Received: 25 Novemb er 2019
Revised: 24 January 2020
Accepted: 12 Fe bruar y 2020
DOI : 10.1111/h ae.13953
Recombinant factor VIII Fc fusion protein for the treatment of
severe haemophilia A: Final results from the ASPIRE extension
Beatrice Nolan1 | Johnny Mahlangu2 | Ingrid Pabinger3 | Guy Young4,5 |
Barbara A. Konkle6 | Chris Barnes7 | Keiji Nogami8 | Elena Santagostino9 | K.
John Pasi10 | Liane Khoo11 | Bent Winding12 | Huixing Yuan13 | Joachim Fruebis14 |
Dan Rudin14 | Johannes Oldenburg15
1Children's Health Irelan d at Crumlin, Dub lin, Ireland
2Haemop hilia Comprehensive Care Cent re, Faculty of Health Scie nces, Charlot te Maxeke Johann esbur g Acade mic Hosp ital an d NHLS , Univer sity of
Witwatersrand, Johannesburg, South Africa
3Medizinische Universität Wien, Vien na, Aus tria
4Children’s Hospit al Los Angeles, Los Ange les, C A, USA
5University of Souther n California Keck Schoo l of Medicine, Los A ngeles, CA , USA
6Bloodworks No rthwe st, Seattle, WA, USA
7The Royal Children’s Hospit al, Par kville, Vic ., Australia
8Nara Medical Universi ty, Kashi wara, Japan
9Angelo Bianchi Bo nomi Hemophilia and Thrombosis Centre, Fondazione IRCC S Ca’ Gr anda, O spedale Maggiore Policlinico, Milan, Italy
10Royal Lo ndon Ha emophilia Cent re, Bar ts and The London School of Medicine and Dentis try, Lon don, UK
11Royal Prince Alfred Hospital, C amperdown, NSW, Australia
12Sobi, Sto ckhol m, Sweden
13Sanofi, Cambridge, MA, USA
14Biover ativ, a Sanofi compa ny, Waltham, M A, USA
15Instit ute of Experimental Ha ematology and Transfusion Medicine, Uni versit y Clini c Bonn, B onn, Germany
Beatri ce Nolan , Children's Heal th Ireland at Cru mlin, Dublin, Ireland.
Joachim Fruebis , BlueRock Therapeutics, C ambridge, MA , USA
Dan Rudin , Global Blood Therapeutics, Sou th San Fra ncisco, CA, USA
Sanofi; Swedish Orphan Biovitru m Abstract
Introduction: The efficacy and safety of recombinant factor VIII Fc fusion protein
(rFVIIIFc) as an extended half-life treatment for severe haemophilia A were dem-
onstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who
completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an
open-label extension study.
This is an op en access arti cle under the ter ms of the Creative Commons Attribution-NonCommercial-NoD erivs L icense, which permits use and distrib ution in
any medium, provided the original work is properly cited, the use is no n-commercial and no modi ficat ions or adaptat ions are made.
© 2020 The Authors. Haemophilia publis hed by Joh n Wiley & Sons Ltd.
NOLA N et AL.
1 | INTRODUCTION
Pr o phy l acti c repl a cem ent of cl o t tin g fa c tor VI II (F VII I) is st and ard - of-
care for people with severe haemophilia A .1 Individualizing prophy-
lactic regimens is essential to decrease the likelihood of spontaneous
bleeds by adjusting plasma FVIII activity to meet individual and life-
time needs.2 Long-term bleed protection preserves joint health and
maintains quality of life, which are increasingly impor tant outcomes
for people with haemophilia because life expectancies are now sim-
ilar to those of the general population.3-5
Prophylactic clotting factor regimens can be individualized by
considering factors such as bleed phenotype, FVIII pharmacoki-
netics, physical activity and treatment preferences.6,7 Even with
individualized regimens, compliance with standard half-life FVIII
prophylaxis is challenging; the short half-life necessitates frequent
infusion, and limitations imposed by maximum trough levels do not
assure complete bleed protection.8 -10 Consequently, extended half-
life (EHL) FVIII products have been designed with structural modifi-
cations to decre ase FVIII clea rance and reduce inf usion frequen cy.11
Recombinant FVIII Fc fusion protein (rFVIIIFc) is manufactured in
a human cell line in an environment free of animal and human addi-
tives. It consi st s of a sing le monome ri c molecul e of re combina nt F VI II
fused to the Fc domain of immunoglobulin G1; the latter binds to the
neonatal Fc receptor and extends FVIII half-life via the natural Fc re-
cycling pathway.12 rFVIIIFc was the first EHL FVIII product approved
by the United States Food and Drug Administration and European
Medicines Agency (EMA) and is currently the only EMA-approved
EHL FVIII product for patients <12 years of age. rFVIIIFc is indicated
for on-demand treatment and control of bleed episodes, routine
prophylaxis to reduce the frequency of bleeds and perioperative
management in children and adults with haemophilia A.13 ,14 rFVIIIFc
has reduced treatment burden by extending the dosing interval and
increasing treatment flexibility through individualized regimens,
while maintaining or increasing bleed protection.15-17 Two Phase 3,
open-label, global studies to assess rFVIIIFc treatment for severe
haemophilia A in previously treated adults and adolescents (A-LONG
[NC T01181128])18 and children (Kids A-LONG [NCT01458106])19
confirmed the safety, effic acy and prolonged activity of rFVIIIFc in all
ages. As a single agent, rFVIIIFc enables comprehensive bleed protec-
tion across clinical scenarios (acute bleed treatment, prophylaxis and
perioperative management). Benefits of rFVIIIFc include improve-
ments in and protection of joint health, attributable to decreased
swelling, increased strength and improved range of motion.17
Eligible subjects completing A-LONG or Kids A-LONG could
enrol in ASPIRE, the Phase 3 long-term extension study. Interim
analyses from ASPIRE provided initial evidence on the long-term
safety and efficacy of rFVIIIFc prophylaxis.20,21 Here, we re po r t final
results from ASPIRE.
