Haemophilia (2017), 1–8 DOI: 10.1111/hae.

13144

ORIGINAL ARTICLE

Treatment of bleeding episodes with recombinant factor

VIII Fc fusion protein in A-LONG study subjects with
severe haemophilia A
A. D. SHAPIRO,* J. N. MAHLANGU,† D. PERRY,‡ J. PASI,§ D. V. QUON,¶ P. CHOWDARY,**
E . T S A O , † † S . L I , † † A . I N N E S , † † G . F . P I E R C E † † and G . A . A L L E N † †
*Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA; †Faculty of Health Sciences, University of the
Witwatersrand and NHLS Hospital, Parktown, Johannesburg, South Africa; ‡Addenbrookes Hospital, Cambridge; §Barts and
The London Comprehensive Care Center, London, UK; ¶Orthopaedic Hemophilia Treatment Center, Los Angeles, CA, USA;
**Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London, UK; and ††Biogen,
Cambridge, MA, USA

Introduction: The Phase 3 A-LONG study demonstrated the safety and efficacy of rFVIIIFc for the control and
prevention of bleeding episodes in severe haemophilia A. Aim: To describe the treatment of bleeding episodes
with rFVIIIFc in the A-LONG study. Methods: A-LONG subjects (<1 IU dL 1 endogenous FVIII) were treated
with individualized prophylaxis (Arm 1), weekly prophylaxis (Arm 2) or episodic treatment (Arm 3). Information
recorded for each bleeding episode included type, location and dose to treat the episode. Results: During
A-LONG, 757 bleeding episodes occurred during the efficacy period; the majority [456 (60%)] occurred in Arm
3 (episodic treatment). Of 93 subjects in the prophylaxis arms who entered the study with target joints, 43
(60%) in Arm 1 and 11 (52%) in Arm 2 did not experience a target joint bleed. Overall, 98% of bleeding
episodes (and 98% of bleeds involving a target joint) resolved with one or two infusions; the median dose per
infusion to treat a bleed was 27 IU kg 1 (27 IU kg 1 for target joints). Using population pharmacokinetic
simulations, FVIII activity levels were predicted to be below the upper limit of normal (150 IU dL 1) in most
patients in the event that rFVIIIFc is used to treat a bleeding episode in close proximity to a prophylactic dose.
Conclusions: These findings demonstrate the efficacy of rFVIIIFc for the treatment of acute bleeding episodes in
subjects with severe haemophilia A, regardless of treatment regimen.

Keywords: bleeding, factor VIII, haemophilia A, phase 3, prophylaxis, recombinant Fc fusion protein

[2]. Individuals on prophylaxis may also require treat-

Introduction
Replacement factor VIII (FVIII) is used to prevent and
treat bleeding episodes in people with haemophilia A
[1]. Although replacement factor prophylaxis is the
standard of care for individuals with severe haemophi-
lia A, some individuals use replacement factor solely
for treatment of bleeding episodes (episodic or on-
demand therapy), often due to resource constraints [1]
or inability to maintain a prophylactic regimen, which
often requires frequent infusions (3–4 times week 1)
Correspondence: Amy D. Shapiro, MD, Indiana Hemophilia and
Thrombosis Center, 8326 Naab Road, Indianapolis, IN 46260,
USA.
Tel.: +1 317 871 0000; fax: +1 317 871 0010;
e-mail: ashapiro@ihtc.org
Accepted after revision 7 November 2016
ment for breakthrough bleeding episodes.
A prophylactic regimen with a reduced infusion fre-
quency could potentially improve adherence, which
may ultimately improve clinical outcomes [3,4]. The
Phase 3 A-LONG study confirmed the prolonged half-
life of recombinant factor VIII Fc fusion protein
(rFVIIIFc) vs. conventional recombinant factor VIII
(rFVIII) and demonstrated the efficacy and safety of
rFVIIIFc for the prevention and treatment of bleeding
episodes in previously treated subjects with severe hae-
mophilia A [5]. Low bleeding rates were observed for
A-LONG subjects treated prophylactically in the
rFVIIIFc extension study, ASPIRE (NCT1454739) [6].
Assessment of efficacy of rFVIIIFc for all bleeding
episodes, both for episodic use and treatment of bleed-
ing events during prophylaxis, is important. As joint
bleeding is common in people with haemophilia A [7],

