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Caplacizumab Improves Platelet Normalization Time,
Reduces Mortality in Acquired TTP
Adding caplacizumab to standard
of care for the treatment of acquired
thrombotic thrombocytopenic pur-
pura (aTTP) shortened the time to
the normalization of platelet counts
compared with standard care alone,
according to a study published
in the New England Journal of
Medicine. However, two-thirds of
patients receiving caplacizumab
experienced a bleeding-related
adverse event (AE).
The standard treatment for
aTTP includes plasma exchange
therapy to replenish ADAMTS13
and immunosuppressive treat-
ment to modulate the formation
of auto-antibodies, lead author
Marie Scully, MD, from the Uni-
versity College London Hospitals,
explained to ASH Clinical News.
“In aTTP, auto-antibodies inhibit
ADAMTS13, a protease that regu-
lates the size of von Willebrand
factor (vWF) multimers, leading
to vWF-mediated platelet adhe-
sion and platelet consumption in
microthrombosis.”
“The faster improvement
in platelet count and sustained
platelet normalization protects
patients from recurrences, until
immunosuppression reduces
anti-ADAMTS13 antibodies and
increases ADAMTS13,” study
co-author Hilde De Winter, MD,
senior medical director for Ablynx
(which supported the study), told
ASH Clinical News. “[This also]
translated into a tangible benefit
for the patients, who needed less
plasma exchange and shorter stays
in the hospital and intensive care
unit.”
In the double-blind, random-
ized, phase III HERCULES trial,
Drs. Scully, De Winter, and re-
searchers evaluated the safety and
efficacy of caplacizumab, an anti-
vWF nanobody, in patients who
had a clinical presentation of aTTP
(defined as both thrombocytope-
nia and microangiopathic hemo-
lytic anemia with schistocytes seen
on blood smear) and had received
exactly one plasma exchange
treatment. People were excluded
from the trial if they had suspected
thrombotic microangiopathies that
ASHClinicalNews.org
were not associated with TTP, such
as hemolytic uremic syndrome.
All 45 eligible patients
received standard of care (daily
plasma exchange and glucocorti-
coids) plus either caplacizumab
10 mg/day (n=72) or placebo
(n=72). Parti-cipants were treated
for 30 days, during which the
investigators monitored time
to platelet count normalization
(≥150×10 9 /L) and discontinuation
of daily plasma exchange therapy
(primary endpoint).
During the treatment period
and 28-day follow-up, treatment
with caplacizumab was associated
with a significantly shorter time to
platelet normalization, compared
with placebo: 2.69 days (95% CI
1.89-2.83] versus 2.88 days (95%
CI 2.68-3.56; p=0.01). The authors
also reported that caplacizumab-
treated patients were 1.55 times
more likely than placebo-treated
patients to have a normalization of
the platelet count at any time point
(p=0.01).
Caplacizumab significantly
outperformed standard-of-care
alone in other secondary out-
comes, including:
• composite of TTP-related
death, TTP recurrence, or a
thromboembolic event: 12%
vs. 49% (p<0.001)
• recurrence of TTP at any
time: 12% vs. 38% (p<0.001)
Disease exacerbation, defined
as recurrence of TTP within 30
days after daily plasma exchange,
occurred in 31 patients (28 in
the placebo group and 3 in the
caplacizumab group). Of these, 28
had an unresolved autoimmune
disease that may have been the
underlying culprit, the researchers
noted. Health-care resource
use also appeared lower in the
caplacizumab group: In the placebo
group, patients required an average
of 9.4 days of plasma-exchange
therapy, compared with 5.8 days
in the caplacizumab group. This
represented a 38-percent shorter
duration of treatment and a
41-percent lower volume of plasma
exchanged (p values not reported).
Duration of hospitalization and
intensive care unit stays were
reduced, as well.
The most commonly reported
AEs in either treatment group were
bleeding-related; mucocutaneous
bleeding occurred most frequently,
in 65 percent and 48 percent of
patients in the caplacizumab and
placebo groups, respectively (p value
“[Patients on
caplacizumab]
needed
less plasma
exchange
and [had]
shorter
stays in the
hospital and
intensive
care unit.”
—HILDE De WINTER, MD
not reported). Most of these events
were mild or moderate in severity
and resolved without intervention,
the authors wrote. Five patients in
the caplacizumab group and nine
patients in the placebo group experi-
enced an AE that led to discontinua-
tion of the of the trial regimen.
During the trial, death occurred
in three patients who received
placebo, while one patient who
received caplacizumab died due
to cerebral ischemia at the end of
treatment, which was considered
unrelated to treatment.
“Overall, caplacizumab showed
value when added to the standard
treatment for aTTP,” the authors
concluded, although “this added
value was associated with a higher
incidence of low-grade mucosal
bleeding than that with placebo.”
As a limitation of the study, Dr.
Winter noted variation in the
immunosuppressive therapy used
among the 92 international sites
involved in the trial. He added
that the trial protocol required
that patients undergo “one plasma
exchange prior to randomization
while, ideally, caplacizumab would
be started on confirmation of TTP.”
The authors report relationships
with Ablynx, which supported the
trial.
REFERENCE
Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab
treatment for acquired thrombotic thrombocytopenic
purpura. N Engl J Med. 2019;380:335-46.
ASH Clinical News
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