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Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.
[phenylketonuria]
Phenylketonuria
is
an
inherited
disease
caused
by
impaired
activity
of
phenylalanine
hydroxylase
,
the
enzyme
that
converts
phenylalanine
to
tyrosine
,
leading
to
accumulation
of
phenylalanine
and
subsequent
neurocognitive
dysfunction
.
Phenylalanine
ammonia
lyase
is
a
prokaryotic
enzyme
that
converts
phenylalanine
to
ammonia
and
trans-cinnamic
acid
.
We
aimed
to
assess
the
safety
,
tolerability
,
pharmacokinetic
characteristics
,
and
efficacy
of
recombinant
Anabaena
variabilis
phenylalanine
ammonia
lyase
(
produced
in
Escherichia
coli
)
conjugated
with
polyethylene
glycol
(
rAvPAL-PEG
)
in
reducing
phenylalanine
concentrations
in
adult
patients
with
phenylketonuria
.
In
this
open
-label
,
phase
1
,
multicentre
trial
,
single
subcutaneous
injections
of
rAvPAL-PEG
were
given
in
escalating
doses
(
0
·
001
,
0
·
003
,
0
·
010
,
0
·
030
,
and
0
·
100
mg
/
kg
)
to
adults
with
phenylketonuria
.
Participants
aged
18
years
or
older
with
blood
phenylalanine
concentrations
of
600
μmol
/
L
or
higher
were
recruited
from
among
patients
attending
metabolic
disease
clinics
in
the
USA
.
The
primary
endpoints
were
safety
and
tolerability
of
rAvPAL-PEG
.
Secondary
endpoints
were
the
pharmacokinetic
characteristics
of
the
drug
and
its
effect
on
concentrations
of
phenylalanine
.
Participants
and
investigators
were
not
masked
to
assigned
dose
group
.
This
study
is
registered
with
ClinicalTrials
.
gov
,
number
NCT
00925054
.
25
participants
were
recruited
from
seven
centres
between
May
6
,
2008
,
and
April
15
,
2009
,
with
five
participants
assigned
to
each
escalating
dose
group
.
All
participants
were
included
in
the
safety
population
.
The
most
frequently
reported
adverse
events
were
injection-site
reactions
and
dizziness
,
which
were
self-
limited
and
without
sequelae
.
Two
participants
had
serious
adverse
reactions
to
intramuscular
medroxyprogesterone
acetate
,
a
drug
that
contains
polyethylene
glycol
as
an
excipient
.
Three
of
five
participants
given
the
highest
dose
of
rAvPAL-PEG
(
0
·
100
mg
/
kg
)
developed
a
generalised
skin
rash
.
By
the
end
of
the
study
,
all
participants
had
developed
antibodies
against
polyethylene
glycol
,
and
some
against
phenylalanine
ammonia
lyase
as
well
.
Drug
concentrations
peaked
about
89
-
106
h
after
administration
of
the
highest
dose
.
Treatment
seemed
to
be
effective
at
reducing
blood
phenylalanine
in
all
five
participants
who
received
the
highest
dose
(
mean
reduction
of
54
·
2
%
from
baseline
)
,
with
a
nadir
about
6
days
after
injection
and
an
inverse
correlation
between
drug
and
phenylalanine
concentrations
in
plasma
.
Phenylalanine
returned
to
near-baseline
concentrations
about
21
days
after
the
injection
.
Subcutaneous
administration
of
rAvPAL-PEG
in
a
single
dose
of
up
to
0
·
100
mg
/
kg
was
fairly
safe
and
well
tolerated
in
adult
patients
with
phenylketonuria
.
At
the
highest
dose
tested
,
rAvPAL-PEG
reduced
blood
phenylalanine
concentrations
.
In
view
of
the
development
of
antibodies
against
polyethylene
glycol
(
and
in
some
cases
against
phenylalanine
ammonia
lyase
)
,
future
studies
are
needed
to
assess
the
effect
of
repeat
dosing
.
BioMarin
Pharmaceutical
.
Diseases
Validation
Diseases presenting
"primary endpoints"
symptom
congenital adrenal hyperplasia
cutaneous mastocytosis
phenylketonuria
x-linked adrenoleukodystrophy
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