© 2017 John Wiley & Sons Ltd 1

2 A. D. SHAPIRO et al.

the occurrence of target joint bleeds and efficacy of Analyses

rFVIIIFc for treatment of those events is important.
Descriptive analyses included median and interquar-
Here, we describe the treatment of bleeding episodes
tile range (IQR) values. Categorical data were sum-
with rFVIIIFc in the A-LONG trial, including the
marized using frequency and percent. The number of
occurrence of target joint bleeds for subjects using
subjects or total number of bleeding episodes was
rFVIIIFc prophylaxis, and the efficacy of rFVIIIFc for
used as the denominator where applicable, with the
the treatment of bleeding episodes both in general and
following exception: for the summary of bleeding
involving target joints. Finally, for individuals on pro-
episode locations, the total number of bleeding epi-
phylaxis, minimizing time spent >150 IU dL 1 factor
sode locations was used as the denominator, as a
activity level after bleeding episode treatment, in addi-
single bleeding episode could involve ≥1 location
tion to an ongoing infusion regimen, is key because
(e.g. a traumatic bleeding episode might involve mus-
high factor activity levels over an extended period of
cle and skin/mucosa). A target joint was defined in
time could theoretically contribute to adverse events
the protocol as a major joint (e.g. hip, elbow, wrist,
such as unmasking of subclinical atherosclerotic
shoulder, knee, ankle) into which repeated bleeding
disease with subsequent vascular thrombosis [8,9].
occurs (frequency of ≥3 bleeding episodes into the
To this end, we use population pharmacokinetic
same joint in a consecutive 6-month period). Pre-
modelling to predict FVIII activity levels over time
study joint annualized bleeding rate (ABR) was
for the use of rFVIIIFc to treat a bleeding episode in
based on each subject’s self-reported number of joint
close proximity (i.e. 24 h) to a scheduled prophylactic
bleeding episodes during the 12 months before the
dose.
study (based on patient logs and/or clinic records).
Post hoc analysis of prestudy vs. on-study joint ABR
Materials and methods comparisons was performed using the signed rank
test.
Study design and population
A-LONG was a Phase 3 study evaluating the safety, Population pharmacokinetic simulations
efficacy and pharmacokinetics of rFVIIIFc [5]. The
A previously validated, two-compartment rFVIIIFc
study included three treatment arms: Arm 1, individu-
population pharmacokinetic model [base model
alized prophylaxis; Arm 2, weekly prophylaxis; and
including below the limit of quantitation (BLQ)] [10]
Arm 3, episodic treatment. Males with severe haemo-
was used to predict factor activity levels in 1000
philia A (<1 IU dL 1 endogenous FVIII level) were eli-
hypothetical patients. Factor activity was modelled
gible for enrolment; study design and population have
under six scenarios with a 25 IU kg 1 dose of
been published [5] and are summarized here (Data S1).
rFVIIIFc used for the treatment of bleeding episode
24 h before or 24 h after a scheduled prophylactic
Management of bleeding episodes dose for patients at steady-state on a regimen of
50 IU kg 1 every 3, 4 or 5 days.
Dosing of rFVIIIFc to treat a bleeding episode was
based on the subject’s clinical condition and known
pharmacokinetic information, and type and severity of Results
bleeding [1]. The study protocol suggested guidelines
for bleeding episode management (Data S1). Subjects
Information on bleeding events was obtained from
As reported previously [5], 165 subjects were enrolled
electronic patient diaries and medical records while
in A-LONG. Demographic and baseline characteristics
the subject received treatment (Data S1). Bleeding epi-
for these subjects were consistent with those of a pop-
sode severity was not collected.
ulation with severe haemophilia A (Table S1).

Outcome measures
Summary of bleeding episodes
Outcomes included number of infusions required to
Of the 163 subjects evaluable for efficacy, 55% of
resolve a bleed, rFVIIIFc dose administered per infusion
subjects in Arm 1, 83% of subjects in Arm 2 and
and total rFVIIIFc dose per bleeding episode. Addition-
100% of subjects in Arm 3 experienced ≥1 bleeding
ally, subjects’ assessment of response to treatment of a
episode during the study period. Of the 757 bleeding
bleed with rFVIIIFc, performed within 8–12 h from the
episodes that occurred across the three treatment
time the rFVIIIFc infusion was given to treat the bleed,
arms, the majority [456 (60%)] occurred in the episo-
and physicians’ global assessment of response to the
dic arm (Arm 3). The types and locations of bleeding
rFVIIIFc regimen throughout the study, performed at
episodes are summarized in Table 1.
study visits, were evaluated (Data S1).

