ArticlePDF Available

Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study

Authors:

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 demonstrated 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. 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 regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic 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, respectively. No inhibitors were observed (0 per 1000 subject‐years; 95% confidence interval, 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 rFVIIIFc treatment for severe haemophilia A.
494  
|
Haemophilia. 2020;26:494–502.wileyonlinelibrary.com/journal/hae
Received: 25 Novemb er 2019 
|
  Revised: 24 January 2020 
|
  Accepted: 12 Fe bruar y 2020
DOI : 10.1111/h ae.13953
ORIGINAL ARTICLE
Clinical haemophilia
Recombinant factor VIII Fc fusion protein for the treatment of
severe haemophilia A: Final results from the ASPIRE extension
study
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
Correspondence
Beatri ce Nolan , Children's Heal th Ireland at Cru mlin, Dublin, Ireland.
Email: drbeatricenolan@gmail.com
Present address
Joachim Fruebis , BlueRock Therapeutics, C ambridge, MA , USA
Dan Rudin , Global Blood Therapeutics, Sou th San Fra ncisco, CA, USA
Funding information
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.
  
|
 495
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.
KEYWORDS
bleed rate, extended half-life, individualized prophylaxis, perioperative haemostasis, rFVIIIFc
496 
|
   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
investigator.
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
terms.
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
  
|
 497
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 paents 12 years of age
Completed ASPIRE,
n = 54 (88.5%)
Completed ASPIRE,
n = 132 (88.0%)
Disconnued 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 violaon,cn = 3 (2.0%)
Withdrawal by subject, n = 5 (3.3%)
Other,dn = 5 (3.3%)
Disconnued early, n = 7 (11.5%)
Protocol violaon,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-LONGaKids A-LONG
Treatment regimen IP (n = 110) WP (n = 27) MP (n = 21) ET (n = 13)
Aged <6 ybAged 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)
Asiaf17 (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,
weekly prophylaxis.
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.
498 
|
   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,
respectively.
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,
respectively.
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
(1.7), respectively.
Overall (N = 211) A-LONG (n = 150)
Kids A-LONG
(n = 61)
≥1 AE, n (%) 184 (87.2) 129 (86.0) 55 (90.2)
≥1 rFVIIIFc-related AE,
n (%)
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)
Upper respiratory
tract infection
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)
Haemophilic
arthropathy
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
  
|
 499
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-
terval), respectively.
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
IP
(n = 110)
WP
(n = 27)
MP
(n = 21)
ET
(n = 13)
0
4
8
12
16
20
24
28
32
01.01.0
9.2
0.51.7
1.7
13.1
0.20.50.91.4
0.11.51.4
14.6
0.7
2.2
4.1
ABR (IQR)
Overall
Spontaneous
Traumatic
Joint
Spontaneous join
t
Subjects from A-LONG
a
19.1
Age <6 y
b,c
IP
(n = 29)
Age 6 to <12 y
d
IP
(n = 30)
0
1
2
3
4
5
00
0.6
0.7
0.4
1.0
0.60.3
1.2
1.6
ABR (IQR)
Overall
Spontaneous
Traumatic
Joint
Spontaneous join
t
Subjects from Kids A-LONG
TABLE 3 Prophylactic dosing during ASPIRE by parent study and treatment regimen
Parent study A-LONGaKids A-LONG
Treatment regimen IP WP MPb
Aged <6 y Aged 6 to <12 y
IP IP
Number of subjects, n 110 27 21 29c,d30e
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.
500 
|
   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
transfusions.
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
Treatment regimen
IP
(n = 110)
WP
(n = 27)
MP
(n = 21) ET (n = 13)
IP
Aged < 6 y
(n = 29)
IP
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
episode, IU/kg
50.4
(30.4-58.8)
33.7
(26. 7-5 4.0 )
40.3
(31.5-63.2)
26.4
(20.4-30.3)
58.4
(33.8-84.4)
52.1
(4 2 .4-75 . 5 )
Abbreviations: ET, episodic treatment; IP, individualized prophylaxis; IQR , interquartile range; MP, modified prophylaxis; WP, weekly prophylaxis.
  
|
 501
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
clinical scenarios.
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
prophylaxis regimens.
ACKNOWLEDGEMENTS
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.
DISCLOSURES
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/.
