Undiagnosed and untreated metabolic disorder can have very severe consequences on the body and on the brain. And this is especially true of diseases causing hyperammonemia because hyperammonemia can produce brain damage and other consequences, including coma and death.

And hyperammonemia is usually consider a medical emergency because it can progress very rapidly. In general, hyperammonemia can be caused by a variety of causes and this include urea cycle disorders, organic acidemia, and liver diseases.

There are some urea cycle disorder in which there is a complete blockage of a specific enzyme. In most cases, this condition present very early in life, usually shortly after birth, one to three days after birth, with severe hyperammonemia progressing to coma and death if there is no treatment. There are several others in which the impairment of the urea cycle is milder.

So first of all, when do we suspect hyperammonemia? We suspect hyperammonemia when children or adults become lethargic. They become very sleepy above and beyond what is expected from their clinical status.

Urea cycle disorder and many other metabolic disorder, many time become evident only when there are specific trigger. The most common trigger for many metabolic disorder is, are infection. Infection many time cause fever and increased need for calories. At the same time, when people have fever, they are not hungry because they feel sick and they stop eating. The combination of increased need for calorie with decreased intake of calorie produce catabolism which is the breakdown of endogenous protein to generate energy. When protein are broken down, the nitrogen backbone of the amino acid is cat- catabolized to produce ammonia and produce hyperammonemia.

Hyperammonemia, especially in infancy, can be really difficult to spot. Oftentimes clinicians suspect sepsis, which is a more relatively common condition compared to a urea cycle disorder.

When a patient’s referred to us because of a possible urea cycle disorder or because of elevated ammonia, we take special care to ask about their symptoms around illness and when they’re healthy. So during illnesses, are they able to eat? Are they vomiting more easily? Do they seem to not be able to recover as well from their illnesses?

Assessing development is probably one of the most important things that we do in our clinic visits, especially for new patients. So we have to make sure that their early developmental milestones were normal, or did they walk on time? Did they talk on time? Um, and how are they doing in school? And then even into adulthood and how are they functioning in their jobs? Are they able to keep normal jobs and have normal social relationships?

And in general, the delays in development can be secondary to repeated episode of hyperammonemia if they are not detected and treated promptly. They just reflect the damage caused by the undetected elevated ammonia level.

We have condition in which the, eh, urea cycle disorder can go undetected for many year.

But anytime that there is a triggering event, such as an infection or increased intake of protein or sometime just plain stress or the administration of steroid, patient can become symptomatic with an elevated ammonia level.

Carbaglu® (carglumic acid) tablets for oral suspension 200mg is a carbamoyl phosphate synthetase 1 (CPS 1) activator indicated in pediatric and adult patients as:

Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency.

Maintenance therapy for the treatment of chronic hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency.

Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA).

Contraindications: None.

NAGS deficiency: Most common adverse reactions (≥13%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache.

PA and MMA: Most common adverse reactions (≥5%) are neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1‑800-FDA-1088 or www.fda.gov/medwatch.

If CARBAGLU is administered during pregnancy to women with NAGS deficiency, health care providers should report CARBAGLU exposure to the pregnancy pharmacovigilance program by calling 1-888-575-8344.

If we suspect a urea cycle disorder, the first test to do is to measure a plasma ammonia level.

The ammonia level can fluctuate widely during the day and specifically they fluctuate with the intake of food. In general, ammonia level increase after, eh, full intake. Sometime we repeat the ammonia not only in a fasting state, but also a couple of hour after the child has eaten.

Plasma ammonia levels can be something that they come back really quickly, but they are oftentimes tricky to get correctly. They have to be processed in a really specific way, in order to have an accurate result. And obviously, an accurate result is really important for us to be able to treat our patient for the best outcomes.

In general, we start management even before having a definitive diagnosis. What that mean is that if the ammonia is elevated, we have to do what it takes to lower it. In patient who are severely sick and sometime already intubated, sometime we have to resort to dialysis to remove the excess ammonia. In other patient, we have to give intravenous drug to bind the nitrogen that generates ammonia in addition to providing caloric support. In children who are able to eat and to swallow, we provide chemicals capable of binding glutamine and glycine sometime that reduce the nitrogen load to the urea cycle and effectively reduce ammonia. This is in addition to a diet which is low in protein that are the natural source of the ammonia.

If the plasma ammonia is elevated, then we need to follow-up with more specific metabolic test that can address what are the specific causes of the lethargy and the hyperammonemia.

Hyperammonemia can occur with many different metabolic disorder and that it is why it is important to measure plasma amino acid, urine organic acid and urine orotic acid. In most cases we also measure plasma acylcarnitine that reflect if there is an organic acidemia or a fatty acid oxidation disorder.

And specifically we look at glutamine. Glutamine becomes elevated in all of the urea cycle disorder. And glutamine is an universal indicator of hyperammonemia.