Haemophilia (2017), 1--8 © 2017 John Wiley & Sons Ltd

 RFVIIIFC FOR THE TREATMENT OF BLEEDING EPISODES 3

In the prophylactic treatment arms [individualized infusion (Arm 1, 86%; Arm 2, 80%; Arm 3, 90%),
(Arm 1) and weekly (Arm 2) prophylaxis], 95 subjects demonstrating the efficacy of rFVIIIFc for treatment
had ≥1 target joint at study entry. Bleeding data dur- of acute bleeds. Similar results were observed for
ing the efficacy period (for Arms 1 and 2, the efficacy
period started with the first prophylactic rFVIIIFc dose
Prestudy joint ABR On-study joint ABR On-study target joint ABR
following the completed pharmacokinetic sampling 40 *
period and ended with the last rFVIIIFc dose adminis- *

tered) were available for 93 of these 95 subjects with

Median (IQR) ABR

30
target joints at study entry, including 72 subjects in
Arm 1 [median (IQR) time on study, 32 (29, 38) 20
*
weeks] and 21 subjects in Arm 2 [median (IQR) time 17.5 18.0

on study, 28 (26, 29) weeks]. With rFVIIIFc prophy-

10
laxis, the median (IQR) target joint ABR was 0.0 (0.0, 8.0

3.0) and 0.0 (0.0, 1.9) in Arms 1 and 2, respectively, 1.7 0.0 0.0 0.0 1.9 0.0
0
in subjects entering the study with target joints. In
Arm 1, 43 (60%) of these subjects did not experience
Prestudy Prestudy Prestudy
any target joint bleeds on study; among subjects in FVIII prophylaxis FVIII episodic FVIII episodic
Arm 2, 11 (52%) did not experience any target joint to on-study to on-study to on-study
rFVIIIFc rFVIIIFc rFVIIIFc
bleeds on study. Compared with subject-reported pre- individualized individualized weekly
study joint ABR, there was a significant reduction prophylaxis prophylaxis prophylaxis
n = 37 n = 24 n = 15
(P < 0.001) in on-study joint ABR in subjects with
target joints at baseline (Fig. 1). Fig. 1. Prestudy vs. on-study joint and target joint ABR in subjects with
target joints at baseline (the subset of subjects with non-missing data for
both prestudy and on-study joint ABR, according to prestudy treatment
rFVIIIFc for treatment of bleeding episodes regimen and on-study prophylactic regimen). ABR, annualized bleeding
rate; IQR, interquartile range; rFVIII, recombinant factor VIII; rFVIIIFc,
Number of infusions. Across all treatment arms, 87% recombinant factor VIII Fc fusion protein. *P < 0.001 for prestudy vs. on-
of bleeding episodes were resolved with one rFVIIIFc study joint ABR.

Table 1. Summary of bleeding episodes.

Arm 1 (individualized Arm 2 (weekly Arm 3 (episodic Total

prophylaxis; n = 117†) prophylaxis; n = 23‡) treatment; n = 23) (N = 163)
Subjects with ≥1 bleeding episode, n 64 19 23 106
Type
Bleeding episodes, n 209 92 456 757
All bleeding episodes, n (%)
Spontaneous 119 (57) 60 (65) 326 (71) 505 (67)
Traumatic 87 (42) 32 (35) 127 (28) 246 (32)
Unknown 3 (1) 0 3 (<1) 6 (<1)
Joint bleeding episodes, n (%)
Spontaneous 93 (62) 47 (70) 265 (72) 405 (69)
Traumatic 56 (37) 20 (30) 99 (27) 175 (30)
Unknown 2 (1) 0 2 (<1) 4 (<1)
Target joint bleeding episodes, n (%)
Spontaneous 53 (63) 29 (83) 162 (82) 244 (77)
Traumatic 31 (37) 6 (17) 33 (17) 70 (22)
Unknown 0 0 2 (1) 2 (<1)
Location
Bleeding episode locations, n§ 224 103 488 815
Location of bleeding episode, n (%)§
Joint¶ 151 (67) 67 (65) 366 (75) 584 (72)
Muscle 35 (16) 23 (22) 82 (17) 140 (17)
Soft tissue 24 (11) 5 (5) 25 (5) 54 (7)
Skin/mucosa 11 (5) 6 (6) 8 (2) 25 (3)
Internal 3 (1) 2 (2) 6 (1) 11 (1)
Unknown 0 0 1 (<1) 1 (<1)
rFVIIIFc, recombinant factor VIII Fc fusion protein.
†
One subject in Arm 1 was excluded from efficacy analyses because he did not receive rFVIIIFc.
‡
One subject in Arm 2 was excluded from efficacy analyses because he withdrew from the study after the pharmacokinetic evaluations (no efficacy assess-
ments could be made).
§
A single bleeding episode could involve ≥1 location (e.g. a traumatic bleeding episode might occur in muscle and skin/mucosa).
¶
The most common joint sublocations were: Arm 1, 29% ankle, 28% elbow, 24% knee; Arm 2, 46% elbow, 25% knee, 17% ankle; and Arm 3, 33%
elbow, 29% ankle, 17% knee.