ORCID
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
REFERENCES
1. National Hemophilia Foundation. MASAC document 241: MA SAC
recommendations concerning Prophylaxis. https://www.hemop
502 
|
   NOLAN et AL.
hilia.org/Resea rcher s-Healt hcare -Provi ders/Medic al-and-Scien
t i f i c - A d v i s o r y - C o u n c i l - M A S A C / M A S A C - R e c o m m e n d a t i o n s /
M A S A C - R e c o m m e n d a t i o n - C o n c e r n i n g - P r o p h y l a x i s . A c c e s s e d
October 25, 2018.
2. Petrini P, Valentino LA , Gringeri A, Re WM, Ewenstein B.
Individualizing prophylaxis in hemophilia: a review. Exper t Rev
Hematol. 2015;8:237-246.
3. Lamber t T, Auerswald G, Benson G, et al. Joint disease, the hallmark
of haemophilia: what issues and challenges remain despite the de-
velopment of effective therapies? Thromb Res. 2014;133:967-971.
4. Oladapo AO, Epstein JD, Williams E, Ito D, Gringeri A, Valentino LA.
Health-related quality of life assessment in haemophilia patient s on
prophylaxis therapy: a systematic review of result s from prospec-
tive clinical trials. Haemophilia. 2015;21:e344-e358.
5. Franchini M, Mannucci PM. Hemophilia A in the third millennium.
Blood Rev. 2013;27:179-184.
6. Oldenburg J. Optimal treatment strategies for hemophilia: achieve-
ments and limitations of current prophylactic regimens. Blood.
2015;125:2038-20 44.
7. rensen B , Auerswald G , Benson G, et al. Rationale for individual-
izing haemophilia care. Blood Coagul Fibronolysis. 2015;26:849-857.
8. Castaman G, Linari S. Prophylactic versus on-demand treatments
for hemophilia: advantages and drawbacks. Expert Rev Hematol.
2018;11:567-576.
9. Pey vandi F, Garagiola I, Boscarino M, Ryan A, Hermans C, Makris M.
Real-life experience in switching to new extended half-life produc ts
at European haemophilia centres. Haemophilia. 2019;25(6):946-952 .
10. Hacker MR, Geraghty S, Manco-Johnson M. Barriers to com-
pliance with prophylaxis therapy in haemophilia. Haemophilia.
2001;7:392-396.
11. Mahdi AJ, Obaji SG, Collins PW. Role of enhanced half-life fac-
tor VIII and IX in the treatment of haemophilia. Br J Haematol.
2015;169 :768-776.
12. Peters RT, Toby G , Lu Q, et al. Biochemical and functional charac-
terization of a recombinant monomeric factor VIII-Fc fusion pro-
tein. J Thromb Haemost. 2013;11:132-141.
13. Bioverativ Therapeutics Inc. ELOCTATE® Prescribing Information.
https://www.eloct ate.com/_asset s/pdf/eloct ate_pi.pdf. Accessed
February 04, 2019.
14. Swedish Orphan Biovitrum AB (publ). Elocta: Summary of Product
Characteristics. https://www.ema.europa.eu/en/docum ents/produ
ct-infor matio n/eloct a-epar-produ ct-infor mation_en.pdf. Accessed
Septemb er 06, 2019.
15. Berntorp E, Negrier C, Gozzi P, Blaas PM, Let hagen S. Dosing regi-
mens, FVIII levels and estimated haemostatic prote ction with spe-
cial focus on rFVIIIFc. Haemophilia. 2016;22:389-396.
16. Chowdar y P, Fosbury E, Riddell A, Mathias M. Therapeutic and rou-
tine prophylac tic properties of rFactor VIII Fc (efraloctocog alfa,
Eloctate®) in hemophilia A . J Blood Med. 2016;7:187-198.
17. Oldenburg J, Kulkarni R , Srivas tava A, et al. Improved joint health
in subjects with severe haemophilia A treated prophylactically
with recombinant factor VIII Fc fusion protein. Haemophilia.
2018;24:77-84.
18. Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recom-
binant factor V III Fc fusion protein in severe hemophilia A. Blood.
2014;123(3):317-325.
19. Young G, Mahlangu J, Kulkarni R , et al. Recombinant factor VIII Fc
fusion protein for the prevention and treatment of bleeding in chil-
dren with severe hemophilia A. J Thromb Haemost. 201 5;13:9 67-9 7 7.
20. Mahlangu J, Ragni M, Gupta N, et al. Long-acting recombinant factor
VIII Fc fusion protein (rFVIIIFc) for perioperative haemostatic man-
agement in severe haemophilia A. Thromb Haemost. 2016 ;116:1-8.