2 | MATERIALS AND METHODS
2.1 | Study design
ASPIRE (NCT01454739) was an open-label, non-randomized,
global extension trial to assess long-term safety and efficacy of
Aim: To report the long-term safety and efficacy of rFVIIIFc in subjects with severe
haemophilia A who enrolled in ASPIRE.
Methods: Previously treated subjects received one or more of the following regi-
mens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or epi-
sodic treatment. Subjects could switch treatment regimen at any time. The primary
endpoint was inhibitor development.
Results: A total of 150 subjects from A-LONG and 61 subjects from Kids A-LONG
enrolled in ASPIRE. Most subjects received the IP regimen (A-LONG: n = 110; Kids
A-LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from
A-LONG and Kids A-LONG was 3.9 (0.1-5.3) years and 3.2 (0.3-3.9) years, respec-
tively. No inhibitors were observed (0 per 1000 subject-years; 95% confidence inter-
val, 0-5.2) and the overall rFVIIIFc safety profile was consistent with prior studies.
For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median
overall ABR for adults and adolescents was <1.0) and extended-dosing intervals were
maintained (median of 3.5 days) for the majority of subjects in ASPIRE.
Conclusion: ASPIRE results, which include up to 5 years of follow-up data, confirm
earlier reports on the consistent and well-characterized safety and efficacy of rFVII-
IFc treatment for severe haemophilia A.
bleed rate, extended half-life, individualized prophylaxis, perioperative haemostasis, rFVIIIFc
NOLAN et AL.
rFVIIIFc for prevention and treatment of bleed episodes in previ-
ously treated adults (≥150 documented prior exposure days [ED])
and children (≥50 EDs) with severe haemophilia A (<1 IU/dL [<1%]
endogenous FVIII activity). Eligible subjects who had completed
a rFVIIIFc Phase 3 safety and efficacy trial (A-LONG: subjects
≥12 years of age [NCT01181128]; Kids A-LONG: subject s <12 years
of age [NC T0145810 6] )18 ,19 co ul d enr ol. Twen ty-ni ne subj ect s from
two smaller safety and pharmacokinetic trials (NCT02083965;
NCT02502149) were subsequently enrolled in ASPIRE but were
excluded from this analysis due to their short duration of treat-
ment in ASPIRE. Exclusion of these subjects did not af fect the re-
ported outcomes. Subjects with a history of anti-FVIII-neutralizing
antibodies (inhibitors), hypersensitivity associated with any FVIII
concentrate or intravenous immunoglobulin, or other coagulation
disorders were excluded. ASPIRE was performed according to the
Declaration of Helsinki, and all procedures were approved by local
ethics committees. Written informed consent was obtained prior
to enrolment from all subjec ts or subject s’ parent or lega l guardian.
Details on study design and treatment have been published pre-
viously.20,21 At enrolment, three prophylactic (individualized prophy-
laxis [IP], weekly prophylaxis [WP] and modified prophylaxis [MP])
regimens and one on-demand (episodic treatment [ET]) regimen
were available to adult and adolescent (≥12 years of age) subjects.