© 2017 John Wiley & Sons Ltd Haemophilia (2017), 1--8

4 A. D. SHAPIRO et al.

bleeding episodes assessed by location and type (data Arms 1, 2 and 3, respectively, and 28 IU kg 1 for the
not shown). Furthermore, 98% of bleeds overall were total population, consistent with the observation that
resolved with one or two infusions, with similar the majority of bleeds required one infusion for reso-
results for each treatment arm (data not shown). Of lution. For bleeding episodes involving target joints,
bleeding episodes involving target joints, 87% the median total dose to treat a bleed for the overall
resolved with one infusion; 98% resolved with one or population was 28 IU kg 1; for spontaneous and trau-
two infusions. matic bleeding episodes, these values were 28 and
29 IU kg 1 respectively.
Dose. In the overall population, the median rFVIIIFc
dose per infusion to treat a bleeding episode was
Assessment of response to treatment
27 IU kg 1 (Fig. 2). The median total rFVIIIFc doses
per bleeding episode were 33, 30 and 27 IU kg 1 for Subjects assessed response to treatment within 8–12 h
after the infusion, which was 12–16 h prior to making
a decision regarding whether to treat with a second
infusion. The majority (78%) of rFVIIIFc infusions
All bleeding episodes
(a) 60 30 were rated by subjects as producing an ‘excellent’ or
(24-51) ‘good’ response; similar assessments were made for
Median IQR dose (IU kg–1)

50
bleeding episodes involving target joints and traumatic
22
40
(20-32)
26 27
(23-33)
bleeding episodes (Fig. 3). Moreover, of the 158 first
(22-31)
30 infusions assessed as producing a moderate response,
73% did not require a second rFVIIIFc infusion. It is
20
likely that these subjects rated their response as ‘mod-
10 erate’ in the first 8 to 12 h, predicting that they would
need another injection after 24 to 48 h for complete
0
Arm 1 Arm 2 Arm 3 Total resolution and found that, in actuality, another injec-
(n = 208) (n = 92) (n = 455) (n = 755) tion was in fact not needed to resolve the bleed.
Physicians’ global assessment of response to
Type of bleed
(b) 60 52 rFVIIIFc was excellent or effective for 99% of the sub-
(30-52)
jects’ visits, and there were no subjects whose
Median IQR dose (IU kg–1)

50 27 response was assessed as ineffective at any visit.

(22-40)
40 27 Results were generally similar across treatment arms.
(23-32)
30

20 Population pharmacokinetic modelling of treatment

of bleeding episodes
10
While peak factor activity level of rFVIIIFc occurs
0
Spontaneous Traumatic Unknown
with kinetics generally similar to standard half-life
(n = 505) (n = 245) (n = 5)

(c) 70 Bleeding episode location ‡

60 33
Median IQR dose (IU kg–1)

(30-50)
50
27 28
27 28 28 (22-36)
40 (23-36)
(22-33) (24-32) (24-33)
30

20

10

0
Joint Target joint § Muscle Soft tissue Internal Skin/mucosa
(n = 584) (n = 316) (n = 140) (n = 53) (n = 11) (n = 25)

Fig. 2. Median dose per infusion for the total population for (a) all bleed-
ing episodes by treatment arm, (b) bleeding episodes by type and (c) bleed-
ing episode locations.† IQR, interquartile range. †Treatment dose
information was incomplete for two bleeding episodes (one each in Arm 1
and Arm 3); thus, these two bleeding episodes are not included in this fig-
ure. ‡A single bleeding episode could involve ≥1 location (e.g. a traumatic Fig. 3. Subjects’ assessment of response to treatment for each bleeding epi-
bleeding episode might occur in muscle and skin/mucosa). §‘Target joint’ is sode, each bleeding episode involving a target joint and each traumatic
a subset of ‘Joint’. bleeding episode.