21. Nolan B, Mahlangu J, Perry D, et al. Long-term safety and efficacy
of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subject s
with haemophilia A. Haemophilia. 2016;22:72-80.
22. Srivas tava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines
for the management of hemophilia. Haemophilia. 2013;19:e1-e47.
23. Hilliard P, Funk S, Zourikian N , et al. Hemophilia joint health score
reliability study. Haemophilia. 2006;12:518-525.
24. Feldman BM, Funk SM, Bergstrom B-M, et al. Validation of a new
pediatr ic joint scoring system from the International Hemophilia
Prophylaxis Study Group: validity of the hemophilia joint health
score. Ar thritis Care Res (Hoboken). 2011;63:223-230.
25. Fischer K, Collins PW, Ozelo MC, Srivastava A, Young G, Blanchette
VS. When and how to start prophyla xis in boys with severe hemo-
philia without inhibitors: communication from t he SSC of the ISTH .
J Thromb Haemost. 2016;14:1105-1109.
26. Wang C, Young G. Clinic al use of recombinant factor VIII Fc and
recombinant factor IX Fc in patients with haemophilia A and B.
Haemophilia. 2018; 24: 414- 419.
27. Keepanasseril A , Stoffman J, Bouskill V, et al. Switching to ex-
tended half-life products in Canada - preliminary data. Haemophilia.
2017;23:e365-e367.
28. Sanofi. Data on file.
29. Kitchen S, Jennings I, Makris M, Kitchen DP, Woods TAL, Walker
ID. Clotting and chromogenic factor VIII assay variabilit y in post-in-
fusion and spiked samples containing full-length recombinant FVIII
or recombinant factor VIII Fc fusion protein (rFVIIIFc). Int J Lab
Hematol. 2019;41:176-183.
SUPPORTING INFORMATION
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 .
org /10.1111/hae.13953
... This new EHL-rFVIII incorporates two new technologies and comprehends a single rFVIII molecule fused to dimeric Fc, a D D3 domain of VWF (FVIII-binding domain), and two XTEN hydrophilic polypeptides. The covalent link to the VWF D D3 domain prevents binding between rFVIII and endogenous VWF. BIVV001 has a half-life that is three to four times longer than that of SHL-rFVIII products [67], resulting in a clinical benefit similar to what was observed with EHL recombinant factor IX products. Until early 2022, BIVV001 remains in phase 3 clinical trial (NCT04161495 and NCT04644575) and is not yet commercially available [68]. ...
Article
Full-text available
Anti-drug antibody (ADA) development is a significant complication in the treatment of several conditions. For decades, the mainstay of hemophilia A treatment was the replacement of deficient coagulation factor VIII (FVIII) to restore hemostasis, control, and prevent bleeding events. Recently, new products have emerged for hemophilia A replacement therapy, including bioengineered FVIII molecules with enhanced pharmacokinetic profiles: the extended half-life (EHL) recombinant FVIII products. However, the main complication resulting from replacement treatment in hemophilia A is the development of anti-FVIII neutralizing alloantibodies, known as inhibitors, affecting approximately 25–30% of severe hemophilia A patients. Therefore, the immunogenicity of each FVIII product and the mechanisms that could help increase the tolerance to these products have become important research topics in hemophilia A. Furthermore, patients with inhibitors continue to require effective treatment for breakthrough bleedings and procedures, despite the availability of non-replacement therapy, such as emicizumab. Herein, we discuss the currently licensed treatments available for hemophilia A and the immunogenicity of new therapies, such as EHL-rFVIII products, compared to other products available.
... For more than 3 years, this treatment has shown to be effective in the prevention and management of bleeding in patients of all ages, reducing the frequency of bleeding and improving joint health. 14 The main objective of the study was to assess the prophylactic efficacy of EHL treatment for reducing the frequency of haemarthrosis in adult patients with severe haemophilia A. The secondary objective was to analyse the prophylactic efficacy of EHL for reducing pain intensity, improving joint state, range of motion, and muscle strength and muscle activation in these patients. ...
