CLINICAL NEWS
Literature Scan
New and noteworthy research from the
medical literature landscape
Early Phase Trial Shows PB2452 Immediately Reverses
Ticagrelor’s Antiplatelet Activity
The monoclonal antibody fragment
PB2452 effectively and immediately re-
versed the antiplatelet effects of ticagrelor
in healthy volunteers, according to results
from a phase I trial published in the New
England Journal of Medicine.
Ticagrelor is an oral P2Y 12 inhibitor
that is used with aspirin to reduce the risk
of ischemic events among patients with
acute coronary syndromes or previous
myocardial infarction, but it is associated
with increased risks of spontaneous major
bleeding during urgent invasive proce-
dures, lead author Deepak L. Bhatt, MD,
from the Brigham and Women’s Hospital
Heart & Vascular Center in Boston, told
ASH Clinical News. “[PB2452] would be
extremely useful in patients [on ticagre-
lor] who have an intracranial hemorrhage
or need emergency cardiac surgery. Right
now, there is no specific antidote available
in these challenging scenarios.”
In this single-center, randomized,
double-blind, placebo-controlled study,
researchers recruited healthy volunteers
(age range = 18-50 years) who were
pretreated with ticagrelor. People with a
contraindication to ticagrelor, a medical
history suggestive of an increased bleed-
ing risk, or an estimated glomerular
filtration rate of <60 mL/min per 1.73 m 2
of body surface area were excluded. No
effort was made to balance the groups on
the basis of age, race or ethnic group, or
sex, the authors reported.
Sixty-four participants were random-
ized 3:1 to receive either PB2452 (n=48)
or placebo (n=16).
A total of 10 sequential dose cohorts
were included in the analysis. In cohorts 1,
2, and 3, participants received a 30-minute
infusion of PB2452 0.1 g, 0.3 g, and 1.0 g,
respectively, or placebo in the absence of
ticagrelor pretreatment to assess the initial
safety of PB2452.
Volunteers in cohorts 4 through 10
were pretreated with loading doses of oral
ticagrelor starting 48 hours before the
investigational drug. In cohorts 4, 5, and
6, people received a 30-minute infusion of
PB2452 at 1 g, 3 g, and 9 g, respectively, or
placebo; in cohorts 7 through 10, volun-
teers received a fixed dose of PB2452 18 g
or placebo.
Thirty percent (n=19) of volunteers
experienced an adverse event (AE): In the
PB2452 group, 17 patients (35%) reported
27 AEs; in the placebo group, 2 patients
(12%) reported three AEs. There were no
ASHClinicalNews.org
dose-limiting toxicities or infusion-related
reactions reported, and no patients died
or experienced an AE that led to treat-
ment discontinuation.
“Changes in mean clinical laboratory
test results, vital signs, and electrocardio-
graphic results were similar across cohorts
among volunteers who received different
doses or regimens of PB2452 and were
similar among those who received PB2452
and those who received placebo,” the
authors reported.
After establishing the safety of PB2452,
the investigators assessed the reversal of
ticagrelor’s antiplatelet effects in cohorts 4
through 10. Platelet function was evaluated
using light transmission aggregometry, a
point-of-care P2Y 12 platelet-reactivity test,
and a vasodilator-stimulated phosphopro-
tein assay. Measurements were taken prior
to and following the 48-hour ticagrelor
pretreatment period and following the ad-
ministration of either PB2452 or placebo.
Forty-eight hours after ticagrelor
pretreatment, platelet aggregation was
suppressed by 80% to 85% in patients
who received placebo and remained sup-
pressed for an additional 24 hours after
ticagrelor was stopped.
In the PB2452 cohorts, however,
volunteers experienced a greater increase
in platelet aggregation than those in the
placebo group. For example, in cohorts 5
and 6, people who received a 30-minute
infusion of PB2452 at doses of 3 g and
9 g had platelet aggregation at approxi-
mately 80% (p<0.02). Ticagrelor reversal
reached maximal levels at 30 minutes,
immediately after completion of the
PB2452 infusion. The duration of rever-
sal was dose-dependent and lasted one to
two hours.