Haemophilia (2017), 1--8 © 2017 John Wiley & Sons Ltd

 RFVIIIFC FOR THE TREATMENT OF BLEEDING EPISODES 5

products, the factor activity level following a prophy-
lactic infusion of rFVIIIFc will be higher at all time
points after the peak concentration is reached due to
its reduced clearance and subsequently prolonged half-
life. If treatment of an acute bleed is required, knowl-
edge of approximate factor activity level at the time
of the bleed may be useful. Table 2 shows predicted
FVIII activity level at various time points after a single
dose of rFVIIIFc 25, 50 or 65 IU kg 1 (e.g. when
rFVIIIFc is used episodically), or following a routine
prophylactic dose of rFVIIIFc. Several prophylaxis reg-
imens were modelled, including administration of
rFVIIIFc 50 IU kg 1 every 3, 4 and 5 days.
A potential concern with treatment of acute bleed-
ing episodes during prophylactic treatment is the peak
factor activity level, which could theoretically con-
tribute to adverse events if factor activity levels are
above the normal range for an extended period of
time. To evaluate FVIII activity when rFVIIIFc is used
to treat a bleed in the context of an rFVIIIFc prophy-
lactic regimen, a validated population pharmacoki-
netic model was used to predict FVIII activity in
patients under several dosing scenarios that repre-
sented three common prophylactic dosing regimens in
the individualized prophylaxis arm (Arm 1) during A-
LONG. In the individualized prophylaxis arm, bleed-
ing episodes rarely occurred in close proximity follow-
ing a prophylactic treatment; 0.2% of prophylactic
treatments were followed by a bleed within 24 h.
Among the bleeding episodes occurring in the individ-
ualized prophylaxis arm, 13% of treatment infusions
(last treatment infusion if >1 infusion was adminis-
tered to treat the bleed) were followed by a prophy-
lactic treatment within 24 h. Of the 301 bleeds
(spontaneous and traumatic) that occurred in Arms 1
and 2, 17 bleeds (5.6%, all bleeds in Arm 1 and
0 bleeds in Arm 2) occurred within 24 h after a
prophylactic dose of rFVIIIFc.
The simulations predicted that the majority of
patients treating a bleed 24 h prior to their next
scheduled prophylactic dose will have peak factor
activity levels below the upper limit of normal
(150 IU dL 1 FVIII activity [11]) following both the
dose to treat the bleed and the scheduled prophylactic
dose; moreover, for the small portion of the popula-
tion with peak factor activity levels >150 IU dL 1, the
time spent >150 IU dL 1 will be brief (Fig. 4a–c).
Similarly, the simulations predicted that most patients
who treat a bleed 24 h after their previous prophylac-
tic dose will also have peak factor activity levels
<150 IU dL 1 following both the dose to treat the
bleed and the next scheduled prophylactic dose, and
the few patients with peak factor activity levels
>150 IU dL 1 will spend only a brief amount of time
>150 IU dL 1 (Fig. 4d–f).
Discussion and conclusions
These findings expand upon primary results from the
A-LONG study [5] and the rFVIIIFc extension study,
ASPIRE [6], by demonstrating the efficacy of rFVIIIFc
for treatment of acute bleeding episodes of different
types and locations, including target joints, in subjects
using rFVIIIFc for prophylactic or episodic regimens.
Overall, the efficacy of rFVIIIFc for treatment of
bleeding episodes was generally similar across treat-
ment arms, with the majority of bleeds requiring one
infusion for resolution, regardless of location or type.
This pattern extended to traumatic bleeding episodes,
with similar proportions of bleeds resolved with one
infusion and similar total rFVIIIFc consumption com-
pared with all other bleed types. No clear trend in
timing of bleeding episodes with regard to prophylac-
tic dosing was observed. The fact that the rFVIIIFc
dose or dosing interval could have been adjusted
based on the subject’s clinical condition likely con-
tributed to the absence of a time trend. Further sepa-
rating the bleeds by dosing regimen produced a
sample size that was not large enough for a robust
time trend analysis.

Table 2. Predicted FVIII activity following a single infusion with rFVIIIFc.†

Median predicted FVIII activity following a single infusion (IU dL 1; 5th, 95th prediction interval)

Dose (IU kg 1) EOI 12 h 24 h 36 h 48 h 72 h 96 h 120 h

25 50 (36, 71) 26 (15, 39) 16 (6, 29) 10 (3, 21) 6 (1, 16) 2 (<0.5, 10) 1 (<0.5, 6) <0.5 (<0.5, 3)
50 100 (73, 143) 51 (30, 79) 31 (13, 57) 20 (6, 43) 13 (3, 33) 5 (<1‡, 19) 2 (<0.5, 11) <1‡ (<0.5, 6)
65 129 (95, 185) 66 (38, 102) 41 (17, 74) 26 (7, 56) 16 (3, 43) 6 (<1‡, 25) 3 (<0.5, 14) 1 (<0.5, 8)

Median predicted FVIII activity level at steady state, following a prophylactic dose (IU dL 1; 5th, 95th prediction interval)

Dosing regimen EOI 12 h 24 h 36 h 48 h 72 h 96 h 120 h

50 IU kg 1
Q3D 107 (72, 156) 54 (30, 97) 34 (14, 71) 21 (6, 53) 13 (3, 41) 5 (<1‡, 23) – –
50 IU kg 1
Q4D 104 (71, 148) 52 (29, 89) 33 (13, 64) 20 (6, 49) 13 (3, 37) 5 (<1‡, 21) 2 (<0.5, 12) –
50 IU kg 1
Q5D 101 (70, 143) 52 (29, 86) 32 (13, 63) 20 (6, 48) 13 (3, 37) 5 (<1‡, 22) 2 (<0.5, 13) <1‡ (<0.5, 7)
FVIII, factor VIII; rFVIIIFc, recombinant factor VIII Fc fusion protein; EOI, end of infusion; Q3D, every 3 days; Q4D, every 4 days; Q5D, every 5 days.
†
Limit of detection is 0.5 IU dL 1.
‡
Value is above the limit of detection and less than 1 IU dL 1.