Paediatric subjects (<12 years of age) were eligible for IP or MP but
could switch to other regimens upon reaching 12 years of age. For
all prophylactic regimens, the dose and inter val were based on the
subject's pharmacokinetic (if available) and clinical profile observed
in the parent study and FVIII trough and peak (recovery) values
during ASPIRE. The IP group received rFVIIIFc at a dose and interval
to target a trough plasma FVIII activity ≤5%, with the lowest effec-
tive dose administered to target trough levels 1%-3%. The IP group
received rFVIIIFc at 25-65 IU/kg every 3-5 days, or twice weekly at
20-65 IU/kg on Day 1 and 40-65 IU/kg on Day 4; subjects <12 years
of age received doses ≤80 IU/kg with dosing intervals ≥2 days. The
WP group received 65 IU/kg rFVIIIFc weekly. If optimal prophy-
laxis could not be achieved with IP or WP treatment, subjects could
switch to a MP regimen personalized by the investigator (Supporting
Information). In the ET group, dose was based on individual bleed
type and severity. During ASPIRE, subjects could switch between
eligible regimens at any time.
Subjects were followed for ≥100 rFVIIIFc EDs across both
parent and extension trials and could continue in the extension
study for 4 years or until rFVIIIFc therapy became commercially
available in their country. Study visits were scheduled at 6-month
(±2 weeks) intervals, with unscheduled visits occurring per the
2.2 | Outcome measures
The primary endpoint was inhibitor development. Inhibitor test-
ing occurred at each s tud y visit or upon suspected inhibitor devel-
opment. A positive inhibitor result was defined as a neutralizing
antibody value ≥0.6 Bethesda units/mL confirmed by Nijmegen-
modified Bethesda assay within 2-4 weeks of the initial occur-
rence. Secondary endpoints were annualized bleed rate (ABR;
overall, spontaneous, traumatic, joint and spontaneous joint) per
subject, total rFVIIIFc EDs, total weekly prophylactic dose and
yearly consumption, physician's global assessment of response
to a treatment regimen (excellent, effective, partially effective
or ineffective [Supporting Information]) and the subject's self-as-
sessment of response to treatment of acute bleeds (4-point scale:
excellent, good, moderate or none). Additional endpoints included
the incidence of adverse events (AE), investigator and surgeon
assessment of haemostatic response to major surgery (defined
previously20), number of rFVIIIFc infusions and dose per infusion
to maintain haemostasis during major surgery22 and Hemophilia
Joint Health Score (HJHS) or modified HJHS (mHJHS) for indi-
viduals <12 and ≥12 years of age, respectively. HJHS is a sensi-
tive tool for detection of early signs of joint damage and is used
to assess joint health in children.17, 2 3 Modifications in the mHJHS
are minor and involve condensing response scales based on rec-
ommendations from the latest HJHS validation study (Suppor ting
Information).17, 2 4 AE s were classified using the Medical Dicti ona ry
for Regulatory Ac tivities system organ classes and preferred
2.3 | Statistical analyses
The safety analysis included data from all subjects who were ex-
posed to ≥1 dose of rFVIIIFc during ASPIRE. The efficacy analysis
included data from all subjects who received ≥1 dose of rFVIIIFc,
but excluded data collected during surgical/rehabilitation periods
and when >28 days elapsed between infusions for subjects receiv-
ing prophylaxis. Efficacy data were stratified by treatment group.
Subjects were included in the summary efficacy analysis of each
treatment group for the period they received that treatment dur-
ing ASPIRE and, therefore, may be represented in ≥1 group in the
summary analyses. Data were analysed separately for subjects from
A-LONG and Kids A-LONG, and paediatric subjects were further
stratif ie d by age (<6 an d 6 to <12 years) at the time of entr y in to Kids
A-LONG. All statistic al analyses were descriptive in nature and no
tests were performed on the efficacy endpoints.
3 | RESULTS
3.1 | Study population
A total of 211 previously treated male subjects from A-LONG
(n = 150) and Kids A-LONG (<6 years of age: n = 30; 6 to <12 years
of age: n = 31) enrolled in A SPIRE (Figure 1). Subject age ranged
from 2 to 66 years (Table 1). All subjects received ≥1 dose of rFVII-
IFc and 88% of subjects (186/211; 132 from A-LONG and 54 from
Kids A-LONG) completed the study. During ASPIRE, 21 subjects
NOLA N et AL.
