RARE Daily

FDA Approves Recordati’s Carbaglu to Treat Acute Hyperammonemia

January 27, 2021

Rare Daily Staff

The U.S. Food and Drug Administration granted approval to Recordati Rare Diseases for a new indication for Carbaglu as an adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia or methylmalonic acidemia in pediatric and adult patients.

Propionic acidemia (PA) and methylmolonic acidemia (MMA) are rare inherited metabolic disorders that result in the dysfunction of a specific step of amino acid catabolism, or breaking down of certain fatty acids, due to deficient enzyme activity.

As a result, toxic metabolites accumulate, which can cause hyperammonemia, a potentially life-threatening condition that can progress to irreversible brain damage, coma, or death if left untreated. PA results from a deficiency of the enzyme propionyl-CoA carboxylase, with symptoms presenting in the first few days of life. MMA results from different types of enzyme deficiencies or defects. The most common cause is a deficiency of the enzyme methylmalonyl-CoA mutase. In both disorders, complete lack of enzyme or very limited enzyme causes more severe symptoms.

Carbaglu is the first and only FDA approved medication for the treatment of acute hyperammonemia due to PA and MMA. It was initially approved by the FDA for N-acetylglutamate synthase (NAGS) deficiency, another rare metabolic disorder, as adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to NAGS deficiency, and maintenance therapy for the treatment of chronic hyperammonemia due to NAGS deficiency.

Carbaglu acts as a replacement for N-acetylglutamate (NAG) in NAGS deficiency, PA, and MMA patients by activating carbamoyl phosphate synthetase (CPS 1), improves or restores the function of the urea cycle, and facilitates ammonia detoxification and urea production.

“There are few approved drugs that treat hyperammonemia, and none that are indicated for the treatment of acute hyperammonemia in PA and MMA patients,” said Mendel Tuchman, medical geneticist and professor emeritus of pediatrics at The George Washington University School of Medicine and Health Science. “Carbaglu has the potential to impact these patients by reducing high plasma ammonia levels during critical situations.”

FDA approval of the new indication was supported by a randomized, double-blind, placebo-controlled, multicenter clinical trial comparing the effectiveness of Carbaglu to placebo in the treatment of hyperammonemic episodes in patients with PA or MMA. The efficacy evaluation, based on 90 hyperammonemic episodes occurring in 24 patients, showed that patients receiving Carbaglu demonstrated a quicker reduction of ammonia compared to patients receiving placebo. The primary endpoint was the time from the first dose to the earlier of blood ammonia level below 50 micromol/L or hospital discharge. Throughout the first three days of treatment, a higher proportion of Carbaglu-treated episodes reached the primary endpoint compared to placebo-treated episodes.

In the clinical trial, at least one adverse reaction was reported in 42.2 percent of the 90 hyperammonemic episodes that occurred. The most common adverse events were neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased.

“People living with these conditions face potentially serious complications from hyperammonemia that, without treatment, can lead to coma or even death,” said Andrea Recordati, CEO of Recordati.

Photo: Andrea Recordati, CEO of Recordati

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