Genetic diseases are present at birth and last a lifetime. For this reason, we like to have confirmation of a diagnosis and the best way to confirm it today is provided by genetic testing. One of the beauty of genetic testing is that we can test today for multiple genes at once that allow us to confirm or exclude a specific diagnosis. Once the diagnosis is establish, then we know exactly what we are treating. Sometime there is evidence of a genetic disease even when the genetic testing is negative but in those cases, we need to continue to pursue the possibility of a genetic condition by doing more in-depth testing.

This animated video is about acute high blood ammonia levels that can occur in propionic acidemia and methylmalonic acidemia, two very rare metabolic diseases. High levels of ammonia in the blood are not good for the body. Ammonia is toxic, especially for the brain, and therefore needs to be eliminated.

In this video, we will explain in a short and simple way, one, how ammonia is formed in the
body, two, how ammonia is eliminated from the body, three, how acute high levels of ammonia can
occur in the body due to propionic acidemia or methylmalonic acidemia, and four, how
CARBAGLU (carglumic acid) tablets for oral suspension 200mg helps to normalize acute high
blood ammonia levels in propionic acidemia and methylmalonic acidemia.

CARBAGLU is a prescription medicine used in all ages to supplement standard of care treatment for
acute hyperammonemia, or high blood ammonia levels, due to propionic acidemia or methylmalonic
acidemia.

Part one, how ammonia is formed in the body.

Ammonia is produced in the body as a result of breaking down or metabolizing proteins. Proteins
are found in many different food categories, especially meat, cheese, and eggs.

Proteins are taken principally from food and broken down into protein building blocks called
amino acids.

Through the bloodstream, these amino acids are transferred to the liver.

Amino acids are then used to create energy and to maintain a healthy body. During this process, the body produces ammonia, and as you already know, high levels of ammonia in blood are not good for the body. Ammonia is toxic, especially for the brain, and therefore is eliminated.

Part two, how ammonia is eliminated from the body.

The process by which ammonia is eliminated is the urea cycle. The urea cycle involves a number
of steps that result in converting ammonia into a substance called urea. The urea is then transferred to the kidneys and excreted in the urine.

Let’s take a closer look at the urea cycle. The urea cycle takes place inside the liver. The liver is the main ammonia detoxification center in the body.

It is like a factory where a number of production steps, one after another, are taken by different
robots. They represent enzymes. These enzymes help to transform the toxic raw material ammonia to
the end product urea.

However, the CPS 1 enzyme, our first robot, can only be activated by the co-factor or helper NAG, depicted by a key.

NAG, which is short for N-acetylglutamate, is formed out of two other substances in the liver,
with help from another enzyme, NAGS.

If CPS 1 is activated by NAG, it can start the process of transforming toxic ammonia into
urea, which is filtered through the kidneys and excreted in urine.

Part three, how acute high levels of ammonia can occur in the body due to propionic acidemia or methylmalonic acidemia.

If you recall, NAG, which is short for N-acetylglutamate, is formed from two other substances in the liver, Acetyl CoA and Glutamate. When the PCC enzyme in Propionic Acidemia or the MUT enzyme in Methylmalonic Acidemia doesn’t work properly and the necessary enzyme reactions do not
occur, certain substances build up in the body, which can affect the urea cycle. Recall that for the urea cycle to work properly, the enzyme NAGS forms the cofactor NAG, which activates CPS 1, the first enzyme in the urea cycle.

In Propionic Acidemia or Methylmalonic Acidemia, there is a buildup of Propionyl CoA and/or Methylmalonyl CoA, and these chemicals, called metabolites, can build up and block the urea cycle.
One way is the presence of an excess amount of metabolites, resulting in the inhibition of NAGS, and
therefore less NAG is produced.

Another way the urea cycle can be blocked is by the depletion of acetyl CoA, a substance necessary to form NAG. This results in less NAG being formed. As a result, CPS1 is not activated and is unable to start the urea cycle, the process that removes toxic ammonia from the blood.

In either case, this results in increased levels of ammonia in the blood that are toxic and dangerous, especially for the brain.

Part four, how CARBAGLU helps to normalize acute high blood ammonia levels due to propionic acidemia or methylmalonic acidemia.

High levels of ammonia need to be lowered as quickly as possible. In acute hyperammonemia due to propionic acidemia or methylmalonic acidemia, one way this can be done is by specifically activating the CPS 1 enzyme and restoring the urea cycle.

Remember, if NAGS is not active, NAG is not produced, so CPS 1 is not able to start the process to remove the toxic ammonia.

One way to get the CPS 1 robot functioning again is to supply it with a substitute for NAG. CARBAGLU is a compound chemically similar to NAG. In patients with propionic acidemia or methylmalonic acidemia, it has the ability to replace NAG and activate CPS 1, the first step of the urea cycle

In this way, it acts like a key starting up the urea cycle and getting it to function again. As a result,
highly toxic ammonia can be converted into urea and eliminated from the body via the
natural pathway.

CARBAGLU is a prescription medicine used in all ages to treat acute hyperammonemia, or
high blood ammonia levels, due to propionic acidemia or methylmalonic acidemia. If you
have any questions about propionic acidemia, methylmalonic acidemia, or CARBAGLU,
please talk to your doctor.