FIGURE 1 Subject disposition for ASPIRE extension study. aSubject was on an episodic treatment regimen and discontinued owing to
a non-serious adverse event of chronic renal failure that was considered unrelated to recombinant factor VIII Fc fusion protein. bSubjects
were withdrawn because of the physician's decision for non-compliance with the study (n = 3). cProtocol violations included non-compliance
with prophylactic dosing (n = 1), use of non-study factor VIII under circumstances that were not an emergency or an accident (n = 2), non-
compliance with study procedures, including infusion timing and concomitant medications (n = 1), lost to follow-up and incomplete end of
study visit (n = 1). dIncludes product becoming commercially available in the subject's country (n = 3), commencing a different clinical trial
(n = 2), inabilit y to comply with the demands of the study (n = 1), early termination (n = 1) and incarceration (n = 1)
Enrolled in ASPIRE, N = 211
From A-LONG, n = 150
All paents ≥12 years of age
n = 54 (88.5%)
n = 132 (88.0%)
Disconnued early, n = 18 (12.0%)
Adverse event,an = 1 (0.7%)
Lost to follow-up, n = 1 (0.7%)
Physician decision,bn = 3 (2.0%)
Protocol violaon,cn = 3 (2.0%)
Withdrawal by subject, n = 5 (3.3%)
Other,dn = 5 (3.3%)
Disconnued early, n = 7 (11.5%)
Protocol violaon,cn = 2 (3.3%)
Withdrawal by subject, n = 2 (3.3%)
Other,dn = 3 (4.9%)
From Kids A-LONG, n = 61
<6 years of age, n = 30
6 to <12 years of age, n = 31
TABLE 1 Subject demographics in ASPIRE by parent study and treatment regimen
Parent study A-LONGa Kids A-LONG
Treatment regimen IP (n = 110) WP (n = 27) MP (n = 21) ET (n = 13)
Aged <6 yb Aged 6 to <12 y
IP (n = 29) MP (n = 2) IP (n = 30) MP (n = 1)
Median (min-max) age, y 31 (13‒66) 32 (19‒63) 33 (14‒59) 35 (14‒57) 4 (2‒6) 6 (6‒6) 9 (6‒12) 9
Geographic location , n (%)
Europec 29 (26.4) 8 (29.6) 2 (9.5) 2 (15.4) 16 (55.2) 0 (0.0) 15 (50.0) 0 (0.0)
North Americad 40 (36.4) 7 (25.9) 4 (19.0) 5 (38.5) 3 (10.3) 1 (50.0) 6 (20.0) 1 (100.0)
Australiae 6 (5.5) 0 (0.0) 6 (28.6) 1 (7.7) 4 (13.8) 1 (50.0) 2 (6.7) 0 (0.0)
Brazil 3 (2.7) 0 (0.0) 0 (0.0) 1 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Asiaf 17 (15.5) 10 (37.0) 9 (42.9) 4 (30.8) 2 (6.9) 0 (0.0) 0 (0.0) 0 (0.0)
South Africa 15 (13.6) 2 (7.4) 0 (0.0) 0 (0.0) 4 (13.8) 0 (0.0) 7 (23.3) 0 (0.0)
Race, n (%)
White 75 (68.2) 18 (66.7) 10 (47.6) 10 (76.9) 19 (65.5) 2 (100.0) 21 (70.0) 1 (100.0)
Black 7 (6.4) 1 (3.7 ) 0 (0.0) 0 (0.0) 4 (13.8) 0 (0.0) 4 (13.3) 0 (0.0)
Asian 23 (20.9) 8 (29.6) 10 (47.6) 3 (23.1) 3 (10.3) 0 (0.0) 1 (3.3) 0 (0.0)
Other 5 (4.5) 0 (0.0) 1 (4.8) 0 (0.0) 3 (10.3) 0 (0.0) 4 (13.3) 0 (0.0)
Ethnicit y, n (%)
Hispanic or Latino 6 (5.5) 1 (3.7) 0 (0.0) 2 (15.4) 1 (3.4) 0 (0.0) 1 (3.3) 0 (0.0)
Not Hispanic or Latino 104 (94.5) 26 (96.3) 21 (100.0) 11 (84.6) 28 (96.6) 2 (100.0) 29 (96.7) 1 (100.0)
Abbreviations: ET, episodic treatment; IP, individualized prophylaxis; max, maximum; min, minimum; MP, modified prophylaxis; WP,
aTwenty-one subjects switched treatment regimens once during the study.
bOne subject switched from IP to MP.
cIncludes Austria, Belgium, France, Germany, Ireland, Italy, Netherlands, Poland, Spain, Sweden, Switzerland and the United Kingdom.
dIncludes Canada and the United States.
eIncludes Australia and New Zealand.
fIncludes China (Hong Kong), India, Israel and Japan.
NOLAN et AL.
from A-LONG and 1 from Kids A-LONG (IP to MP) switched to an
on-study regimen; most switches were to MP to allow a preventive
dose before strenuous activity (Supporting Information). No subject
switched regimens more than once.
3.2 | Duration and exposure
For subjects from A-LONG, the median (range) cumulative treatment
duration in A-LONG and ASPIRE was 4.5 (0.7-5.9) years, which in-
cludes 3.9 (0.1-5.3) years in ASPIRE only. For paediatric subjects, cor-
responding values were 3.5 (0.4-4.4) years and 3. 2 (0.3-3.9) years,
For subjects from A-LONG , the median (range) cumulative num-
ber of EDs in A-LONG and ASPIRE was 333 (36-735) days, which
includes 268 (8-660) days in ASPIRE only. For paediatric subjects,
corresponding values were 375 (42-529) days and 332 (18-467) days,
3.3 | Safety
No subject developed an inhibitor during ASPIRE (0 per 100 0
subject-years; 95% confidence interval, 0-5.2). rFVIIIFc was well
tolerated with an AE pattern consistent with those expected for
subjects with severe haemophilia A (Table 2). One subject from
A-LONG receiving ET discontinued ASPIRE owing to a non-seri-
ous AE of chronic renal failure (elevated serum creatinine due to
chronic kidney disease) that was considered unrelated to rFVIIIFc.