Article
Full-text available
Background: Prophylactic treatment is the gold standard in the treatment of patients with haemophilia. Prophylaxis with extended half-life (EHL) treatment has shown long-term safety and efficacy in patients with haemophilia. Aim: To evaluate the efficacy of prophylaxis with EHL treatment in the frequency of haemarthrosis and musculoskeletal health in adult patients with severe haemophilia A. Methods: Prospective cohort study. Forty-six patients with severe haemophilia A were recruited. The frequency of haemarthrosis (self-reports), joint condition (Haemophilia Joint Health Score), pain intensity (visual analogue scale), range of motion (goniometry), and strength (dynamometry) and muscle activation (surface electromyography) were evaluated. Three assessments were carried out: at baseline (T0), at 6 months (T1) and at 12 months following treatment (T2). Results: There were significant changes in the within-subject effect in the frequency of haemarthrosis in elbow (F(1.05;96.20) = 3.95; P < .001) and knee (F(1.73;157.99) = 9.96; P < .001). Significant within-subject effect in elbow pain intensity (F(2;182) = 63.51; P < .001) was found. The mean values of the frequency haemarthrosis in elbow (from .66±1.01 to .04±.20) and knees (from .55±.68 to .33±.53) decrease after the period study. The intensity of elbow pain and (from 3.08±1.69 to 2.67±1.73), decrease after the 12-month follow-up period. Conclusions: Prophylaxis with extended half-life treatment reduces the frequency of haemarthrosis in elbow and knee in adult patients with haemophilia. EHL treatment reduces the intensity of elbow pain in patients with haemophilic arthropathy.
... These strategies to improve pharmacokinetic (PK) parameters resulted in a significant extension of FIX concentrates half-life, usually 3 to 5 times longer than SHL-FIX products. [12][13][14][15][16] However, EHL-recombinant FVIII (rFVIII) products achieved only 1.5 to 1.8 times longer half-life than SHL-FVIII products [17][18][19][20][21][22][23][24] This minor improvement in PK parameters is probably due to the function of von Willebrand factor (VWF). In the circulation, FVIII needs to be bound to VWF for stabilization. ...
Article
Full-text available
Hemophilia A and B are hereditary bleeding disorders, characterized by factor VIII or IX deficiencies, respectively. For many decades, prophylaxis with coagulation factor concentrates (replacement therapy) was the standard‐of‐care approach in hemophilia. Since the 1950s, when prophylaxis started, factor concentrates have been improved with virus inactivation and molecule modification to extend its half‐life. The past years have brought an intense revolution in hemophilia care, with the development of nonfactor therapy and gene therapy. Emicizumab is the first and only nonreplacement agent to be licensed for prophylaxis in people with hemophilia A, and real‐world data show similar efficacy and safety from the pivotal studies. Other nonreplacement agents and gene therapy have ongoing studies with promising results. Innovative approaches, like subcutaneous factor VIII and lipid nanoparticles, are in the preclinical phase. These novel agents, such as extended half‐life concentrates and emicizumab, have been available in resource‐constrained countries through the constant efforts of the World Federation of Haemophilia Humanitarian Aid Program. Despite the wide range of new approaches and therapies, the main challenge remains the same: to guarantee treatment for all. In this article, we discuss the evolution of hemophilia care, global access to hemophilia treatment, and the current and future strategies that are now under development. Finally, we summarize relevant new data on this topic presented at the ISTH 2021 virtual congress.
Article
The availability first in the 1970s of plasma-derived and then in the 1990s of recombinant clotting factor concentrates represented a milestone in hemophilia care, enabling not only treatment of episodic bleeding events but also implementation of prophylactic regimens. The treatment of hemophilia has recently reached new landmarks. The traditional clotting factor replacement therapy for hemophilia has been substituted over the last 10 years by novel treatments such as bioengineered factor VIII and IX molecules with extended half-life and non-factor treatments including the bispecific antibody emicizumab. This narrative review is dedicated to these newer therapies, which are contributing significantly to improving the long-term management of prophylaxis in hemophilia patients. Another section is focused on the current state of gene therapy, which is a promising definitive cure for severe hemophilia A and B.
Article
Background and objective A cost-minimization model was developed to compare recombinant factor VIII Fc (rFVIIIFc) and emicizumab as prophylaxis for hemophilia A without inhibitors. Methods The model was based on 100 patients from the healthcare payer perspective in the UK, France, Italy, Spain and Germany (5-year time horizon). Costs included: drug acquisition; emicizumab wastage by bodyweight (manufacturer’s dosing recommendations); additional FVIII for breakthrough bleeds. Scenario analyses (UK only): reduced emicizumab dosing frequency; emicizumab maximum wastage. Results Total incremental 5-year savings for rFVIIIFc rather than emicizumab use range from €89,320,131 to €149,990,408 in adolescents/adults (≥12 years) and €173,417,486 to €253,240,465 in children (<12 years). Emicizumab wastage accounts for 6% of its total cost in adolescents/adults and 26% in children. Reducing the emicizumab dosing frequency reduces the incremental cost savings with rFVIIIFc, but these remain substantial (adolescents/adults, >€92 million; children >€32 million). Maximum emicizumab wastage increases by 86% and 106%, respectively, increasing the incremental cost savings with rFVIIIFc to €125,352,125 and €105,872,727, respectively. Conclusion Based on cost-minimization modelling, rFVIIIFc use for hemophilia A prophylaxis in patients without inhibitors is associated with substantial cost savings in Europe, reflecting not only higher acquisition costs of emicizumab, but also other costs including wastage related to available vial sizes.
