Orphan Europe Carbaglu® Surveillance Protocol

Among the urea cycle disorders, N-acetylglutamate synthase (NAGS) deficiency is the rarest type. In 2010, carglumic acid (Carabglu) was approved by the United States Food and Drug Administration (FDA) "as an adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme NAGS, and as maintenance therapy for chronic hyperammonemia due to NAGS deficiency." As post-marketing requirements, the US FDA requests that Orphan Europe (OE) conduct:

1604-2: A registry of patients, with NAGS deficiency being treated with carglumic acid to obtain long-term clinical safety information. Data will include patient demographics, details of treatment with carglumic acid, other therapies for hyperammonemia, dietary protein management, clinical status, neurocognitive and psychomotor status, growth and development status, and adverse events. Information from this registry is submitted to the FDA annually (in annual reports) with a final report submitted at 15 years post-approval.

1604-3: A study of the effects of carglumic acid on pregnancy and fetal outcomes. This study can be performed as a sub-study within the registry for all patients with NAGS deficiency. Information on pregnancy and fetal outcomes should be submitted annually (in annual reports) with a final report submission at 15 years post-approval.

This patient registry or surveillance protocol will be facilitated by collaboration with the existing National Institutes of Health (NIH) sponsored Urea Cycle Disorders Consortium (UCDC) Longitudinal Study of Urea Cycle Disorders (RDCRN Protocol #5101) (including NAGS deficiency) in the United States. The Longitudinal Study is sponsored by the NIH and other philanthropic sources. It is an academically governed network with the objective to conduct a longitudinal multidisciplinary investigation of the natural history, morbidity and mortality in people with UCD. It therefore aims to collect data on all patients with NAGS deficiency in the US. Measures in the Longitudinal Study are compatible with a Carbaglu post-marketing study including: developmental outcome, medical history, interval medical history, adverse events (interim events), pregnancy history, physical exam, vital signs, laboratory evaluation, dietary history, and medication records. Additional data on drug related adverse events and pregnancy outcomes will is collected for OE for FDA reporting.

Inclusion criteria

• Confirmed diagnosis of NAGS deficiency or suspicion of NAGS deficiency
• Carbaglu intake for the treatment of NAGS
• Enrolled in the Longitudinal Study of Urea Cycle Disorders (RDCRN protocol #5101)

Exclusion criteria

• Cases of hyperammonemia caused by other urea cycle disorders
• Organic acidemia, lysinuric protein intolerance
• Mitochondrial disorders
• Congenital lactic acidemia,
• Fatty acid oxidation defects
• Primary liver disease will be excluded
• Individuals with extreme low birth weight (<1,500 grams) will be also excluded.