No paediatric subjects discontinued treatment because of an AE.
One subject from Kids A-LONG developed urticaria, which was
considered unrelated to study treatment, and discontinued ASPIRE
owing to the use of non-study F VIII. Three AEs in 2 A-LONG sub-
jects were considered related to rFVIIIFc treatment (headache
and hot flush [n = 1]; chromaturia [n = 1]). These AEs were mild in
severity and did not lead to study discontinuation. There were no
treatment-related serious AEs, deaths, anaphylaxis, serious hyper-
sensitivity events or vascular thrombotic events.
3.4 | ABRs and joint health
ABRs remained low and stable throughout ASPIRE in the prophylaxis
groups and were lowest in subjects from A-LONG following the IP
regimen (median for all ABR categories <1.0; Figure 2 and Supporting
Information). Median ABR for spontaneous joint bleeds was 0.0 for
subjects of all ages receiving IP. ABRs were also low for subjects with
impaired joint health (≥1 target joint at entry into the parent trials;
Suppor ting Information). In this group, median (interquartile range
[IQR]) overall ABR during ASPIRE for subject s from A-LONG was 0.7
(0.0-2.8) for IP (n = 72), 2.2 (0.3-5.2) for WP (n = 16), 5.0 (2.9-11.0)
for MP (n = 16) and 16.1 (0.0-37.8) for ET (n = 11). Corresponding
values for subjects with ≥1 target joint at entry into Kids A-LONG
were 1.1 (0.6-2.2) for IP (n = 7) and 4.1 for MP (n = 1) during ASPIRE.
From the be gin ning to th e end of ASPIRE, the mean (standard devia-
tion) changes in mHJHS for adult and adolescent subjects (n = 72)
and HJHS for paediatric subjects (n = 35) were −2.5 (7.1) and −0.5
Overall (N = 211) A-LONG (n = 150)
(n = 61)
≥1 AE, n (%) 184 (87.2) 129 (86.0) 55 (90.2)
≥1 rFVIIIFc-related AE,
2 (0.9) 2 (1.3) 0 (0.0)
Most common AEs (≥10% per parent study population), n (%)
Nasopharyngitis 43 (20.3) 37 (24.7) 6 (9.8)
30 (14.2) 17 (11.3) 13 (21.3)
Fall 30 (14.2) 14 (9.3) 16 (26.2)
Arthralgia 26 (12.3) 19 (12.7) 7 (11.5)
Headache 24 (11.4) 13 (8.7) 11 (18.0)
Diarrhoea 20 (9.5) 15 (10.0) 5 (8.2)
Cough 17 (8.1) 9 (6.0) 8 (13.1)
15 (7.1) 15 (10.0) 0 (0.0)
Vomiting 14 (6.6) 6 (4.0) 8 (13.1)
Seasonal allergy 13 (6.2) 5 (3.3) 8 (13.1)
Tonsillitis 13 (6.2) 2 (1.3) 11 (18.0)
Abbreviations: AE, adverse event ; rFVIIIFc, recombinant factor VIII Fc fusion protein.
aDoes not include AEs during major surgical or rehabilitation periods.
TABLE 2 AEsa during ASPIRE overall
and by parent study
NOLA N et AL.
3.5 | Dosing interval, factor
consumption and compliance
Median IP dosing interval was approximately 3.5 days for all age
groups (Table 3). For subjects from A-LONG, median WP and MP dos-
ing inter vals were 7.0 and 5.0 days, respectively (Table 3). Most sub-
jects (A-LONG: 71%; Kids A-LONG: 89%) maintained dosing intervals
achieved in the parent studies. For adults and adolescents, the dosing
inte rval lengthen ed for 21% of subj ec ts and shor tened for 8% of sub -
jects; 23% lengthened their dosing interval to >5 days. For paediatric
subj ect s, cor res pon din g va lue s wer e 7% and 5% , re spe c tivel y, and 3%
(all <6 years of age) leng thened their dosing interval to >5 days.