Article
Full-text available
Background: Surgical procedures impose hemostatic risk to people with hemophilia, which may be minimized by optimal factor (F) replacement therapy. Methods: This analysis evaluates the efficacy and safety of extended half-life factor replacement recombinant FVIII and FIX Fc fusion proteins (rFVIIIFc and rFIXFc) during surgery in phase 3 pivotal (A-LONG/Kids A-LONG and B-LONG/Kids B-LONG) and extension (ASPIRE and B-YOND) studies. Dosing regimens were determined by investigators. Injection frequency, dosing, blood loss, transfusions, and hemostatic response were assessed. Results: Forty-five major (n = 31 subjects) and 90 minor (n = 70 subjects) procedures were performed in hemophilia A; 35 major (n = 22) and 62 minor (n = 37) procedures were performed in hemophilia B. Unilateral knee arthroplasty was the most common major orthopedic procedure (hemophilia A: n = 15/34; hemophilia B: n = 8/24). On the day of surgery, median total dose in adults/adolescents was 81 IU/kg for rFVIIIFc and 144 IU/kg for rFIXFc; most major procedures required ≤2 injections (including loading dose). Through days 1-14, most major procedures had ≤1 injection/day. Hemostasis was rated excellent (rFVIIIFc: n = 39/42; rFIXFc: n = 29/33) or good (n = 3/42; n = 4/33) in evaluable major surgeries, with blood loss comparable with subjects without hemophilia. Most minor procedures in adults/adolescents required one injection on the day of surgery, including median loading dose of 51 IU/kg (rFVIIIFc) and 80 IU/kg (rFIXFc). No major treatment-related safety concerns were identified. No subjects developed inhibitors or serious vascular thromboembolic events. Conclusions: rFVIIIFc and rFIXFc were efficacious and well tolerated for the management of perioperative hemostasis across a wide spectrum of major and minor surgeries in hemophilia.
Article
Introduction In Africa, where access to diagnosis and treatment of hemophilia is the lowest in the world, prophylaxis is rarely used in preference to on-demand treatment. There are limited data of prophylaxis treatment from sub-Saharan Africa. The aim of this study was to evaluate clinical outcomes and inhibitor development in people with hemophilia receiving low-dose prophylaxis (LDP) in a sub-Saharan African setting. Methods We conducted a three-year prospective study. A once or twice weekly prophylaxis regimen of 25 IU/kg of rFVIIIFc or 30 IU/kg of rFIXFc was given to Hemophilia A and B, respectively. We evaluated clinical outcomes and inhibitors occurrence, determined by screening and titration using the Nijmegen technique. Results A total of 15 patients were included in the LDP regimen. The mean age was 6.3 years (1.5 - 10). A significant reduction was noted in the annualized bleeding rate, from 7.53 to 1.33 (p = 0.0001); the annualized joint bleeding rate passed from 3.6 to 1.4 (p = 0.001) and the proportion of severe bleeding, from 86.1% to 16.7% (p = 0.0001). The Hemophilia Joint Health Score (HJHS) moved from 9.6 to 3.4 (p = 0.0001) and the Functional Independence Score in Hemophilia (FISH) improved from 25.8 to 30.9 (p = 0.0001). School absenteeism decreased from 7.33% to 2.59%. Adherence to prophylaxis was 89.5% versus 60%. Consumption was 580 IU/kg/year versus 1254.6 IU/kg/year before and after prophylaxis, respectively. Incidence of inhibitors was 23% (3 /13 HA). Conclusion The LDP in Hemophilia improves the clinical outcome without a surplus risk of inhibitor development. Using extended half-life clotting factor concentrates (CFCs) is better for prophylaxis in resource-limited countries, as they allow better compliance in treatment.
