Biomedical Engineering Reference
In-Depth Information
9.4 DEVELOPMENT AND CLINICAL
APPLICATION OF AN INTERLEUKIN 1 TRAP:
RILONACEPT
related serious adverse events. Injection site reaction, gen-
erally considered mild, was the most commonly reported
adverse event. Although the safety and efficacy of rilonacept
in gouty arthritis remain to be evaluated by the US FDA,
these results suggest that rilonacept may prove useful in
maintenance therapy to prevent gout flares brought about
upon
This body of work demonstrated the feasibility of generating
therapeutically effective Cytokine Traps composed of in-
line receptor ectodomains (or parts thereof) fused to Fc, and
opened the way for clinical applications. The IL-1 Trap
(rilonacept) was initially tested in rheumatoid arthritis.
Although it showed some clinical activity and substantially
decreased C-reactive protein (CRP), the study failed to meet
its primary endpoints, and development of rilonacept for
rheumatoid arthritis was discontinued. Subsequently, rilo-
nacept was demonstrated in clinical trials to be successful in
reducing the symptoms of cryopyrin associated periodic
syndrome (CAPS), a spectrum of rare autoinflammatory
conditions, and became the first approved therapeutic for
familial cold autoinflammatory syndrome and Muckle-
Wells syndrome [62,134]. In the CAPS clinical program,
rilonacept was generally well tolerated, and the most fre-
quent side effects were injection site reactions and upper
respiratory tract infections.
Since its FDA approval for CAPS, rilonacept has been
tested in other disease settings (Table 9.1), notably for gout.
Preclinical research [135] combined with successful appli-
cation of a mouse IL-1 Trap in a model of gouty arthritis
[136] and initial reports of clinical utility of IL-1 blockade
[137] opened the way for testing rilonacept in chronic gouty
arthritis patients. A first proof-of-concept clinical trial dem-
onstrated that inhibition of IL-1
b
by rilonacept was well
tolerated in patients with chronic active gout and also
improved symptoms and reduced flares [138,139]. A Phase
II study provided evidence that rilonacept could provide
prophylaxis against gout flares induced by the initiation of
allopurinol therapy. More recently, Phase III trials were
designed to address the safety and efficacy of rilonacept
either in patients undergoing an acute gout attack (SURGE
trial, NCT00855920), or in a prophylactic setting (PRE-
SURGE1, NCT00829829; PRE-SURGE2, NCT00958438;
RE-SURGE, NCT00856206). Although the final results of
these studies have not been published in a peer-reviewed
journal, initial analysis of the SURGE trial showed that
rilonacept was not effective in significantly improving
ongoing gout pain during an acute gout attack compared
to indomethacin, when used either alone or in conjunction
with indomethacin. In contrast, when rilonacept was used in
a prophylactic mode (PRE-SURGE1, NCT00829829), it
met its primary endpoint, reducing the number of gout flares
by more than 70%. Rilonacept also met both of its two main
secondary endpoints, of reducing the number of patients
with one gout flare during the treatment period, and of
reducing the number of patients with two or more gout
flares during the treatment period. In these studies, rilona-
cept was generally well tolerated with no reported drug-
initiation
of
urate-lowering
therapy
such
as
allopurinol.
9.5 DEVELOPMENT AND CLINICAL
APPLICATION OF A VEGF TRAP
The experience gained in engineering Traps was also uti-
lized during the development of a Trap targeting vascular
endothelial growth factor (VEGF) and placental growth
factor (PGF). Development of the VEGF Trap presented a
new technical challenge: the first versions of VEGFR1-Fc,
composed of the first three Ig domains of VEGFR1, were
fairly potent blockers of VEGF in vitro, but displayed very
poor pharmacokinetic properties in vivo, with low bio-
availability and rapid clearance. The poor pharmacokinetic
profile of early versions of the VEGF Trap were traced to a
highly basic region present in the third Ig domain of
VEGFR1; this basic region was a main contributor to the
high-isoelectric point of these traps and conferred interac-
tion with extracellular matrix. This problem was akin to that
observed with Noggin protein [140,141]. Following the
lessons from Noggin, either chemical modification to negate
the positive charges on the third Ig domain of VEGFR1 or
deletion of this region resulted in a Trap (“VEGF Trap
D
B1
”)
with an improved pharmacokinetic profile. The properties of
VEGF Trap
D
B1
were further improved by deletion of the first
Ig domain of VEGFR1, which is also highly basic, and
replacement of the third Ig domain with the corresponding
domain of VEGFR2 (which does not contain a basic region),
to generate the final version, VEGF Trap
R1R2
(Figure 9.4)
that combined a superior pharmacokinetic profile with
increased affinity for VEGFA. This new Trap was effica-
cious in blocking tumor progression in several mouse
models [142], and also appeared to be more efficacious
than a corresponding mouse monoclonal against human
VEGF [143].
The VEGF Trap is in clinical development for both
ophthalmologic (VEGF Trap-Eye [144]) and oncologic
(aflibercept [145-148]) indications. VEGF Trap has
substantially higher affinity for VEGF compared to the
antibodies bevacizumab [149] and ranibizumab
[32,65,150,151]. This may prove to be an important differ-
entiator in age-related macular degeneration (AMD), where
these drugs are administered by intravitreal route, and
decreased injection frequency is desirable. A theoretical
analysis concluded that effective blockade of VEGF would
be maintained for 80 days by VEGF Trap-EYE compared to
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