There was no change in median (IQR) weekly factor con-
sumption for adults and adolescents (n = 128) from the end of
A-LONG (75 [70-91] IU/kg) to the end of ASPIRE (75 [70-97] IU/
kg) (Table 3). For paediatric subjects (n = 61), median (IQR) weekly
factor consumption was higher in ASPIRE (95 [75-116] IU/kg)
than the end of Kids A-LONG (75 [75-105] IU/kg). Overall, 94%
(190/202) and 95% (192/202) of subject s in a prophylactic reg-
imen were dose compliant (within 80%-125% of the prescribed
dose) and inter val compliant (within ±1 day of the prescribed in-
3.6 | Global assessment of response to prophylaxis
Over 99% of physicians’ assessment s of responses at subject visits
were excellent (87% [1464/1680]) or effective (13% [210/1680]).
FIGURE 2 ABRs during ASPIRE by
parent study and treatment regimen.
ABR, annualized bleed rate; ET, episodic
treatment; IP, individualized prophylaxis;
IQR, interquartile range; MP, modified
prophylaxis; WP, weekly prophylaxis.
aTwenty-one subjects switched treatment
regimens once during the study. bOne
subject switched from IP to MP. cThe two
subjects <6 y of age receiving MP had
overall, spontaneous, traumatic, joint and
spontaneous joint ABR IQRs of 3.4-4.1,
2.0-3.1, 1.0-1.3, 1.3-4.1 and 1.3-3.1,
respectively. dThe single subject 6 to
<12 y of age receiving MP had both an
overall ABR and traumatic ABR of 1.0
(n = 110)
(n = 27)
(n = 21)
(n = 13)
Subjects from A-LONG
Age <6 y
(n = 29)
Age 6 to <12 y
(n = 30)
Subjects from Kids A-LONG
TABLE 3 Prophylactic dosing during ASPIRE by parent study and treatment regimen
Parent study A-LONGa Kids A-LONG
Treatment regimen IP WP MPb
Aged <6 y Aged 6 to <12 y
Number of subjects, n 110 27 21 29c,d 30e
Median (IQR) dosing interval, d 3.5 (3.5-5.0) 7.0 ( 7. 0 -7.1) 5.0 (4.0-6.9) 3.5 (3.5-3.5) 3.5 (3.5-3.5)
Median (IQR) weekly dose, IU/kg 79.5 (73.7-100.9) 65.7 (61.9-67. 2) 70.6 (62.3-90.4) 101.9 (88.7-118.7) 94.9 (81.7-109.1)
Abbreviations: IP, individualized prophylaxis; IQR, interquartile range; MP, modified prophylaxis; WP, weekly prophylaxis.
aTwenty-one subjects switched treatment regimens once during ASPIRE.
bMP was not available in A-LONG.
cOne subject switched from IP to MP.
dThe two subjects <6 y of age receiving MP had dosing intervals of 2.3-5.5 d and weekly doses of 81.5-118.7 IU/kg.
eThe single subject 6 to <12 y of age receiving MP had a dosing interval of 3.5 d and a weekly dose of 84.5 IU/kg.
NOLAN et AL.
The remainder (0.4% [6/1680]) were graded as partially effective; no
responses were graded as ineffective during ASPIRE.
3.7 | Control of acute bleed episodes
Overall, >75% of acute bleed episodes were controlled by one rF VII-
IFc infusion and >93% with ≤2 infusions (Table 4). The majority of
first infusions (≥73%) were rated as having excellent or good re-
sponses by subjects.
3.8 | Perioperative management
During ASPIRE, 39 major and 69 minor surgeries were performed
in 26 and 54 subjects, respectively. The most common major sur-
geries included unilateral knee, elbow and ankle ar throplasties; ar-
throscopy thoracotomy; spinal surgery; and ureteroscopy. Two of
the 39 major surgeries were performed in A-LONG , and the reha-
bilitative period extended into ASPIRE. Of the 37 major surgeries
in AS PIR E, 33 we re ass ess e d for ha emo stat ic re s pon se and all we r e
rated as excellent (94% [31/33]) or good (6% [2/33]). For adult s
and adolescents, 74% required one rFVIIIFc infusion to maintain
haemostasis during major surgery; 17% required two infusions,
and specific infusion data were missing for the remaining subjects
(9%) receiving surgery. For paediatric subjects, one rFVIIIFc infu-
sion was sufficient to maintain haemostasis during both major sur-
geries. The median rFVIIIFc dose per infusion during surgery was
59.6 IU/ kg for ad ults and adoles cent s an d 51. 8 IU/kg fo r pa ed iatr ic
subjects. Most major surgeries (92%) did not require red blood cell
4 | DISCUSSION
ASPIRE was a large international study enrolling subject s of all ages
(range, 2-66 years) with demographic diversity, long-term (up to
5.3 years) follow-up and flexibility in rFVIIIFc dosing with the option
to switch treatment regimen at any time. With individualized dosing
assuming an essential role in the management of severe haemophilia
A, the unique design of ASPIRE approximated real-world practice.