Article
Introduction: Only few studies have presented results from real-world clinical use of Extended Half-Life (EHL) products in children with haemophilia (CWH). Aim: To retrospectively examine real-life experience with EHL factor VIII products use in CWH A, comparing with clinical experience from standard half-life products (SHL). Methods: A retrospective review of medical records of CWH A who have been prescribed EHL factor concentrates was conducted. All before/after comparisons were performed with the Wilcoxon matched-pairs signed-ranks test. Results: Twenty-three children with severe haemophilia A were enrolled in the study (3-6 years old: n = 4, 7-12 years old: n = 7 and 13-18 years old: n = 12). Median length of time that patients were treated with EHL products was 78 weeks. Median dosing interval was significantly lengthened from 2.3 to 3.5 days after switching from SHL to EHL concentrates. Mean trough FVIII levels were significantly increased from 2.3% to 4.1% after treatment with EHL products. Also, CWH A had a reduction of mean annual bleeding rate (ABR) and mean annual joint bleeding rate (AJBR) from 1 and .8 to .3 and .2, respectively, following treatment with EHL concentrates (ABR: p = .02, AJBR: p = .05). However, after switching to factor EHL, actual FVIII consumption, including bleeds, was significantly increased from 94 IU/kg/week to 118 IU/kg/week in CWH A. There was no inhibitor development. Conclusion: This study demonstrates the successful transition of 23 CWH A from SHL to EHL factor concentrates.
Article
PUPs A-LONG evaluated safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, Phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at study start, 20 (19%) had family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI]: 21.8%-41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI: 8.8%-24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 non-treatment-related death due to intracranial hemorrhage (onset prior to first rFVIIIFc dose). The overall median (interquartile range) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within expected range, although high-titer inhibitor development was on the low end of the range reported in literature. rFVIIIFc was well-tolerated and effective as prophylaxis and for treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).
Article
This review compares the methodology of published clinical studies investigating the extended-half-life (EHL) factor VIII (FVIII) products, rFVIIIFc (efmoroctocog alfa, Elocta®/Eloctate®), BAY 94-9027 (damoctocog alfa pegol, Jivi®), BAX 855 (rurioctocog alfa pegol, Adynovate®) and N8-GP (turoctocog alfa pegol, Esperoct®) including the phase 2/3 studies, A-LONG (NCT01181128), PROTECT VIII (NCT01580293), PROLONG-ATE (NCT01736475) and pathfinder2 (NCT01480180), respectively, and their corresponding pediatric studies and extensions. Study results are interpreted from a treating physician’s perspective, translating into evidence-based, real-life use of the different EHL recombinant FVIII products for personalized prophylaxis. The similarities between the studies include methodology, objectives, study design and cohort size. The differences include duration, prophylactic dosing intervals, number of patient arms, use of control group and randomization, and treatment allocation. Comparing these studies broadens physicians’ understanding of each treatment’s applicability. Further evaluation of study data and future real-world studies should help physicians to confidently individualize and select treatment for each patient.
Article
Full-text available
rFVIIIFc (efraloctocog alfa, Eloctate®) is an extended half-life (EHL) factor VIII licensed for use in patients with hemophilia A for prophylaxis and treatment of bleeding and surgical episodes. Pharmacokinetic studies in adults have shown a mean 1.5-fold increase in half-life compared to full-length factor VIII. When compared to adults, the half-life is decreased by 8% in adolescents between 12 and 17 years, by 18% in children 6 to < 12 years, and by 33% in children between the ages of 2 and < 6 years. There is a considerable interindividual variation in the prolongation of the half-life particularly in children and across the age groups, the range extending from no increase to a 2.5-fold increase. In addition to age, von willebrand factor (VWF) antigen level has demonstrated a significant impact on rFVIIIFc half-life, with higher VWF levels associated with greater prolongation of half-life. The pivotal and pediatric clinical trials have demonstrated the efficacy and safety of rFVIIIFc for use in regular prophylaxis and in management of bleeds and surgery. In these studies, just under half the participants showed a zero annualized bleed rate (ABR), and the median ABR (1.6 in the pivotal study for the individualized prophylaxis arm) showed a further decrease in the extension study. On average, the patients required fewer infusions (reduced by at least a third), and the mean weekly consumption seems to be in keeping with standard recombinant factor VIII. EHL rFVIIIFc has made decreased infusion frequency a possibility. However, the interindividual variability in dose and infusion frequency highlights the need for a personalized approach based on individual patient’s half-life and/or response to treatment.
