Written in Blood
Ravulizumab: A New Complement Inhibitor for Patients
With Paroxysmal Nocturnal Hemoglobinuria
Ravulizumab was noninferior
to eculizumab in patients with
paroxysmal nocturnal hemoglo-
binuria (PNH) who had never re-
ceived treatment with complement
inhibitors, according to findings
from the multicenter, randomized,
phase III ALXN1210-PNH-301
study. The study’s findings, which
were published in Blood, also
suggested that treatment with the
newer, more potent complement
inhibitor was associated with bet-
ter quality of life than treatment
with eculizumab.
“From a patient and health-
care perspective, a fourfold longer
dosing interval of ravulizumab vs.
eculizumab may reduce treatment
burden and health-care resource
[use],” the authors, led by Jong
Wook Lee, MD, from Seoul St.
Mary’s Hospital and the Catho-
lic University of Korea, wrote.
“[Ravulizumab also] may expand
access to patients who are unable
to comply with the [biweekly] dos-
ing of eculizumab.”
Results from the study sup-
ported the U.S. Food and Drug
Administration’s approval of
ravulizumab for the treatment
of adult patients with PNH in
December 2018.
“[Ravulizumab
showed]
robust results
… despite the
challenges of
using a highly
efficacious
comparator.”
—JONG WOOK LEE, MD
The trial included 246 adult
patients with PNH from 123 cen-
ters and 25 countries. Patients were
eligible for inclusion if they had a
documented diagnosis of PNH,
confirmed by high-sensitivity flow
cytometry of red and white blood
cells with granulocyte or monocyte
clone size of at least 5 percent and a
lactate dehydrogenase (LDH) level
12
ASH Clinical News
≥1.5 times the upper limit of nor-
mal (ULN). Those with current or
previous exposure to a complement
inhibitor, a history of bone marrow
transplantation, platelet count
<30,000/μL, or absolute neutrophil
count <500 /μL at screening were
excluded.
Prior to randomization, patients
underwent a four-week screening
period and were stratified based
on their transfusion history and
LDH level at screening. Participants
were then randomized 1:1 to either
ravulizumab (n=125) or eculizumab
(n=119).
Ravulizumab was adminis-
tered at a loading dose of 2,400
mg, 2,700 mg, or 3,000 mg
(depending on weight) on day 1,
followed by maintenance doses of
3,000 mg, 3,300 mg, or 3,600 mg
on day 15 and every eight weeks
thereafter. Patients assigned to
eculizumab received induction
doses of 600 mg on days 1, 8, 15,
and 22, followed by maintenance
dosing of 900 mg on day 29 and
every two weeks thereafter.
All patients completed a 26-
week treatment cycle with their
assigned therapies.
The study evaluated two co-
primary endpoints: transfusion
avoidance (defined as the propor-
tion of patients who remained
transfusion-free and did not
need a transfusion through day
183 of follow-up) and hemolysis
(measured by LDH normalization
to a ULN of 246 U/L from day 29
through day 183).
By 26-week follow-up,
ravulizumab was noninferior to
eculizumab for both co-primary
endpoints, although the authors
added that “point estimates for both
endpoints favored ravulizumab.”
Ninety-two of 125 patients
(73.6%) receiving ravulizumab
and 80 of 121 patients (66.1%)
receiving eculizumab avoided
transfusions, for a difference of
6.8 percent (95% CI –4.66% to
18.14%; p for inferiority <0.0001).
In addition, 53.6 percent of
ravulizumab-treated patients
and 49.4 percent of eculizumab-
treated patients achieved LDH
normalization (odds ratio = 1.19;
95% CI 0.80-1.77; p for inferiority
<0.0001).
Noninferiority was also ob-
served in all secondary endpoints,
including percentage change in
LDH levels (between-group dif-
ference = 0.83; 95% CI –5.21 to
3.56; p for inferiority <0.0001) and
quality-of-life scores (measured
via FACIT-Fatigue scale; between-
group difference = 0.67; 95% CI
–1.21 to 2.55; p for inferiority
<0.0001).
The researchers also noted that
patients who received ravulizumab
reached LDH normalization an
average of five days earlier than
those who received eculizumab
(24 days vs. 29 days, respectively;
p value not reported); a greater
proportion of patients assigned to
ravulizumab achieved normaliza-
tion of LDH throughout the study.
The less-frequent, every-eight-
week dosing with ravulizumab
appeared to be associated with
better quality of life, compared
with eculizumab: A higher pro-
portion of ravulizumab-treated
patients experienced a ≥10-point
improvement on quality-of-life
questionnaires and had greater
improvements in physical func-
tioning scores (between-group
difference = 4.8 points and 3.7
points, respectively; p values not
reported).
No treatment discontinuations
were observed for ravulizumab,
while two patients discontinued
treatment with eculizumab. The
incidence of adverse events (AEs)
was similar between the treat-
ment arms, with headache being
the most frequently reported AE
(36.0% in ravulizumab and 33.1%
in eculizumab). Eleven patients
(8.8%) in the ravulizumab group
and nine (7.4%) in the eculizumab
group experienced a serious AE,
which included pyrexia, neutro-
penia, pneumonia, and infection.
One patient in the eculizumab
arm died of lung cancer (unrelated
to treatment) during the extension
phase of the study, the authors
reported.
The study findings are limited
by the open-label design, which
may have introduced bias, but the
investigators noted that this was
“the largest controlled study of
patients with PNH who were naïve
to complement inhibitor therapy”
and ravulizumab showed “robust
results … across a broad selection
of clinically relevant endpoints,
despite the challenges of using a
highly efficacious comparator.”
The authors report financial
relationships with Alexion, the
sponsor of the trial. ●
REFERENCE
Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al.
Ravulizumab (ALXN1210) vs eculizumab in adult patients
with PNH naive to complement inhibitors: the 301 study.
Blood. 2018 December 3. [Epub ahead of print]
January 2019 Annual Meeting Edition