To attain more rapid and sustained ti-
cagrelor reversal in the remaining cohorts,
the investigators increased the total dose
of PB2452 to 18 g delivered with an initial
bolus and longer infusions of 8, 12, and 16
hours. They found that when PB2452 was
administered as a 6-g bolus followed by a
12- or 16-hour infusion, reversal occurred
within five minutes after initiation of infu-
sion and was sustained for 16 to 24 hours
(p<0.04).
The authors also found that platelet
function (measured on all three assays)
was restored to baseline levels within 24
hours after PB2452 administration.
“We were glad to see that the onset
of reversal of ticagrelor’s effect occurred
within five minutes, which makes the
drug ideal in cases of life-threatening
bleeding where speed of reversal may be
important,” Dr. Bhatt commented, when
asked about the findings’ implications.
“We hope to study PB2452 next in pa-
tients with actual bleeding complications
or in need of urgent or emergent surgery,
as there is no reason to think the drug
would behave differently [in them] than
in the healthy volunteers we have studied
to date.”
The inclusion of only healthy volunteers
and the lack of patients with atherosclerosis,
as well as the small sample size, represent
potential limitations of the study.
The U.S. Food and Drug Administra-
tion granted PB2452 breakthrough-therapy
designation in April 2019. If it is approved,
Dr. Bhatt believes the reversal agent could
be life-saving for patients who have severe
bleeding complications after receiving
ticagrelor. “If PB2452 were available, it
[could] accelerate adoption of ticagrelor as
the preferred oral ADP receptor antagonist,
as its effects could be reversed, while no
specific reversal agent exists for clopido-
grel, prasugrel, or even aspirin for that
matter,” he added.
The authors report relationships with
PhaseBio Pharmaceuticals, which sup-
ported the study.
REFERENCE
Bhatt DL, Pollack CV, Weitz JI, et al. Antibody-based ticagrelor reversal
agent in healthy volunteers. N Engl J Med. 2019 March 17. [Epub ahead
of print]
No Benefit in Adding
Rituximab to MBVP in
CNS Lymphoma
Results from a phase III trial suggest there
is no survival benefit of adding the anti-
CD20 monoclonal antibody rituximab to
a standard methotrexate-based chemo-
therapy regimen for patients with primary
central nervous system (CNS) lymphoma.
The findings were published in Lancet
Oncology.
In this open-label, multicenter,
randomized trial, an international team
of researchers from 23 hospitals in the
Netherlands, Australia, and New Zealand
recruited non-immunocompromised
adult patients with newly diagnosed CNS
lymphoma. Based on earlier phase II and
single-arm studies that suggested that
rituximab improved response rates in
patients with primary CNS lymphomas –
the majority of which are CD20-positive
– they hypothesized that rituximab plus
a high-dose methotrexate combination
would improve survival rates, compared
with chemotherapy alone.
A total of 199 patients were stratified
according to treatment center, age, and
Eastern Cooperative Oncology Group–
WHO performance status. Participants
were then randomized to receive either:
• MBVP: two 28-day treatment cycles of
methotrexate 3 g/m 2 on days 1 and 15,
teniposide 100 mg/m 2 on days 2 and 3,
carmustine 100 mg/m 2 on day 4, and
prednisolone 60 mg/m 2 on days 1-5
(n=100)
• R-MBVP: MBVP plus rituximab 375
mg/m 2 on days 0, 7, 14, and 21 in cycle
1 and days 0 and 14 in cycle 2 (n=99)
At the end of induction, patients who
responded to therapy received high-dose
cytarabine; responders age 60 or younger
also received low-dose whole-brain
radiotherapy. Median age for all patients
was 61 years (interquartile range [IQR] =
55-67 years).
The study’s primary endpoint was
ASH Clinical News
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