Article
Full-text available
Aim: To use Pharmacokinetic (PK) simulations to illustrate potential differences in clinical outcomes between prophylaxis with conventional recombinant factor VIII (rFVIII) and rFVIIIFc, an extended half-life rFVIII covalently fused to the Fc domain of human IgG1. Methods: Population PK estimates from 180 (rFVIIIFc) and 46 (rFVIII) severe haemophilia A patients were used to simulate FVIII activity over time at various rFVIIIFc dosing regimens compared to rFVIII 30 IU kg(-1) three times weekly in a typical adult patient. Results: rFVIII dosed 3x30 IU kg(-1) weekly gave trough levels of 2.7, 2.8 and 0.7 IU dL(-1) , and time spent below 1, 3 and 5 IU dL(-1) of 0.2/1.2/2.3 days week(-1) . rFVIIIFc 2 x 45 IU kg(-1) gave higher troughs (4.4 and 1.7 IU dL(-1) ) and shorter time spent below 1, 3 and 5 IU dL(-1) (0/0.6/1.3 days week(-1) ), with same total factor consumption. rFVIIIFc 2 x 30 IU kg(-1) gave similar troughs (3.0 and 1.2 IU kg(-1) ) and time spent below 1, 3 and 5 IU dL(-1) (0/1.0/2.1 days week(-1) ), despite total factor consumption being reduced by one-third. The same dose and interval of rFVIIIFc (3 x 30 IU kg(-1) ) gave substantially higher troughs (7.8, 8.5 and 3.3 IU dL(-1) ) and markedly shorter time spent below 1, 3 and 5 IU dL(-1) (0/0/0.4 days week(-1) ). Conclusion: The lower clearance of rFVIIIFc compared to conventional rFVIII gives rFVIIIFc the potential of improved bleed prevention and reduced injection frequency at similar factor consumption. Although additional clinical data are required to confirm the conclusions, the simulations clearly show the potential of rFVIIIFc of increased flexibility to tailor treatment to the individual patient, and to advance the standard of care in haemophilia.
Article
The concept of replacement therapy in haemophilia is changing significantly thanks to the switch from standard products to extended half‐life products. These novel drugs are showing beneficial effects overcoming current prophylaxis limitations by reducing the infusion frequency, maintaining a higher trough level to ensure a lower risk of bleeding, and making treatment significantly less distressing to patients by improving the quality of life. Real‐life data on the efficacy of novel drugs and their impact on routine management of haemophilia A and B patients are still limited. This manuscript reports the results of a European survey conducted by the European Association for Haemophilia and Allied Disorders (EAHAD) at the beginning of 2018 on the clinical management of patients using extended half‐life recombinant FVIII and FIX fusion products, since at the time of the survey none of the PEGylated products were available yet. We report data on the efficacy of these novel drugs by 33 European haemophilia centres that have already switched to extended half‐life fusion products, showing a significant reduction in the number of infusions and a satisfactory trough levels in the clinical care of haemophilia patients, with a greater impact for haemophilia B.
Article
Introduction Variability in FVIII measurement is a recognized problem. There are limited data for samples containing recombinant Factor VIII Fc fusion protein (rFVIIIFc). Many studies use samples for which factor concentrate has been spiked into FVIII deficient plasma in vitro. This approach requires validation. Aim/Methods Four samples were distributed in a UK National External Quality Assessment Scheme for Blood Coagulation (NEQAS BC) survey. One contained Advate (full‐length recombinant FVIII) (rFVIII) added to FVIII deficient plasma, one was from a severe haemophilia A patient after infusion of Advate, one was prepared by addition of rFVIIIFc (marketed as Elocta/Eloctate) to FVIII deficient plasma and the fourth was collected from a severe haemophilia A patient following rFVIIIFc (Eloctate) infusion. Fifty‐three haemophilia centres (UK and Scandinavia) performed one‐stage FVIII assays and 27 performed chromogenic FVIII assays. Results/Conclusions One‐stage assays gave significantly lower results than chromogenic assays by 7% (P < 0.01) and 13%(P < 0.001) for post‐Advate and Advate spiked samples, and by 22% (P < 0.001) and 23% (P < 0.001) for post‐rFVIIIFc and rFVIIIFc spiked samples. The interlaboratory variation was similar for all samples, with CVs of 12%‐16% (chromogenic) and 10%‐13% (one stage). The data indicate that either product can be safely monitored by one‐stage or chromogenic assay. Spiked samples behaved in a similar way to post‐infusion samples for both products and could be substituted for post‐infusion samples for use in proficiency testing exercises (ie, samples were commutable).
