et al
Table 3. AEs in subjects receiving subcutaneous injection of ACE910
Dose of ACE910 (mg/kg)
Placebo
n (%)
AEs
0.001
n (%)
0.01
n (%)
0.1
n (%)
0.3
n (%)
1
n (%)
Japanese
Total subjects with at least 1 AE
Nasopharyngitis
2 (20.0)
2 (33.3)
1 (16.7)
3 (50.0)
0 (0.0)
2 (33.3)
1 (10.0)
0 (0.0)
0 (0.0)
2 (33.3)
0 (0.0)
1 (16.7)
Stomatitis
0 (0.0)
1 (16.7)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Diarrhea
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
Erythema of eyelid
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Pyrexia
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Seasonal allergy
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
Headache
1 (10.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
White
Total subjects with at least 1 AE
Abdominal pain upper
2 (33.3)
NA
NA
2 (33.3)
1 (16.7)
2 (33.3)
0 (0.0)
NA
NA
1 (16.7)
0 (0.0)
0 (0.0)
Diarrhea
1 (16.7)
NA
NA
0 (0.0)
0 (0.0)
0 (0.0)
Bite
0 (0.0)
NA
NA
0 (0.0)
1 (16.7)
0 (0.0)
Excoriation
1 (16.7)
NA
NA
0 (0.0)
0 (0.0)
0 (0.0)
Headache
1 (16.7)
NA
NA
0 (0.0)
0 (0.0)
0 (0.0)
Syncope
0 (0.0)
NA
NA
0 (0.0)
0 (0.0)
1 (16.7)
Bilirubin conjugated increased
0 (0.0)
NA
NA
0 (0.0)
0 (0.0)
1 (16.7)
Blood bilirubin increased
0 (0.0)
NA
NA
0 (0.0)
0 (0.0)
1 (16.7)
Nasopharyngitis
0 (0.0)
NA
NA
1 (16.7)
0 (0.0)
0 (0.0)
Hemorrhage subcutaneous
1 (16.7)
NA
NA
0 (0.0)
0 (0.0)
0 (0.0)
NA, not applicable.
throughout the study, including before ACE910 administration, and
had no prior treatment with antibody preparations (commercially
available or investigational). Antibodies were invariably detectable at
plasma dilutions of 1:160. Notably, the time course of plasma ACE910
concentration, APTT, and peak height of TG in FVIII-neutralized
plasma were not different for this subject compared with those of other
subjects in the same dose group (Figure 7A-C). The white subject,
although initially ADA negative, tested positive 12 and 16 weeks
after ACE910 administration. Antibodies were detectable at plasma
dilutions of 1:1280 at 12 weeks and 1:2560 at 16 weeks. The half-life
Figure 6. Coagulation markers and platelet count
after single subcutaneous injection of ACE910. The
time courses of D-dimer (A), TAT (B), PT-INR (C), and
platelet count (D) after single subcutaneous injection of
placebo (black circle), 0.001 mg/kg (light blue diamond), 0.01 mg/kg (pink reverse triangle), 0.1 mg/kg
(green square), 0.3 mg/kg (blue triangle), and 1 mg/kg
(red circle) of ACE910 in Japanese healthy subjects are
shown. Results are presented as mean 6 standard
deviation. The data out of the quantification range were
imputed by the limit of quantification values.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
of ACE910 for this subject was relatively short at ;9 days. Correspondingly, in FVIII-neutralized plasma, the effect of ACE910 on
both APTT and peak height of TG dissipated earlier compared with
ADA-negative subjects in the same dose group (Figure 7D-F).
However, no significant changes in coagulation parameters, such as
APTT, TG, PT-INR, FVIII:C, FIX:C, and FX:C, in plasma without
FVIII neutralization were observed for this subject (data not shown).
The ADA subtype was not IgE in either ADA-positive subject, and
no AEs related to either abnormal coagulability or allergic reaction
were observed.