© 2017 John Wiley & Sons Ltd Haemophilia (2017), 1--8

6 A. D. SHAPIRO et al.

Bleeding 24 hours before a scheduled prophylaxis dose Bleeding 24 hours after a scheduled prophylaxis dose
(50 IU kg–1 Q3D dosing regimen) (50 IU kg–1 Q3D dosing regimen)
(a) (d)
Bleed Bleed
Prophylaxis treatment Prophylaxis Prophylaxis treatment Prophylaxis
63.7 121.4 Median C max 83.4 112.1 Median Cmax
(40.0, 106.6) (79.9, 190.8) (95% PI) (50.3, 140.0) (74.0, 178.6) (95% PI)
1000 1000
FVIII activity (IU dL–1)

FVIII activity (IU dL–1)

150 IU dL–1 150 IU dL–1
100 100
97.5th 97.5th
10 75th 10 75th
Median Median
25th 25th
1 1
2.5th 2.5th
0.1 0.1
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Time (days) Time (days)

Bleeding 24 hours before a scheduled prophylaxis dose Bleeding 24 hours after a scheduled prophylaxis dose
(50 IU kg–1 Q4D dosing regimen) (50 IU kg–1 Q4D dosing regimen)
Bleed Bleed
treatment Prophylaxis treatment Prophylaxis
(b) Prophylaxis (e) Prophylaxis
55.5 117.5 Median Cmax 83.9 106.4 Median Cmax
(35.4, 93.9) (76.3, 188.5) (95% PI) (49.3, 138.7) (68.3, 164.0) (95% PI)

1000 1000
FVIII activity (IU dL–1)

FVIII activity (IU dL–1)

150 IU dL–1 150 IU dL–1
100 100
97.5th 97.5th
10 75th 10 75th
Median Median
1 25th 1 25th
0.1 2.5th 0.1 2.5th
0.01 0.01
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (days) Time (days)

Bleeding 24 hours before a scheduled prophylaxis dose Bleeding 24 hours after a scheduled prophylaxis dose
(50 IU kg–1 Q5D dosing regimen) (50 IU kg–1 Q5D dosing regimen)
(c) Bleed (f) Bleed
treatment Prophylaxis treatment Prophylaxis
Prophylaxis Prophylaxis
52.8 117.0 Median Cmax 81.8 103.2 Median Cmax
(35.2, 82.5) (77.1, 180.7) (95% PI) (48.2, 136.2) (69.5, 156.8) (95% PI)
FVIII activity (IU dL–1)

1000
FVIII activity (IU dL–1)

150 IU dL–1
1000 150 IU dL–1
100 100
10 97.5th 10 97.5th
75th 75th
1 Median 1 Median
0.1 25th 0.1 25th
0.01 2.5th 0.01 2.5th
0.001 0.001
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Time (days) Time (days)

Fig. 4. Simulated FVIII activity vs. time profiles for treatment of a bleeding episode with 25 IU kg 1 rFVIIIFc 24 h before a scheduled rFVIIIFc prophylaxis
dose for (a) a 50 IU kg 1 every 3 days regimen, (b) a 50 IU kg 1 every 4 days regimen and (c) a 50 IU kg 1 every 5 days regimen; and for treatment of a
bleeding episode 24 h after a scheduled rFVIIIFc prophylaxis dose for (d) a 50 IU kg 1 every 3 days regimen, (e) a 50 IU kg 1 every 4 days regimen and (f) a
50 IU kg 1 every 5 days regimen.† FVIII, factor VIII; rFVIIIFc, recombinant factor VIII Fc fusion protein; Cmax, maximum plasma concentration; PI, predic-
tion interval; Q3D, every 3 days; Q4D, every 4 days; Q5D, every 5 days. †These dosing scenarios were chosen to represent three common prophylactic dosing
regimens in the individualized prophylaxis arm (Arm 1) during the clinical study. A treatment dose of 25 IU kg 1 was modelled, to approximate the median
dose used to treat bleeding episodes during the study. An interval of 24 h between the prophylactic dose and a dose administered to treat a bleeding episode
was modelled, as this would likely be the shortest potential interval between a prophylactic dose and a dose administered for treatment of bleeding. Arrows
indicate the time of infusion to treat a bleeding episode or for scheduled prophylaxis, as indicated above each arrow. The predicted median Cmax value and
95% PI immediately following each infusion are shown above the corresponding arrow. A FVIII activity level of 150 IU dL 1 is indicated by a horizontal
dashed line.