Article
Introduction: Early long-term prophylaxis is the standard of care to prevent joint bleeding and chronic arthropathy in patients with severe hemophilia. Areas covered: Despite the obvious prophylaxis advantages upon the clinical outcomes, there are still several drawbacks to be addressed for the optimal patients’ compliance. Frequency of treatment due to short half-life of conventional FVIII and FIX concentrates, difficult venous access, adherence to the prescribed therapy and costs may represent significant critical issues. The development of inhibitors also makes replacement therapy ineffective, preventing patients from receiving long-term prophylaxis. This paper will review these drawbacks and the tools to overcome these limitations, mainly thanks to the use of extended half-life products and the development of novel non-conventional therapeutic approaches. Expert commentary: The use of extended half-life products may help in reducing the burden of the frequent intravenous administration and in better tailoring an individualized prophylaxis. The development of novel therapeutic approaches, like the bi-specific antibody mimicking the coagulation function of FVIII or inhibition of anticoagulant proteins may facilitate prophylaxis treatment not only in patients with inhibitors, but also in severe hemophilia patients without inhibitors. Exciting opportunities are emerging for improving prophylaxis in hemophilia.
Article
Introduction: Although clinical trials have demonstrated extended half-life (EHL) VIII and IX fusion proteins to be safe and efficacious in patients with haemophilia A and B, studies on real-world clinical application have not been performed. Aim: To retrospectively examine the real-world experience of rFVIII Fc and rFIX Fc in patients. Methods: A retrospective review of existing medical records of patients with haemophilia A or haemophilia B who had been prescribed rFVIII Fc or rFIX Fc was conducted from the Children's Hospital Los Angeles Haemostasis and Thrombosis Centre database. Results: A total of 36 male subjects enroled in the study (17 patients with haemophilia A and 19 patients with haemophilia B; 0-18 years of age, N = 27; >18 years of age, N = 9). Patients had a reduction of their ABR and AJBR following initiation of EHL factors. For patients with haemophilia A, the ABR and ABJR fell from 2.3 and 1.8 to 1.3 and 0.71, respectively. For patients with haemophilia B, the ABR and ABJR fell from 2.5 and 2.1 to 0.82 and 0.37, respectively. Five of 36 patients reverted from EHL back to standard half-life (SHL) factor treatment. Overall, treatment with EHL factors reduced factor consumption by nearly half compared to treatment with SHL factors in patients with haemophilia B. Conclusion: This study demonstrates the largely successful transition of 36 patients from SHL to EHL factor products.
Article
Introduction: Joint arthropathy is the long-term consequence of joint bleeding in people with severe haemophilia. Aim: This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis. Methods: ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25-65 IU/kg every 3-5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients. Results: Forty-seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A-LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A-LONG baseline (23.4), mean improvement at ASPIRE Year 2 was -4.1 (95% confidence interval [CI], -6.5, -1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A-LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: -2.4, P = .09; prestudy episodic treatment: -7.2, P = .003). Benefits were seen in subjects with target joints (-5.6, P = .005) as well as those with severe arthropathy (-8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (-1.4, P = .008), range of motion (-1.1, P = .03) and strength (-0.8, P = .04). Conclusions: Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.
Article
The Phase 3 A-LONG and Kids A-LONG studies demonstrated prolonged half-life of rFVIIIFc compared with rFVIII, and safety and efficacy of rFVIIIFc in subjects with severe haemophilia A. Eligible subjects from A-LONG and Kids A-LONG continued rFVIIIFc treatment by enrolling in ASPIRE, an ongoing extension study. Based on combined data from the primary studies and ASPIRE interim data, the safety and efficacy of rFVIIIFc in subjects requiring surgery were evaluated. Perioperative dosing regimens were determined by investigators with guidance based on pharmacokinetic data and recommendations from a clinical dosing committee. In addition to dosing frequency, factor consumption, blood loss, transfusions, bleeding episodes, and haemostatic response were assessed. Across studies, 21 subjects underwent 23 evaluable major surgeries, including 19 orthopaedic surgeries; 41 subjects underwent 52 minor surgeries, including 30 dental procedures. No major and 10 minor surgeries were performed in paediatric subjects. Of the major (n=22) and minor (n=32) surgeries assessed for haemostatic response, all were rated as excellent or good by the investigator/surgeon. During most major surgeries (95.7 %), haemostasis was maintained with one rFVIIIFc infusion. Blood loss in major surgeries was consistent with similar surgeries in subjects without haemophilia. Across studies, rFVIIIFc was well tolerated; no subject developed an inhibitor.