CLINICAL NEWS
On Location Updates in Thrombosis and Hemostasis
Interim Fitusiran Phase II Open-Label Extension (OLE) Study Results*
Interim
Fitusiran
Phase and
2 Open-Label
(OLE) Study Results*
Antithrombin
Levels
Thrombin Extension
Generation
FIGURES.
Antithrombin Levels and Thrombin Generation
Thrombin Generation
Antithrombin Levels
0.9
50 mg monthly (N=13) 135
80 mg monthly (N=20) 120
0.8
50 mg monthly (N=13)
HV Median ‡
80 mg monthly (N=20)
HV Range
(64 – 210 nM) ‡
105
0.7
0.6
0.5
0.4
0.3
0.2
90
75
60
45
30
15
0
0.1
'
1
'
30
'
60
'
90
'
180
'
270
Days since first dose
'
360
0
'
1
1 ____ _ _ ___
30
Days since first dose: _
_ _____ _____ 60
_____ _ _ _ _ _ _ _ _ _ _ __ 90
_______ ___ 180
___ __ _ ______ __ 270
_______ _ _ _ _ ___ 360
____ _ _ __
N † = 13
13
13
13
10
10
6
†
19
17
16
12
9
4
N = 19
8
[+/-
1.0
'
30
'
60
'
90
'
180
'
270
Days since first dose
'
360
1 ____ _ _ ___
30
Days since first dose: _
_ _____ _____ 60
_____ _ _ _ _ _ _ _ _ _ _ __ 90
_______ ___ 180
___ __ _ ______ __ 270
_______ _ _ _ _ ___ 360
____ _ _ __
N † = 12
10
11
11
9
8
5
†
17
15
13
12
7
4
N = 17
*Data transfer 15June2017
AT, antithrombin; SEM, standard error of the mean; HV, Healthy Volunteer
†Only patients with >56 days in OLE included in analysis; patients excluded from TG analysis if they administered factor or bypassing agent within 48 hours
‡Healthy volunteers with AT lowering <25% (Pasi KJ, et al. N Engl J Med. 2017; epub ahead of print.)
Fitusiran is an investigational medicine. Its safety and efficacy have not been established by any health authorities.
*Data transfer 15June2017
AT, antithrombin; SEM, standard error of the mean; HV, Healthy Volunteer
†Only patients with >56 days in OLE included in analysis; patients excluded from TG analysis if they administered factor or bypassing agent within 48 hours
‡Healthy volunteers with AT lowering <25% (Pasi KJ, et al. N Engl J Med. 2017; epub ahead of print.)
a nearly 80 percent reduction in antithrombin levels.
Thrombin-generation levels appeared to return to the
lower end of the normal range ( FIGURES ).
Patients experienced a total of 93 bleeding events (25
in 10 patients without inhibitors and 68 in 5 patients with
inhibitors). Sixteen patients (48%) experienced no bleeding
events during the study, for an overall median annualized
bleeding rate of one (range = 0-3). The authors noted that
all bleeding events were managed with replacement factor
or bypassing agent.
A phase III trial evaluating fitusiran 80 mg once-monthly
is under way.
The study is limited by its open-label, non-randomized
design and small patient population.
The study was supported by Alnylam Pharmaceuticals, the
manufacturer of fitusiran.
The authors report no conflicts.
REFERENCE
Pasi KJ, Georgiev P, Mant T, et al. Fitusiran, an investigational RNAi therapeutic targeting
antithrombin for the treatment of hemophilia: interim results from a phase 2 extension study
in patients with hemophilia A or B with and without inhibitors. Abstract ASY 01.2. Presented at
the International Society of Thrombosis and Haemostasis 2017 Congress, June 8-13, 2017; Berlin,
Germany.
Emicizumab Significantly Decreases Bleeding Rate, Compared With
No Treatment in Patients With Hemophilia A
In the phase III HAVEN-1 study,
preventive treatment with emi-
cizumab significantly reduced
bleeding rates, compared with no
treatment in patients with hemo-
philia A with inhibitors. Lead author
Johannes Oldenburg, MD, PhD,
from the Universitätsklinikum Bonn
in Germany, presented the findings
at the 2017 Congress of the Interna-
tional Society on Thrombosis and
Haemostasis, and the New England
Journal of Medicine simultaneously
published the results.
Emicizumab is a recombinant,
humanized, bispecific monoclonal
antibody that bridges activated factor
IX and factor X to restore the function
of activated factor VIII (FVIII). “These
data may support a genuine paradigm
shift in the management of [this patient
group],” Dr. Oldenburg said.
The open-label, multicenter,
randomized HAVEN-1 trial began
on November 17, 2015, and enrolled
109 male patients (≥12 years old;
median age = 28 years; range = 12-75
years) from 43 centers in 14 countries.
Patients were included if they had
congenital hemophilia A, had a history
of a high titer of FVIII inhibitor, and
were receiving episodic or prophylactic
treatment with bypassing agents.
Patients were assigned to one of
four treatment groups:
• arm A: patients who received prior
episodic treatment with bypassing
50
ASH Clinical News
agents and received subcutaneous
emicizumab 3.0 mg/kg once-
weekly for four weeks, followed by
1.5 mg/kg thereafter (n=35)
• arm B: patients who only
received episodic tre