Phase 3 Trial of Concizumab in Hemophilia with Inhibitors

概要

new england
journal of medicine
The

established in 1812

August 31, 2023

vol. 389  no. 9

Phase 3 Trial of Concizumab in Hemophilia with Inhibitors
T. Matsushita, A. Shapiro, A. Abraham, P. Angchaisuksiri, G. Castaman, K. Cepo, R. d’Oiron, M. Frei‑Jones,
A.-S. Goh, J. Haaning, S. Hald Jacobsen, J. Mahlangu, M. Mathias, K. Nogami, J. Skovgaard Rasmussen,
O. Stasyshyn, H. Tran, K. Vilchevska, L. Villarreal Martinez, J. Windyga, C.W. You, N. Zozulya, B. Zulfikar,
and V. Jiménez‑Yuste, for the explorer7 Investigators*​​

a bs t r ac t
BACKGROUND

Concizumab is an anti–tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept
in patients with hemophilia A or B with inhibitors.
METHODS

We conducted the explorer7 trial to assess the safety and efficacy of concizumab
in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or
concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4).
After a treatment pause due to nonfatal thromboembolic events in three patients
receiving concizumab, including one from the explorer7 trial, concizumab therapy
was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed
by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab
plasma concentration as measured at week 4). The primary end-point analysis
compared treated spontaneous and traumatic bleeding episodes in group 1 and
group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed.

The authors’ full names, academic degrees, and affiliations are listed in the Appendix. Dr. Matsushita can be contacted
at tmatsu@med.nagoya-u.ac.jp or at the
Department of Transfusion Medicine,
Nagoya University Hospital, 65 Tsurumaicho, Showa-ku, Nagoya 466-0065, Japan.
*A list of the explorer7 investigators is
provided in the Supplementary Appendix, available at NEJM.org.
N Engl J Med 2023;389:783-94.
DOI: 10.1056/NEJMoa2216455
Copyright © 2023 Massachusetts Medical Society.

CME

at NEJM.org

RESULTS

Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2;
the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized
bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to
19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio,
0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate
for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma
concentrations of concizumab remained stable over time.
CONCLUSIONS

Among patients with hemophilia A or B with inhibitors, the annualized bleeding
rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by
Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.)

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n e w e ng l a n d j o u r na l

urrent guidelines for treatment
of hemophilia recommend prophylaxis
for all severe bleeding phenotypes to prevent arthropathy and improve quality of life.1 Patients with hemophilia A or B can be treated with
intravenous factor VIII or IX concentrates, respectively, including extended half-life products.
Repeated venipuncture is not always feasible,
especially in children, and a central venous access
device is often required. Treatment burden is further increased by potential complications related
to the central venous access device (e.g., infections
and thrombosis related to the device).2,3 The development of inhibitors (neutralizing antibodies
to factor-replacement products) may limit the effectiveness of factor-replacement therapies, thereby
increasing disease burden.4,5 Despite the growing
availability of non–factor-replacement therapies,
treatment for breakthrough bleeding with bypassing agents (e.g., recombinant activated factor VII or
activated prothrombin complex concentrate) may
be needed in patients with inhibitors that could
further increase the difficulty and complexity of
treatment.6 Overall, these features may negatively
affect treatment adherence and outcomes.7
To address these issues, research has focused
on non–factor-replacement therapies that can either promote coagulation independently of factor
VIII and factor IX, such as the factor VIII–mimetic
emicizumab (approved for subcutaneous prophylaxis in hemophilia A with or without inhibitors),
or inhibit anticoagulant pathways.8,9 Subcutaneous prophylaxis, as compared with intravenous
bypassing agents, may reduce treatment burden
in patients with inhibitors. Guidelines from the
World Federation on Hemophilia recommend emicizumab prophylaxis over bypassing agents for
patients with hemophilia A and persistent inhibitors in whom induction of immune tolerance had
failed or was never attempted.1 However, bypassing agents may be needed to treat breakthrough
bleeding episodes in patients with hemophilia A
with inhibitors, even if they are receiving emiciz­
umab prophylaxis.
For patients with hemophilia B with inhibitors, no effective prophylactic treatments or easily
administered subcutaneous therapies are available. Success rates with induction of immune
tolerance among patients with hemophilia B with
inhibitors remain low, and such therapy has potentially severe consequences, including nephrotic
syndrome.1 Overall, these factors result in poor

of

m e dic i n e

outcomes for patients with hemophilia B with
inhibitors.1
Concizumab is a monoclonal antibody to tissue factor pathway inhibitor (TFPI) that is under
investigation for subcutaneous prophylaxis in all
hemophilia subtypes.10 Concizumab inhibits TFPI
activity through high-affinity binding to the TFPI
Kunitz-2 domain, blocking TFPI binding to active
factor X (and thereby preventing its inhibition)
and maintaining factor Xa production by the tissue factor–factor VIIa complex. These activities
normalize thrombin generation and result in a
reduction in the number of bleeding episodes.10-12
Results from the phase 2 explorer4 trial of
concizumab established proof of concept in patients with hemophilia A or B with inhibitors.13,14
Phase 3 trials of concizumab in patients with
hemophilia are ongoing, although they were temporarily paused in March 2020 owing to nonfatal
thromboembolic events in three patients receiving concizumab. The trials resumed after thorough
investigation of all available data and subsequent
implementation of risk-mitigation measures.15,16
We report here the findings of the phase 3 explorer7 trial, which aimed to confirm the efficacy
and safety of daily subcutaneous concizumab
prophylaxis in patients with hemophilia A or B
with inhibitors.

Me thods
Trial Design

The explorer7 trial is a prospective, multicenter,
open-label, phase 3a trial that compared concizu­
mab prophylaxis with no prophylaxis. The trial
included two randomization groups (groups 1
and 2) and two nonrandomization groups (groups
3 and 4) (Fig. S1 in the Supplementary Appendix, available with the full text of this article at
NEJM.org). Patients with hemophilia A or B with
inhibitors (of any severity) were included if they
were at least 12 years of age when providing
written informed consent (which was obtained
for all trial patients), had a body weight of at
least 25 kg at screening, and had previously received a prescription of or had been treated with
bypassing agents in the 24 weeks before screening (if not being transferred from the explorer4
trial). Exclusion criteria are provided in the Supplementary Methods section in the Supplementary Appendix.
Patients receiving on-demand treatment with

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The New England Journal of Medicine
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Concizumab in Hemophilia with Inhibitors

bypassing agents (including those from the noninterventional explorer6 study [ClinicalTrials.gov
number, NCT03741881]) were randomly assigned
in a 1:2 ratio to continue to receive on-demand
treatment (i.e., no prophylaxis) for 24 weeks or
more (group 1) or to receive concizumab prophylaxis for 32 weeks or more (group 2). On completion of the main part of the trial, the patients in
group 1 could receive concizumab prophylaxis.
Patients who had previously received concizumab
in the explorer4 trial were transferred to group
3 and received concizumab prophylaxis. Patients
who had received prophylaxis with a bypassing
agent and additional patients receiving on-demand
treatment were recruited to group 4 and received
concizumab prophylaxis.
The sponsor (Novo Nordisk) was responsible
for designing the trial, preparing the initial trial
protocol and statistical analysis plan, and performing the statistical analyses. Data were collected
locally by explorer7 investigators. The authors
vouch for the accuracy and completeness of the
data and for the adherence of the trial to the
protocol, available at NEJM.org. All the authors
contributed to the interpretation of the data and
to the writing of the manuscript. Medical writing
support (funded by Novo Nordisk) was provided
by Ashfield MedComms, an Inizio company, under the supervision of the authors. ...