Sunday, May 7, 2017

Glycerol phenylbutyrate for urea cycle disorders

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.

To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs).
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.
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.
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.

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.
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).
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.
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.

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.

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).

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.

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.

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…

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.

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