Similar to studies of conventional rFVIII products A-LONG subjects had ≥1 target joint at baseline.
[12–15], the most common bleeding episode location rFVIIIFc was efficacious for the treatment of bleeds
during A-LONG was a joint (72%). The majority of involving target joints, with the majority resolving

Haemophilia (2017), 1--8 © 2017 John Wiley & Sons Ltd

 RFVIIIFC FOR THE TREATMENT OF BLEEDING EPISODES
with one infusion and similar total rFVIIIFc consump-
tion compared with all bleeding episodes. Addition-
ally, 60% [individualized prophylaxis (Arm 1)] and
52% [weekly prophylaxis (Arm 2)] of subjects with
target joints at baseline had no bleeds involving their
target joints during A-LONG.
The efficacy of rFVIIIFc for treatment of acute
bleeding episodes is comparable to, or even favourable
compared with, that observed for standard half-life
rFVIII products (no data for direct comparisons are
available). In A-LONG, 98% of bleeds resolved with
one or two rFVIIIFc infusions. In a meta-analysis of
six clinical studies of rAHF-PFM (ADVATEâ; Baxter
Healthcare Corp., Westlake Village, CA, USA), 90%
of bleeds resolved with one or two infusions (no dos-
ing information provided) in children, adolescents and
adults with moderately severe to severe haemophilia A
(≤2 IU dL 1 FVIII level) using prophylaxis or episodic
treatment [12]. A postmarketing surveillance study of
sucrose-formulated rFVIII (KOGENATEâ FS; Bayer
Inc., Toronto, ON, Canada) showed that 85.4% of
bleeds resolved with one or two infusions [mean  SD
doses, 33.9  15.8 IU kg 1 (trauma-related);
33.3  15.6 IU kg 1 (spontaneous)] in subjects of any
age using prophylaxis or episodic treatment for mod-
erately severe to severe haemophilia A (<2 IU dL 1
FVIII level) [13]. Two clinical studies of moroctocog
alfa (REFACTOâ; Wyeth Pharmaceuticals Inc.,
Philadelphia, PA, USA) in subjects with moderately
severe to severe haemophilia A (≤2 IU dL 1 FVIII
level) showed that 92.5% (subjects ≥12 years using
prophylaxis; median dose, 30.6 IU kg 1) and 86.7%
(subjects ≥6 years using prophylaxis or episodic treat-
ment; median dose, 37.6 IU kg 1) of bleeds resolved
with one or two infusions [14]. Finally, in a study of
turoctocog alfa (NOVOEIGHTâ; Novo Nordisk Inc.,
Plainsboro, NJ, USA), 89% of bleeds resolved with
one or two infusions (mean consumption from start to
stop of a bleed, 45.6 IU kg 1) in adolescents and
adults with severe haemophilia A (≤1 IU dL 1 FVIII
level) using prophylaxis [15].
Pharmacokinetic data collected during A-LONG
showed that maximal FVIII activity is rapidly achieved
after rFVIIIFc infusion. The lower clearance of
rFVIIIFc compared with rFVIII (P < 0.001 [5]) may
have contributed to the observed efficacy of rFVIIIFc
for treatment of acute bleeds; for example, higher
FVIII activity levels after the initial peak may have
resulted in fewer bleeds requiring a second infusion
for resolution.
A potential concern with treatment of acute bleeds
during prophylaxis is peak factor activity level,
which could theoretically contribute to adverse
events such as unmasking subclinical atherosclerotic
disease with subsequent vascular thrombosis if factor
activity levels are elevated for an extended period of
time. Given the rapid peak in FVIII activity and
© 2017 John Wiley & Sons Ltd
7
prolonged half-life of rFVIIIFc, we used a population
pharmacokinetic model to simulate factor activity
levels for rFVIIIFc treatment of bleeding in close
proximity to a regular prophylactic dose, including
treatment (e.g. traumatic bleed) 24 h after a prophy-
lactic dose [this rarely occurred during the study
(0.2% of prophylactic treatments)]. These simula-
tions demonstrated that, for a small proportion of
patients, predicted FVIII activity levels may briefly
(i.e. for a few hours) peak >150 IU dL 1. Impor-
tantly, no serious thrombotic events were reported
during A-LONG, including subjects who underwent
surgery with intensive dosing; a non-serious perianal
venous thrombosis was reported in one subject dur-
ing the postoperative period, which was likely a rec-
tal haemorrhoid and considered mild and unrelated
to rFVIIIFc by the Investigator [5].
Determination of an appropriate dose of replace-
ment factor for treatment of a bleeding episode has
been evaluated through several generations of
replacement factor products [16–18]. Here, rFVIIIFc
doses used to treat bleeds were comparable to litera-
ture-reported doses for other FVIII products [19].
Importantly, appropriate treatment depends on bleed
severity and location; a limitation of this study was
that information on the severity of bleeds was not
collected and, moreover, such information would
have been difficult to standardize. In addition, there
were no life-threatening bleeding episodes during
A-LONG [5], such as those involving the central ner-
vous system or airway, and thus appropriate rFVIIIFc
dosing for such an event has not yet been reported.
Another limitation was the timing of subjects’ assess-
ment of response to bleeding episode treatment. The
assessment was performed 8–12 h from the rFVIIIFc
infusion, whereas the decision regarding a second
infusion was not made until 24 h after the first infu-
sion. Depending on the severity of the bleed, pain,
swelling and reduced range of motion may remain
8–12 h after infusion, when the assessment was
made, but may resolve by 24 h. Indeed, 73% of
infusions rated moderate at 8–12 h did not require a
second rFVIIIFc infusion. In support of the efficacy
profile, overall, both subjects’ assessment and physi-
cians’ global assessment of response to rFVIIIFc were
favourable.
In general, the treatment dose for breakthrough
bleeds for individuals on prophylaxis is outlined in the
rFVIIIFc (Eloctateâ; Biogen Idec, Cambridge, MA,
USA) US package insert [20], under Dosing for
Control of Bleeding Episodes. In summary, these
results expand upon those previously reported for
A-LONG and demonstrate that rFVIIIFc can be used
to effectively treat acute bleeding episodes of any type
for subjects on episodic (on-demand) or prophylaxis
treatment, regardless of the severity or location of the
bleeding episode, including target joints.
Haemophilia (2017), 1--8
8 A. D. SHAPIRO et al.

