haemophilia A). rFVIIIFc has a lower clearance,
compared with conventional rFVIII therapies,
of approximately 33%, as well as 1.5-fold longer
half-life and a greater mean elimination half-life
(19.0 versus 12.4 hours) in adults and adolescents
with haemophilia A. 3 There is also potential to
individualise dosing with rFVIIIFc according to
according to clinical and patient objectives, either
by reducing the number of injections per week
and/or weekly consumption while at least
maintaining the desired trough level, based on
modelling of pharmacokinetic profiles of patients
receiving FVIII replacement in the Phase I/IIa and
Phase III studies. 2,4,5 Recombinant factor IX Fc
fusion protein (rFIXFc; Alprolix ® , approved in
2016 for the treatment of haemophilia B) also
demonstrates a reduced clearance and prolonged
half life when compared with conventional rFIX. 6
Clinical experience with recombinant
Factors VIIIFc and FIXFc
rFVIIIFc and rFIXFc were evaluated in the pivotal
Phase III A-LONG (NCT01181128) and B-LONG
(NCT01027364) studies 3,6 and paediatric studies 7,8
(NCT01458106 and NCT01440946). Extension
studies (NCT0145473 and NCT01425723) have
also been conducted 9,10 in haemophilia A and B.
Overall, rFVIIIFc and rFIXFc count with >3.5 and
~4.0 years of real-world evidence, respectively
(Figure 2). 11–14
Data from the Phase III A-LONG trial showed
a median ABR for rFVIIIFc of 1.6 for patients on
individualised prophylactic treatment and 3.6 for
those receiving a weekly prophylactic regimen vs.
33.6 for patients receiving on-demand treatment.
The median rates for annualised spontaneous
bleeding and joint bleeding were zero, and 45.3%
of patients experienced no bleeding episodes.
Moreover, the majority of the bleeding episodes
was controlled with 1–2 injections of clotting
factor. 3 A post hoc analysis of A-LONG data
showed reduced ABRs with individualised rFVIIIFc
prophylaxis in the last three months of the study,
compared to before the study, with a median
dosing interval of 3.5 days and 98.8% of the patients
decreasing injection frequency. 3,15
A post-hoc analysis of data showed prophylaxis
with rFVIIIFc also resulted in continuous
improvements in the Modified Haemophilia Joint
Health scores (mHJHs) during the extension study
(ASPIRE), which was approximately 4 years in
adults and adolescents, and 3 years in children.
The components of the mHJHs showing the
greatest improvements were swelling, range of
motion, and strength, with a mean change in
total score from the A-LONG baseline of –4.1 after
2 years. 16,17 In addition, health-related QoL scores
in the sports and leisure, physical health, and
feeling subdomains in the Haem-A-QoL
questionnaire also improved over time. 18
Compared with conventional rFIX therapies,
rFIXFc presented a 4.8 longer half-life, with
reduced ABRs in adults and adolescents in the
Phase III B-LONG study (reduction by 83% and 87%
for weekly and interval-adjusted prophylaxis
compared with episodic treatment); the median
prophylactic dosing interval in this study was
14 days, achieved by 53.8% of the patients in the
last three months of treatment. 6,19 Subsequent
analysis showed that more than three-quarters
of patients receiving prophylaxis continued or
increased their physical activity, and physical
health and sports and leisure scores also
improved in the B-LONG study. 20,21
Additionally, rFIXFc shows efficacy when used
for perioperative management, with haemostasis
rated as ‘excellent’ by investigators in the majority
of major and minor surgeries from the pre-
operative dose until the end of the procedure with
a single infusion, and no serious adverse events
deemed to be related to the blood coagulation
factor or the development of neutralising inhibitor
antibodies. 10,22,23 rFVIIIFc also showed efficacy in
the perioperative management of major and
minor surgeries. 3,7,9,24
Finally, interim data from the ASPIRE and
B-YOND extension studies confirmed the long-
term safety of both products, with no inhibitor
development during the parent studies, 9,10 and
real-world surveillance data confirms the
unchanged benefit–risk profiles. 11–14
rFVIIIFc and rFIXFc are currently being tested
in previously untreated patients in the PUPs
A-LONG (NCT02234323) and PUPs B-LONG
(NCT02234310) studies. rFVIIIFC is not approved
for immune tolerance induction (ITI) in
haemophilia patients with inhibitors; however,
two prospective studies are ongoing to assess
rFVIIIFc for ITI in patients with severe
haemophilia A who are undergoing the first
treatment for ITI (NCT03093480) or who have
failed prior ITI therapy (NCT03103542).
figure 2
Clinical experience with rFVIIIFc in haemophilia A and rFIXFc in haemophilia B
Previously treated
patients
Phase I/IIa study Complete
Phase III pivotal study Complete
Phase III paediatric study Complete
Phase extension study Complete – interim
results available, clinical
observation period of
>4 years
Real-world experience
>3.5 and ~4 years of real-world use with Elocta and Alprolix respectively with unchanged risk-benefit profile
(as of February 2018)
98
HHE 2018 | hospitalhealthcare.com