Discussion
This was the first-in-human study of ACE910, a bispecific antibody
that mimics FVIII cofactor function with potential application to
the treatment of hemophilia A. Results demonstrated that a single
subcutaneous injection of ACE910 at doses up to 1 mg/kg is well
tolerated in both Japanese and white healthy male adults. In addition,
the PK and PD profiles favorably support its utility as a long-acting
hemostatic drug, and no obvious racial differences were observed.
Previous studies demonstrated that ACE910 has a high bioavailability (102.3%) and long half-life (23.6-26.5 days) following
subcutaneous administration in cynomolgus monkeys.17 The present
study confirmed that ACE910 is absorbed into plasma after subcutaneous injection in humans. Within the dose range tested, plasma
ACE910 concentrations increased in a dose-proportional manner, and
the elimination phase of the plasma ACE910 concentration-time profile
was monophasic regardless of dose. This linear PK profile enables
accurate prediction of plasma ACE910 concentration according to
dose. Notably, the mean half-life of ACE910 ranged between 28.3 and
34.4 days, dramatically longer than current drugs (FVIII agents: 8-12 hours1;
rFVIIa: 2.3-6.0 hours9-12; aPCC: 4-7 hours [TG-based half-life]13)
and drugs recently approved or under development (#19 hours).5,21-24
Concizumab is a humanized anti-tissue factor pathway inhibitor
antibody and is also subcutaneously available in humans. However,
because of the target-mediated drug disposition of concizumab, its
half-life is shorter than ACE910.25 The apparent extended half-life
of ACE910 compared with other humanized antibodies (12-20
days)26 might be a consequence of a reduced isoelectric point resulting
from the amino acid–substituting antibody engineering technology
applied.16,27
The current findings suggest that target-mediated drug disposition is
negligible for ACE910. Target-mediated drug disposition is a nonlinear
PK mechanism characteristic of antibody-based drugs.26,28,29 Binding
of antibody-based drug to its target antigen is likely to increase drug
clearance and decrease antigen clearance in a concentration-dependent
manner. Within the dose range tested, ACE910 exhibited a linear PK
profile and did not affect the clearance of FIX or FX, indicating that an
immune complex is unlikely to form. This is supported by the in vitro
affinities of ACE910 for FIX and FX (dissociation constants of 1.6 and
1.8 mM, respectively),30 which are much higher than the plasma concentrations of ACE910 (highest observed mean Cmax 5.92 mg/mL 5 41 nM),
FIX (approximate baseline mean 5.2 mg/mL 5 93 nM), or FX (approximate baseline mean 7.4 mg/mL 5 125 nM).
In normal plasma without FVIII neutralization, ACE910 tended to
shorten APTT. However, because there were no clinical findings and
laboratory tests indicative of hypercoagulability, the change was not
considered a clinically relevant coagulation abnormality. Notably,
when endogenous FVIII activity was depleted ex vivo by addition
of anti-FVIII neutralizing antibodies, plasma samples from healthy
FIRST-IN-HUMAN STUDY OF ACE910 IN HEALTHY SUBJECTS
1639
subjects mimicked the FVIII deficiency seen in hemophilia A patients,
and ACE910 shortened APTT and increased peak height of TG in
a dose-dependent manner. As a consequence of the long half-life,
ACE910 exhibited a long-lasting PD response throughout the study
(maximum of 24 weeks). These results demonstrated the proof of
pharmacology of ACE910 in humans.