These final results of ASPIRE are consistent with those of the
A-LONG and Kids A-LONG Phase 3 trials and an earlier interim
analysis17,1 9, 20 and confirm the long-term, well-characterized safet y
and efficacy of rFVIIIFc in previously treated subjects with severe
haemophilia A. rFVIIIFc was well tolerated across all age groups
and did not lead to development of inhibitors or treatment-related
serious AEs. Most subjects received IP, which was associated with
low ABRs in subjects of all ages. Median ABR (overall and all ABR
subcategories) in adults and adolescents receiving IP was <1.0, with
similar outcomes reported for children. ABR data for IP support
rFVIIIFc dosing according to the pharmacokinetic profile of a sub-
ject. Perioperative rFVIIIFc infusion provided excellent haemostatic
control during surgery for most subjects. Extended-dose intervals
achieved in the parent trials were lengthened or maintained for most
subjects in ASPIRE.
Prophylaxis with FVIII should ideally be initiated before onset
of repeated joint bleeds, to preserve long-term joint function and
prevent or diminish chronic pain and joint disability.25 Median ABR
for spontaneous joint bleeds was 0.0 for all subjec ts receiving IP. For
subjects receiving IP that had ≥1 target joint at entry into A-LONG,
median overall ABR during ASPIRE was 0.7. Furthermore, mHJHS
and HJHS decreased from the beginning to the end of ASPIRE.
These improvements in joint health suggest that the clinical benefits
of rFVIIIFc prophylaxis may go beyond ABR reduction.
The results in ASPIRE are complemented by reports de-
scribing real-world use of prophylactic rFVIIIFc for people with
severe haemophilia A. Wang and Young (2018) performed a ret-
rospective review of medical records of 17 patients with severe
haemophilia A receiving prophylaxis with recombinant FVIII who
switched to rFVIIIFc. After switching, ABR and annualized joint
bleed rate decreased from 2.3 and 1.8 to 1.3 and 0.7, respectively.
rFVIIIFc dosing frequency ranged from twice weekly to once
every 5 days, and weekly factor consumption decreased in 53%
(9/17) of patient s after starting rFVIIIFc prophylaxis. No patient
developed inhibitors while on rF VIIIFc treatment (median [range]
follow-up of 230 [133-329] days) and no treatment-related AEs
were reported.26 Keepanasseril et al evaluated the real-world ex-
perience with rFVIIIFc in Canada for the first 8 months after ap-
proval by Health Canada in 2014. There was a 19% decrease in
factor consumption among 62 patients with severe haemophilia A
who switched from prophylaxis with a standard half-life product
TABLE 4 Control of acute bleed episodes in ASPIRE by parent study and treatment regimen
Parent study A-LONG Kids A-LONG
(n = 110)
(n = 27)
(n = 21) ET (n = 13)
Aged < 6 y
(n = 29)
Aged 6 to <12 y
(n = 30)
Episodes required ≤2 transfusions, % 93.7 97.1 94.3 99.2 93.5 93.4
Episodes required ≤1 transfusions, % 82.5 91.5 85.7 97.9 7 9.9 75.8
Median (IQR) total dose per bleed
(26. 7-5 4.0 )
(4 2 .4-75 . 5 )
Abbreviations: ET, episodic treatment; IP, individualized prophylaxis; IQR , interquartile range; MP, modified prophylaxis; WP, weekly prophylaxis.
NOLA N et AL.
to rFVIIIFc. Reasons for switching included to improve quality of
life, improve compliance and reduce bleed frequency. No patient
receiving rFVIIIFc developed inhibitors during the follow-up pe-
riod.27 Peyvandi et al conducted a real-world survey to determine
the ef ficacy of EHL products in Europe. After switching to an EHL
pro duct , 66% (15/23) of respondi ng haemophilia treat me nt cent re s
reported ≥30% reduction in the number of transfusions and 43%
(9/21) reported a ≥20% reduction of bleeds.9 As of 5 June 2019,
the estimated patient exposure to rFVIIIFc is approximately 12 900
person-years cumulatively since launch, based on commercial sales
(excludes humanitarian sourced data).28
In recent years, the haemophilia A treatment landsc ape has
changed significantly. Prophylaxis and individualized care are in-
creasingly becoming the global standard and non-factor therapies
are emerging. Still, factor-based therapies remain fundamental and
essential single-agent treatments for the comprehensive manage-
ment of adults and children with haemophilia across a wide range
of clinical situations. Extensive clinical trial and real-world evidence
of safet y and efficacy show that rFVIIIFc, as an EHL molecule, may
provide bleed protection, resolve target joints and enhance joint
protection without a burdensome dosing frequency.17 rFVIIIFc
provides effective treatment of acute bleeds, and prophylaxis with
rFVIIIFc may intensify protection during high physical activity, pro-
vide effective perioperative management and improve quality of
life.17-21 Further, standard laboratory assays can be used to reliably
monitor rFVIIIFc levels.29 This study increases our understanding
of the safety and efficacy profile of personalized prophylaxis with
rFVIIIFc for adults and children with severe haemophilia A across
5 | CONCLUSION
The results of the ASPIRE extension trial confirm findings from
the Phase 3 A-LONG and Kids A-LONG studies that long-term
rFVIIIFc prophylaxis with an extended-dose interval has a fa-
vourable safety profile, is well tolerated in previously treated
subjec t s wit h severe haemo ph il ia A and is n ot asso ci at ed wi th in -
hibitor development. Prophylaxis was efficacious across all ages
and was associated with low ABRs and improvements in joint
health, an important goal for treatment of severe haemophilia
A. The data from this long-term follow-up study demonstrate
the value of rFVIIIFc for managing acute bleeds and periopera-
tive haemostasis and for providing protection via personalized
ASPIRE was sponsored by Sanofi (Cambridge, MA, USA) and Sobi
(Stockholm, Sweden). Medical writing and editing support were pro-
vided by Rebecca Lawson, PhD, Francis Golder, BVSc, PhD, DACVAA
and Jennifer Alexander, MSc, MBA , CMPP, of JK Associates Inc, a
member of the Fishawack Health (Conshohocken, PA, USA) and was
funded by Sanofi and Sobi.