Indications and usage.
Carbaglu® (carglumic acid) tablets for oral suspension 200mg is a prescription drug used in all
ages to supplement standard of care treatment for acute high blood ammonia levels (hyperammonemia) due to propionic acidemia or methylmalonic acidemia.

Important safety information.
Contraindications: None. Most common side effects in ≥5% of patients are: lower than normal white blood cells, reduced red cells in the blood, vomiting, abnormal levels of minerals in the body, decreased appetite, low blood sugar levels, lack of energy/unresponsiveness, brain disease that alters brain structure or function, and inflammation of the pancreas/ increase in a type of protein made by the pancreas that helps the body digest fats.

To report SUSPECTED side effects, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

This animated video is about NAGS deficiency, a very rare metabolic disease, causing high ammonia levels in the body. High levels of ammonia in the blood are not good for the body. Ammonia is toxic, especially for the brain and therefore needs to be eliminated.

In this video, we will explain in a short and simple way, one, how ammonia is formed in the body, two, how ammonia is eliminated from the body, and three, what happens with blood ammonia levels and NAGS deficiency, how high levels of ammonia can occur in the body due to NAGS deficiency, and how CARBAGLU (carglumic acid) normalizes ammonia levels and NAGS deficiency.

CARBAGLU, is a prescription medicine used to treat acute and chronic hyperammonemia, high blood ammonia levels, due to NAGS deficiency.

Part one, how ammonia is formed in the body.

Ammonia is produced in the body as a result of breaking down or metabolizing proteins. Proteins are found in many different food categories, especially meat, cheese, and eggs.

Proteins are taken principally from food and broken down into protein building blocks called amino acids.

Through the bloodstream, these amino acids are transferred to the liver.

Amino acids are then used to create energy and to maintain a healthy body. During this process, the body produces ammonia, and as you already know, high levels of ammonia in blood are not good for the body. Ammonia is toxic, especially for the brain, and therefore is eliminated.

Part two, how ammonia is eliminated from the body.

The process by which ammonia is eliminated is the urea cycle. The urea cycle involves a number of steps that result in converting ammonia into a substance called urea. The urea is then transferred to the kidneys and excreted in the urine.

Let’s take a closer look at the urea cycle. The urea cycle takes place inside the liver. The liver is the main ammonia detoxification center in the body.

It is like a factory where a number of production steps, one after another, are taken by different
workers. They represent enzymes. These enzymes help to transform the toxic raw material ammonia to the end product urea.

However, the CPS1 enzyme, our first worker, can only be activated by the co-factor NAG, depicted by a key.

NAG, which is short for N-acetylglutamate, is formed out of two other substances in the liver, with help from another enzyme NAGS.

If CPS1 is activated by NAG, it can start the process of transforming toxic ammonia into urea, which is filtered through the kidneys and excreted in urine.

Part three, what happens with blood ammonia levels and NAGS deficiency.

If the worker NAGS is not active, NAG is not produced, so CPS1 is not able to start the process to remove the toxic ammonia.

This results in an increase of ammonia in the blood to toxic levels, which are dangerous, especially for the brain.

Part four, how CARBAGLU normalizes blood ammonia levels in NAGS deficiency.

High levels of ammonia need to be lowered as quickly as possible. In NAGS deficiency, this can be done by specifically activating the CPS1 enzyme and restoring the urea cycle.

Remember, if NAGS is not active, NAG is not produced, so CPS1 is not able to start the process to remove the toxic ammonia.

One way to get the CPS1 worker functioning again is to supply it with a substitute for NAG. CARBAGLU is a compound chemically similar to NAG. In patients with NAGS deficiency, it has the ability to replace NAG and activate CPS1, the first step of the urea cycle.

In this way, it acts like a key starting up the urea cycle and getting it to function again. As a result, highly toxic ammonia can be converted into urea and eliminated from the body via the natural pathway.

CARBAGLU, is a prescription medicine used to treat acute and chronic hyperammonemia, high
blood ammonia levels due to NAGS deficiency. If you have any questions about NAGS deficiency or CARBAGLU, please talk to your physician.

Indications and usage. CARBAGLU, is a prescription drug used in all ages to help treat a rare inherited disorder called NAGS deficiency, a lack or shortage of NAGS enzyme activity, which leads to high blood ammonia levels or hyperammonemia. CARBAGLU is used to supplement standard of
care treatment of acute high blood ammonia levels (hyperammonemia) due to the lack or shortage of NAGS enzyme activity.

CARBAGLU is used to maintain normal blood ammonia levels due to the lack or shortage of NAGS enzyme activity.

Important safety information. Contraindications: None. Most common side effects in ≥13% of patients are: vomiting, abdominal pain, fever, inflammation of the tonsils, reduced red cells in the blood, diarrhea, ear infection, infections, inflammation of the throat and nasal passages, hemoglobin decreased in red blood cells, and headache.

To report SUSPECTED side effects, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.