Interestingly, at a dose of 1 mg/kg, APTT in FVIII-neutralized
plasma reached the level equivalent to normal plasma with endogenous
FVIII activity, although the peak height of TG did not. This discrepancy
might be because FVIII-mimetic bispecific antibodies do not require
activation to exhibit their pharmacological effect, which could result in
earlier acceleration of coagulation. Therefore, the FVIII-equivalent
activity of ACE910 estimated from APTT is likely to be higher than that
estimated from peak height of TG.15,17,30 A previous study in a
nonhuman primate model of acquired hemophilia A suggested that
peak height of TG exhibits a FVIII-mimetic activity closer to reality
than APTT in terms of hemostatic activity.17
To investigate the potential of ACE910 as prophylaxis in patients
with hemophilia A, we simulated the plasma ACE910 concentration
profile during repeated subcutaneous administration, using a population PK modeling and simulation approach (supplemental Methods;
supplemental Table 3). Our simulation suggests that the plasma
ACE910 concentration at steady state reaches 40 mg/mL or higher at a
weekly maintenance dose of 1 mg/kg. Because of its long half-life, the
predicted peak-to-trough fluctuation in plasma ACE910 concentration
is small (;5% of the difference between peak and trough levels), even
with weekly dosing (supplemental Figure 6). The hemostatic potency
of ACE910 at a plasma concentration of 44 mg/mL (300 nM) was
assumed to be equivalent to that of 10 U/dL FVIII (10% FVIII:C) in the
previous in vitro activated factor XI–triggered TG assay.16 Based on
this assumption, weekly dosing of 1 mg/kg ACE910 is expected to
provide constant hemostatic activity equivalent to ;10% FVIII:C. This
predicted time course of hemostatic activity is superior to current
treatments for hemophilia A. In addition, the simulated plasma
ACE910 concentration is higher than that demonstrated to prevent
spontaneous joint bleeding in a primate model of acquired hemophilia
A (;30 mg/mL).18 These PK and PD profiles suggest that ACE910 has
the potential to reduce bleeding frequency in patients with severe
hemophilia A to that of patients with mild hemophilia A, even at less
frequent dosing compared with existing FVIII and bypassing drugs.
Furthermore, ACE910 may change the treatment paradigm from the
current approach of maintaining trough levels of FVIII:C .1%1,6 to a
new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level. On-demand use of ACE910 for
bleeding events is a subject for future investigation.
ACE910 up to 1 mg/kg was well tolerated in healthy Japanese
and white subjects without any serious AEs leading to study
withdrawal. Importantly, although ACE910 exhibited a procoagulant
effect in FVIII-neutralized plasma, markers indicative of in vivo
hypercoagulability (D-dimer and TAT) did not change, even in healthy
subjects with normal endogenous FVIII activity. Furthermore, there
were no consumptive coagulopathy-related AEs, including PT-INR
and platelet count abnormalities. Thus, ACE910 is unlikely to exhibit
its procoagulant effect in vivo without coagulation triggers, which
is supported by in vitro findings that the FVIII-mimetic activity of
ACE910 depends on FIXa and phospholipid.15,30 These results also
suggest that ACE910 exhibits an advantageous therapeutic window in
patients with hemophilia A who lack endogenous FVIII activity, at an
even higher dose/exposure level than that tested in this study.
The ADA-positive rate for ACE910 (2 of 48 subjects; 4.2%) was
similar to that of other humanized antibodies (,1% to 10%, in most
cases).29,31 Although 1 subject developed ADAs that affected both the
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1640
UCHIDA et al
BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
Figure 7. Effect of anti-ACE910 antibodies on PK and PD of ACE910. The PK and PD profiles in ADA-positive subject (red open square) and ADA-negative subjects (black
open circle) are shown. (A) Plasma ACE910 concentration in the Japanese 0.1 mg/kg group. (B) APTT in the Japanese 0.1 mg/kg group. (C) Peak height of TG in
the Japanese 0.1 mg/kg group. (D) Plasma ACE910 concentration in the white 0.1 mg/kg group. (E) APTT in the white 0.1 mg/kg group. (F) Peak height of TG in the white
0.1 mg/kg group. The data out of the quantification range were imputed by the limit of quantification values. One observed data point of TG was excluded because of being
judged as an outlier, considering its unlikely time course and drug concentration dependency.
PK and PD profiles of ACE910, there appeared to be no impact on
endogenous coagulation function. Because the molecular structure of
ACE910 differs from FVIII,15 ACE910 is unlikely to induce ADAs that
cross-react with FVIII (ie, FVIII inhibitors). In addition, the ADAs
detected in 2 subjects were not IgE, and allergic symptoms such as
anaphylaxis were not observed. These findings lead to a preliminary
conclusion that induction of acquired coagulation disorders, interference with the hemostatic activity of concomitant therapies, and
acquisition of hypersensitivity are unlikely to occur with ACE910
therapy even if ADAs develop.