BN has been a study investigator for Sobi, Biogen/Bioverativ, a Sanofi
company/Sanofi, CSL, Bayer and Sanofi; received honoraria from Sobi
(honoraria donated to Irish Haemophilia Society); JM has received re-
search grants from and has been on the advisory board for BioMarin,
Baxalta, Catalyst Biosciences, CSL, Novartis, Novo Nordisk, Pfizer,
Roche, Sanofi, Spark, Roche and Unique; and has been on the speak-
er's bureau for ISTH, Novo Nordisk, Pfizer, Roche, Sanofi, Takeda
and the World Federation of Hemophilia; IP has received honoraria
from and acted as a consultant for Sobi, CSL Behring, Bayer, Shire,
Pfizer, Novo Nordisk and Biotest; GY has received honoraria from
and/or has acted as a consultant for Bayer, Bioverativ, CSL Behring,
Genentech/Roche, Grifols, Novo Nordisk, Spark, Takeda and Unique;
BAK has acted as a paid consultant for BioMarin Pharmaceutical Inc,
Genentech/Roche, Bioverativ/Sanofi and Spark Therapeutics; re-
ceived research funding from Bioverativ/Sanofi, Shire/Takeda, Spark
Therapeutics, Octapharma, Pfizer, Sangamo and uniQure; CB has
acted as a paid consultant for Sanofi; KN, ES, LK , HY and JF have no
competing interests; KJP has received honoraria from Sanofi, Sobi,
Biotest, Octapharma, Novo Nordisk, Roche, Takeda, BioMarin and
Catalyst Biosciences as a member of scientific advisory boards and
symposia; BW is an employee of Sobi; DR is currently employed by
Global Blood Therapeutics (GBT) with stock/options; is a past em-
ployee of Bioverativ and was provided with pay and stock at the time
but no longer has any other financial interest; JO has received grants
and personal fees from Bayer, Biotest, CSL Behring, Novo Nordisk,
Octapharma and Shire, and personal fees from Chugai, Grifols, Pf izer,
Roche and Sobi out side the submitted work. Personal fees were re-
ceived for travel support, participation in advisory boards and partici-
pating in symposia as a chair or speaker.
DATA AVAIL AB I LI T Y STATE MEN T
Qualified researchers may request access to patient level data and
related study documents including the clinical study report, study
protocol with any amendments, blank case report form, statistical
analysis plan and dataset specifications. Patient level data will be
anonymized and study documents will be redacted to protect the
priv ac y of our tr ia l pa r ti ci pants . Fu rth er details on Sanof i's dat a sh ar-
ing criteria, eligible studies and process for requesting access can be
found at: https://www.clini calst udyda tareq uest.com/.
Beatrice Nolan https://orcid.org/0000-0003-0145-4736
Johnny Mahlangu https://orcid.org/0000-0001-5781-7669
Guy Young https://orcid.org/0000-0001-6013-1254
Barbara A. Konkle https://orcid.org/0000-0002-3959-8797
Keiji Nogami https://orcid.org/0000-0002-2415-2194
K. John Pasi https://orcid.org/0000-0003-3394-2099
Johannes Oldenburg https://orcid.org/0000-0003-3038-2145
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Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Nolan B, Mahlangu J, Pabinger I, et al.
Recombinant factor VIII Fc fusion protein for the treatment of
severe haemophilia A: Final result s from the ASPIRE extension
stud y. Haemophilia. 2020;26:494–502. ht t p s: //d o i .