Berry SA, Lichter-Konecki U, Diaz GA, McCandless SE, Rhead
W, Smith W, Lemons C, Nagamani SC, Coakley DF, Mokhtarani M, Scharschmidt BF,
Lee B. Glycerol phenylbutyrate treatment in children with urea cycle
disorders: pooled analysis of short and long-term ammonia control and outcomes. Mol
Genet Metab. 2014 May;112(1):17-24.
Abstract
OBJECTIVE:
To evaluate glycerol phenylbutyrate (GPB) in the treatment
of pediatric patients with urea cycle disorders (UCDs).
STUDY DESIGN:
UCD patients (n=26) ages 2months through 17years were
treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label
crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and
glutamine levels during equivalent steady-state dosing of GPB and sodium
phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also
received GPB in one of three 12-month, open label extension studies, which
assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid
levels, and patient growth.
RESULTS:
Mean ammonia exposure on GPB was non-inferior to NaPBA in
each of the individual crossover studies. In the pooled analyses, it was
significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872
[516] μmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs.
35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range
during 12months of GPB dosing and, when compared with the 12months preceding
enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced
fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than
with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7]
μmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as
well as other essential amino acids, remained within the normal range during
12months of GPB dosing. Mean height and weight Z-scores were within normal
range at baseline and did not change significantly during 12months of GPB
treatment.
CONCLUSIONS:
Dosing with GPB was associated with 24-hour ammonia exposure
that was non-inferior to that during dosing with NaPBA in individual studies
and significantly lower in the pooled analysis. Long-term GPB dosing was
associated with normal levels of glutamine and essential amino acids, including
branched chain amino acids, age-appropriate growth and fewer HA crises as compared
with the 12month period preceding enrollment.
Nagamani SC, Diaz GA, Rhead W, Berry SA, Le Mons C,
Lichter-Konecki U, Bartley J, Feigenbaum A, Schulze A, Longo N, Berquist W, Gallagher
R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Vockley J,
Kronn D, Zori R, Cederbaum S, Merritt JL 2nd, Wong D, Coakley DF,
Scharschmidt BF, Dickinson K,Marino M, Lee BH, Mokhtarani M. Self-reported
treatment-associated symptoms among patients with urea cycle disorders participating in glycerol
phenylbutyrate clinical trials. Mol Genet Metab. 2015
Sep-Oct;116(1-2):29-34.
Abstract
BACKGROUND:
Health care outcomes have been increasingly assessed through
health-related quality of life (HRQoL) measures. While the introduction of
nitrogen-scavenging medications has improved survival in patients with urea cycle
disorders (UCDs), they are often associated with side effects that may affect
patient compliance and outcomes.
METHODS:
Symptoms commonly associated with nitrogen-scavenging
medications were evaluated in 100 adult and pediatric participants using a non-validated
UCD-specific questionnaire. Patients or their caregivers responded to a
pre-defined list of symptoms known to be associated with the use of these
medications. Responses were collected at baseline (while patients were
receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol
phenylbutyrate (GPB).
RESULTS:
After 3 months of GPB dosing, there were significant
reductions in the proportion of patients with treatment-associated symptoms
(69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1;
p<0.0001), and frequency of the more commonly reported individual symptoms
such as body odor, abdominal pain, nausea, burning sensation in mouth,
vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in
both pediatric and adult patients. The presence or absence of symptoms or
change in severity did not correlate with plasma ammonia levels or NaPBA dose.
CONCLUSIONS:
The reduction in symptoms following 3 months of open-label
GPB dosing was similar in pediatric and adult patients and may be related to
chemical structure and intrinsic characteristics of the product rather than its
effect on ammonia control.
_____________________________________________________________________
Horizon Pharma plc (NASDAQ:HZNP), a biopharmaceutical
company focused on improving patients' lives by identifying, developing,
acquiring and commercializing differentiated and accessible medicines that
address unmet medical needs, today announced the U.S. Food and Drug
Administration (FDA) has approved its supplemental New Drug Application (sNDA)
to expand the age range for RAVICTI® (glycerol phenylbutyrate) Oral Liquid to
people two months of age and older who have urea cycle disorders (UCDs) that
cannot be managed by dietary protein restriction and/or amino acid
supplementation alone. RAVICTI initially
was approved by the FDA in 2013 for adults and children as young as two years
of age.
"Through our ongoing collaboration with physicians and
parents of children living with UCDs, we understand the devastating effects of
hyperammonemic events early in a child's life," said Jeffrey W. Sherman,
M.D., FACP, executive vice president, research and development and chief
medical officer, Horizon Pharma plc.