The PK and safety profiles of ACE910 were similar between
Japanese and white healthy subjects, consistent with observations for
other antibody-based drugs.32 Generally, racial differences in body
weight and target antigen levels may contribute to the PK profile of
antibody drugs.29 However, because of the body weight–adjusted
dosing scheme and the negligible target-mediated drug disposition, this
does not seem to occur for ACE910. This is further supported by the
similar PD response observed for Japanese and white subjects. Overall,
these findings indicate that dose adjustment between races is unlikely to
be necessary.
Although this study presents important data pertaining to the clinical
PK, PD, and safety profiles of ACE910, there are some limitations. All
data were obtained from healthy subjects who received only a single
subcutaneous administration up to 1 mg/kg, with an aim to minimize
the potential risk of hypercoagulability when ACE910 is administered
in the presence of normal FVIII activity. The accurate prediction of the
prophylactic effect of ACE910 on bleeding events in hemophilia A
patients, based only on PK and PD findings in healthy subjects, is
limited. Further studies of the safety, tolerability, PK, PD, and efficacy
of ACE910 in patients with hemophilia A are needed, and the first
clinical investigation of ACE910 in patients with hemophilia A is
underway (registered at www.clinicaltrials.jp as #JapicCTI-121934).
In conclusion, this first-in-human study of ACE910 demonstrated
that subcutaneous injection of ACE910 at doses up to 1 mg/kg was well
tolerated with a longer plasma half-life compared with currently used
treatments for hemophilia A in both Japanese and white healthy male
adults. The FVIII-mimetic procoagulant activity of ACE910 was
successfully evaluated in a dose-dependent manner with no clear
indications that ACE910 leads to hypercoagulability. The PK and PD
profiles were similar between Japanese and white subjects. Based on
these findings, ACE910 is expected to be a more effective prophylactic
treatment of hemophilia A patients and has the potential to offer a more
convenient regimen (once-weekly, subcutaneous injection) than existing therapies.
Acknowledgments
The authors thank the following colleagues at Chugai Pharmaceutical Co. Ltd.: Naoki Kotani for writing support, Shingo Maisawa
and Hiroko Miwa for support in the conduct of the research, and
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
BLOOD, 31 MARCH 2016 x VOLUME 127, NUMBER 13
Toshihiko Aranishi for support in planning and conducting the
statistical analysis. The authors also thank the subjects for their
involvement in this study. The authors acknowledge the medical
writing assistance provided by Ying Ke, and Rebecca Lew, CMPP,
of ProScribe, part of the Envision Pharma Group (www.proscribe.
com.au), funded by Chugai Pharmaceutical Co. Ltd.
This study was sponsored by Chugai Pharmaceutical Co. Ltd.
Authorship
Contribution: All authors participated in the interpretation of study
results, and in the drafting, critical revision, and approval of the
final version of the manuscript; K.Y., N.F., T.K., and M.S. were
FIRST-IN-HUMAN STUDY OF ACE910 IN HEALTHY SUBJECTS
1641
involved in the study design; N.U., T.S., and S.K. conducted the
research; and K.Y. analyzed the data and planned and conducted
the statistical analysis.
Conflict-of-interest disclosure: K.Y., N.F., and T.K. are
employees of Chugai Pharmaceutical Co. Ltd. M.S. received
research support paid to his institution from Chugai Pharmaceutical
Co. Ltd. and has received consulting honoraria from Chugai
Pharmaceutical Co. Ltd. and F. Hoffmann-La Roche. K.Y. and
M.S. are inventors of the patents relating to anti-FIXa/X bispecific
antibodies. The remaining authors declare no competing financial
interests.
Correspondence: Midori Shima, Department of Pediatrics, Nara
Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522,
Japan; e-mail: [email protected].
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2016 127: 1633-1641
doi:10.1182/blood-2015-06-650226 originally published
online December 1, 2015
A first-in-human phase 1 study of ACE910, a novel factor VIII−mimetic
bispecific antibody, in healthy subjects
Naoki Uchida, Takehiko Sambe, Koichiro Yoneyama, Naoki Fukazawa, Takehiko Kawanishi, Shinichi
Kobayashi and Midori Shima
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