Acknowledgements
This study was funded by Biogen and Sobi. Editorial support was pro-
vided by Courtney St. Amour, PhD, of MedErgy, and was funded by Bio-
gen and Sobi.
Author contributions
ADS, JNM, DP, JP, DVQ and PC contributed to the data collection,
interpretation of data and drafting and revision of the manuscript. ET, SL
and AI contributed to the design of data analyses, interpretation of data,
drafting and revision of the manuscript and performed the analyses. GFP
contributed to the design and conceptualization of the research, design of
data analyses, interpretation of data and drafting and revision of the
manuscript. GAA contributed to the design of data analyses, interpreta-
tion of data and drafting and revision of the manuscript. All authors had
access to the final data, participated in data analysis and interpretation
and vouched for the completeness and accuracy of the data.
Disclosures
ADS has served on speakers’ bureaus for Baxalta, Novo Nordisk and Bio-
gen; has served on advisory boards for Baxalta, Novo Nordisk, Bayer and
Biogen; has served on global steering committees for Baxalta and Bayer;
has received consulting fees from Baxalta, Novo Nordisk, Biogen, Chugai
Pharma USA, Prometics and Kedrion Biopharma; and has received
research funding from Baxalta, Bayer, CSL Behring, Biogen, Novartis,
Octapharma, Cangene Pharmaceuticals, PTC Therapeutics, Prometics and
Kedrion Biopharma; all consulting fees and honoraria are directed to the
Indiana Hemophilia and Thrombosis Center, and are not accepted per-
sonally. JNM has served as an advisor for Amgen, Bayer and Novo Nor-
disk; and has received funding for clinical trials from Bayer, Novo
Nordisk, Biogen, CSL Behring and Inspiration. DP has received research
funding from and been a paid consultant for Biogen. JP has served on
advisory boards for Bayer, BPL, Octapharma, Biogen and Pfizer; and has
received educational and travel grants from Octapharma, Pfizer, Biogen
and Novo Nordisk. DVQ reports involvement in the A-LONG clinical
trial; has served on speakers’ bureaus for Baxalta, Biogen and Novo Nor-
disk; and has served on advisory boards for Baxalta, Novo Nordisk,
Bayer and Biogen. PC has received honoraria and travel grants from Bax-
alta, Novo Nordisk, Bayer, Pfizer, CSL Behring, Biogen and Sobi; has
served on advisory boards for Baxalta, Biogen, CSL Behring, Novo Nor-
disk, Pfizer and Sobi; and has received research funding from CSL Behr-
ing, Novo Nordisk and Pfizer. ET and AI are employees of and hold
equity interest in Biogen. SL, GFP and GAA are shareholders and former
employees of Biogen. All brand names are trademarks of their respective
owners. Editorial support was funded by Biogen and Sobi. Biogen and
Sobi reviewed and provided feedback on the paper. The authors had full
editorial control of the paper, and provided their final approval of all
content.

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Supporting Information
Additional Supporting Information may be
found in the online version of this article:
Data S1. Supplemental Methods and Sup-
plemental Table 1 (Demographic and baseline
characteristics).

Haemophilia (2017), 1--8 © 2017 John Wiley & Sons Ltd