"The approval by the FDA of our sNDA to expand RAVICTI to children
as young as two months is an important step in helping young children with
UCDs. We will continue to invest in
RAVICTI to address the unmet needs of those with UCDs, as well as help their
caregivers and family members more confidently tackle the challenges of the
disease."
The approval is based on three studies that assessed monthly
ammonia control and hyperammonemic crises (HACs) in pediatric patients with
UCDs two months to two years of age.
Patients were treated with RAVICTI for an average of eight months, and
received RAVICTI either at study initiation or by enrolling on stable doses of
sodium phenylbutyrate or sodium benzoate then switching to equivalent doses of
RAVICTI. Results found RAVICTI to be safe
and effective in the pediatric patients studied, with RAVICTI-treated patients
maintaining stable ammonia levels relative to their pre-study enrollment.
"This approval represents a significant advance for
very young children with UCDs, one of the most vulnerable patient populations,
as more severe cases of the disease tend to present earlier in life and can
lead to serious long-term impairments if not diagnosed and treated early,"
said Susan Berry, M.D., professor and division director for genetics and
metabolism, department of pediatrics, University of Minnesota and primary
investigator for the RAVICTI studies leading to the sNDA approval.
A UCD is a rare genetic disorder that affects approximately
1 in 35,000 live births in the United States.
It is caused by an enzyme deficiency in the urea cycle, a process that
is responsible for converting excess ammonia from the bloodstream and
ultimately removing it from the body.
Because of this, people with a UCD experience hyperammonemia, or
elevated ammonia levels in their blood, that can then reach the brain and cause
irreversible brain damage, coma or death.
UCD symptoms may first occur at any age depending on the severity of the
disorder, with more severe defects presenting earlier in life.
About RAVICTI
RAVICTI was first approved in the U.S. in February 2013 for
the chronic management of adult and pediatric patients ≥2 years of age with
UCDs that cannot be managed by dietary protein restriction and/or amino acid
supplementation alone. In April 2017,
the indication for RAVICTI was expanded to include children as young as two
months of age.
INDICATIONS AND USAGE
RAVICTI is a nitrogen-binding agent indicated for chronic
management of patients 2 months of age and older with urea cycle disorders
(UCDs) who cannot be managed by dietary protein restriction and/or amino acid
supplementation alone. RAVICTI must be
used with dietary protein restriction and, in some cases, dietary supplements
(e.g., essential amino acids, arginine, citrulline, protein-free calorie
supplements).
LIMITATIONS OF USE
RAVICTI is not indicated for the treatment of acute
hyperammonemia in patients with UCDs because rapidly acting interventions are
essential to reduce plasma ammonia levels.
The safety and efficacy of RAVICTI for the treatment of
N-acetylglutamate synthase (NAGS) deficiency has not been established.
CONTRAINDICATIONS
Patients less than 2 months of age: Children less than 2 months of age may have
immature pancreatic exocrine function, which could impair hydrolysis of
RAVICTI, leading to impaired absorption of phenylbutyrate and hyperammonemia.
Patients with known hypersensitivity to phenylbutyrate: Reactions include wheezing, dyspnea,
coughing, hypotension, flushing, nausea and rash.
WARNINGS AND PRECAUTIONS
Neurotoxicity:
Phenylacetate (PAA), the major metabolite of RAVICTI, may be toxic at
levels of 500 µg/mL or greater. Reduce
RAVICTI dosage if symptoms of neurotoxicity, including vomiting, nausea,
headache, somnolence or confusion, are present in the absence of high ammonia
or other intercurrent illnesses.
Reduced phenylbutyrate absorption in pancreatic
insufficiency or intestinal malabsorption:
Low or absent pancreatic enzymes or intestinal disease resulting in fat
malabsorption may result in reduced or absent digestion of RAVICTI and/or
absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely…
ADVERSE REACTIONS
In ≥10% of adult patients:
diarrhea, flatulence, and headache occurred during 4-week treatment
(n=44) with RAVICTI; nausea, vomiting, diarrhea, decreased appetite, dizziness,
headache and fatigue occurred during 12-month treatment (n=51) with RAVICTI.
In ≥10% of pediatric patients ages 2 to 17 years: upper abdominal pain, rash, nausea, vomiting,
diarrhea, decreased appetite and headache occurred during 12-month treatment
(n=26) with RAVICTI.
In ≥10% of pediatric patients ages 2 months to less than 2
years: neutropenia, vomiting, diarrhea,
pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash and papule
occurred during 12-month treatment (n=6) with RAVICTI.
http://ir.horizon-pharma.com/releasedetail.cfm?ReleaseID=1023660
No comments:
Post a Comment