N-Carbamylglutamate (Carbaglu) In The Treatment Of Hyperammonemia

Hyperammonemia associated with several rare inherited disorders frequently causes mental
retardation, developmental disabilities and death. The overall goal of this study is to
investigate the short-term efficacy and safety of the orphan drug, N-Carbamyl-L-glutamate
(Carbaglu®, abbreviated as NCG), for the treatment of hyperammonemia in rare inherited
disorders: carbamyl phosphate synthetase I (CPSI) deficiency, NAGS deficiency, ornithine
transcarbamylase (OTC) deficiency, propionic acidemia (PA) and methylmalonic acidemia (MMA).

The primary aims are:

1. To investigate whether 3-day treatment with NCG can improve or restore ureagenesis
capacity in patients with NAGS, CPSI or OTC deficiency using as surrogate markers: [13C]
label incorporation into urea and plasma levels of ammonia, urea and glutamine. In
addition, to determine whether treatment with NCG in OTC deficiency increases the
production of a nitrogen containing intermediate, orotic acid, as a mechanism for
eliminating nitrogen in lieu of urea.

2. To investigate whether ureagenesis capacity is deficient in patients with PA and MMA and
whether 3-day treatment with NCG can improve or restore ureagenesis capacity in all or
some of these patients.

3. To evaluate the safety of short-term (3-day) treatment with NCG in the above patients
using clinical and laboratory parameters.

The hypothesis is that ureagenesis capacity as evidenced by [13C] incorporation into urea is
deficient in each of these five disorders and that treatment with NCG will improve or restore
ureagenesis in patients affected by them. The study will be conducted in the General Clinical
Research Centers (GCRC) of the Children's National Medical Center, Washington, D.C. and the
Children's Hospital of Philadelphia. Patients (1 day to 70 years of age) with any of the five
disorders are eligible for the study. They will all be tested in a short-term trial using
surrogate markers (incorporation of [13C] label from Na-acetate into urea, and plasma levels
of ammonia, urea and glutamine) before and immediately following 3 days of treatment with
NCG. The patients will also be evaluated for short-term safety of NCG using clinical and
laboratory parameters. The results of this study will provide important efficacy data, which
should help to bring Carbaglu®) to the US market for the benefit of patients with any of
these orphan diseases found to be responsive to NCG in this trial.

Inclusion Criteria:

1. Between 1 day - 70 years of age

2. Viable neonates, neonates with uncertain viability are excluded Diagnosed with one of
the following five inborn errors of metabolism: NAGS, CPSI,PA, MMA, or OTC deficiency.

3. Diagnostic requirements:

- NAGS deficiency - Identification of pathogenic mutation and/or decreased (<20% of
control) NAGS enzyme activity in liver

- CPSI deficiency - decreased (<20% of control) CPSI enzyme activity in liver
deficiency of liver CPSI in the presence of normal or substantial activity of OTC
(Tuchman et al 1980) and/or molecular confirmation of deleterious mutations
(Summary et al 2003).

- High level of clinical suspicion of NAGS or CPSI deficiency - Failure to meet
diagnostic criteria for either NAGS or CPSI deficiency as listed above, but:

1. Recurrent hyperammonemic episodes (NH3 >70umol/l) with elevated plasma
glutamine (>/= 800umol/l)

2. Urinary orotate levels within normal limits ( creatinine)

3. Absence of argininosuccinic acid in blood or urine

4. Low or normal level of citrulline ( umol/l) and ornithine (
- OTC deficiency- Identification of pathogenic mutation and/or-pedigree analysis
consistent with familial hyperammonemia segregating in an x-linked semi-dominant
pattern and/or -<20% of control OTC activity in liver and/or -elevated urinary
orotate (>20%umol/mmol creatinine) after allopurinol challenge test

- PA and MMA- diagnostic urine organic acid analysis and confirmation of absence of
responsiveness to biotin and vitamin B12 respectively.

Exclusion Criteria:

- Subjects acutely ill on day of the study

- Pregnant females- documentation of a negative pregnancy test within a week prior to
testing is required for females 12 years and older, unless having a menstrual period
during that week or other circumstances which preclude pregnancy (e.g. hysterectomy,
menopause)

- Subjects with hyperammonemia caused by other urea cycle disorders, lysinuric protein
intolerance, mitochondrial disorders, congenital lactic academia, fatty acid oxidation
defects and primary liver disease

- Subjects requiring a peripherally inserted central catheter (PICC) for blood draws may
need to be moderately sedated and are excluded

- Subjects with hemoglobin < 9 g/dl