Carglumic acid (Carbaglu) by Orphan approved for treating high ammonia levels in blood

Carglumic acid (Carbaglu) may soon get approval to treat a condition that results in too much ammonia in the blood or hyperammonemia.

The condition, N-acetylglutamate synthase or NAGS deficiency, is an extremely rare, genetic disorder that can be present in babies soon after birth.

The safety and efficacy of Carbaglu was studied in 23 patients with NAGS who received the treatment for times ranging from six months to 21 years.

In these patients, Carbaglu reduced blood ammonia levels within 24 hours and normalized ammonia levels within three days. The majority of those in the study appeared to maintain normal plasma ammonia levels with long-term Carbaglu treatment.

US FDA requested a Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) for the review of Carbaglu which is currently in the process of New Drug Approval (NDA) review in the USA.

The EMDAC held their meeting on 13th January 2010 in which the efficacy, potential side effects and overall risk/benefit profile of Carbaglu were discussed. The EMDAC was very positive and notably the vote was unanimous for its risk/benefit profile.

Carbaglu (carglumic acid) currently has marketing authorization in Europe since 2003 for the treatment of N-Acetyl Glutamate Synthase (NAGS) deficiency.

What is NAGS deficiency?

NAGS deficiency is one of the urea cycle disorders (UCD). UCD are inherited metabolic disorders resulting from a deficiency in one of the six enzymes involved in urea synthesis, which leads to hyperammonaemia. Accumulation of ammonia in the body causes irreversible brain damage, coma, and eventually death.

The first hepatic enzyme N-Acetyl Glutamate Synthase (NAGS) activates the urea cycle. In case of NAGS deficiency the activity of this enzyme could be completely (severe, early onset) or partially (late onset, less severe) affected.

NAGS deficiency is transmitted by a recessive autosomal mechanism. The gene coding for NAGS in located on the chromosome 17.

Urea cycle disorders are estimated to affect 1 in every 25,000 to 50,000 births. NAGS deficiency is the rarest among the UCD.
Clinical presentation of NAGS deficiency

The NAGS deficiency can clinically present as early onset NAGS deficiency when there is a null mutation of the NAGS gene, it usually manifests a few hours after babys delivery.

Initial symptoms of hyperammonaemia in the newborn are non-specific; failure to feed, inability to maintain normal body temperature with a low core body temperature, and drowsiness.

Symptoms will progress from sleepiness to abnormal drowsiness and coma. In the newborn that appears normal the progression of symptoms may be very rapid and may lead to cerebral oedema.

In contrast to the early onset forms of NAGS deficiency, the clinical picture and development of late onset forms vary widely. They may occur in the first months of life or in adulthood, and may involve episodes of acute decompensation or chronic gastrointestinal, neurological or psychiatric signs.

Many patients present with symptoms in early childhood triggered by other factors like infections, stress, trauma, etc. There are even documented cases of adults becoming symptomatic after a traumatic event, such as childbirth.

There are specific tests for each type of UCD. The NAGS deficiency is detected by checking a blood ammonia level and amino acid levels. The diagnosis is usually confirmed by liver biopsy and/or DNA test.

Orphan Europe was acquired by Recordati in December 2007. Orphan Europe provides orphan products to patients all over the world with the help of 130 medical, scientific and marketing specialists in over 15 countries. New subsidiaries are being created, the latest ones being set up in the Middle East region.

An orphan drug is a medicinal product developed for the treatment of a rare disease. In Europe, the official definition of a rare disease is a disease affecting less than 5 per 10, 000 inhabitants, is fatal, or severely debilitating.

Currently over 6000 rare diseases are known, which means that several million people are affected all over the world –over 25 million in Europe alone. Today, treatment exists for only 200-300 of these 6000 diseases. Rare diseases are often genetic, meaning that newborns, children, and young adults often are affected.

Standard clinical trials are not feasible for orphan drug development. Patients exhibit a wide range of heterogeneous symptoms often needing individually tailored regimens. The use of placebo controlled trials is usually not ethically possible and standardized treatments are not available for comparison. Since the very few patients are scattered all over the world, it is virtually impossible to bring them together in one trial.

Orphan Europe has a product portfolio of ten products treating different rare diseases. Most of these products have a European orphan drug designation and have a European marketing authorization. Some of our products are still under clinical development or are currently in the process of registration. These products are distributed to patients at the request of the treating physicians under a “named patient use” regulation.