Treating with CARBAGLU

CARBAGLU® (carglumic acid) tablets for oral suspension 200mg is a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1) in liver mitochondria.

  • CPS 1 is the first enzyme of the urea cycle, the pathway which converts ammonia into urea.
  • NAG is the product of N-acetylglutamate synthase (NAGS), a mitochondrial enzyme.
  • NAG is the cofactor of CPS 1, and in the absence of NAG, CPS 1 is not activated.
  • Carglumic acid acts as a replacement for NAG in PA, MMA, and NAGS deficiency patients by activating CPS 1.1,2
  • CARBAGLU thus acts as a key to start the urea cycle, enabling it to function as it should to maintain normal blood ammonia levels.2,3

Indications and Usage

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).

Important Safety Information

  • 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, health care providers should report CARBAGLU exposure to the pregnancy pharmacovigilance program by calling 1-888-575-8344.

You and your patients can learn more about the urea cycle, NAGS deficiency, and how CARBAGLU activates the CPS 1 enzyme, the first step of the urea cycle.

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CARBAGLU clinical data: Results of a prospective study of PA and MMA patients with acute hyperammonemia

The efficacy of CARBAGLU in the treatment of acute hyperammonemia in patients with PA or MMA was evaluated in a randomized, double-blind, placebo-controlled, multicenter clinical trial of 24 patients with PA (n=15) or MMA (n=9). Ninety hyperammonemic episodes (42 treated with CARBAGLU, 48 treated with placebo) were included. Eligible hyperammonemic episodes, defined as an admission to the hospital with a plasma ammonia level ≥ 70 micromol/L, were randomized 1:1 to receive CARBAGLU or placebo, in addition to standard of care, for 7 days or until hospital discharge, whichever occurred earlier. Patient dosages were based on body weight (patients < 15 kg) or body surface area (patients > 15 kg) and were divided into 2 equal doses administered 12 hours apart. The primary endpoint was time from the first dose of drug to the earlier of plasma ammonia level < 50 micromol/L (normal range) or hospital discharge.1

Objectives

  • The overall study objective was to determine whether treatment with CARBAGLU was efficacious and safe in accelerating the resolution of hyperammonemia in participants with severe neonatal-onset PA or MMA.3

Efficacy

Patients Receiving CARBAGLU Demonstrated a Quicker Reduction of Plasma Ammonia Level Compared to Patients Receiving Placebo

  • The median time to reach the primary endpoint was 1.5 days in the CARBAGLU group compared to 2.0 days in the placebo group, driven exclusively by an effect on plasma ammonia normalization. 1
  • A higher proportion of CARBAGLU-treated episodes reached the primary endpoint compared to placebo-treated episodes through treatment day 3.1

Safety

Adverse Reactions Reported in ≥ 1 Episode of Hyperammonemia in the Prospective Study of PA and MMA Patients

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.1
  • At least 1 adverse reaction was reported during the course of hyperammonemic episodes in 42.2% of the 90 hyperammonemic episodes included in the study. The most common adverse reactions (≥5%) during hyperammonemic episodes were:1
    • Neutropenia
    • Anemia
    • Vomiting
    • Electrolyte imbalance
    • Decreased appetite
    • Hypoglycemia
    • Lethargy/Stupor
    • Encephalopathy
    • Pancreatitis/Lipase increased

CARBAGLU clinical data: Results of a retrospective study of NAGS deficiency patients

The efficacy of CARBAGLU in the treatment of hyperammonemia due to NAGS deficiency was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who received CARBAGLU treatment for a median of 7.9 years (range 0.6 to 20.8 years). Treatment with CARBAGLU was divided in two regimens. For acute treatment, patients received a total daily dose of 100 to 250 mg/kg per day primarily administered in 2 to 4 divided doses for the first few days of treatment. For maintenance treatment, the dosage was reduced over time based upon biochemical and clinical responses.1

Objectives

Primary

The primary objective was to review the clinical and biological response of NAGS deficiency patients to carglumic acid within the first 7 days of treatment (short-term) and at the last report (long-term).

  • For the short-term analysis, ammonemia was the primary biomarker supported by glutaminemia and citrullinemia results.
  • For the long-term analysis, all three biomarkers (ammonemia, glutaminemia and citrullinemia) were considered equally.2

Secondary

A secondary objective was:2

  • Evaluation of patient clinical development, that is, neurological and psychomotor status, and anthropometric development (growth) parameters.

Efficacy

Plasma ammonia levels at baseline and after treatment with CARBAGLU

  • All 13 patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 micromol/L. By day 3, normal plasma ammonia levels were attained in patients for whom data were available. 1
  • Long-term efficacy was measured using the last reported plasma ammonia level for each of the 13 patients analyzed (median length of treatment was 6 years; range 1 to 16 years). The mean and median ammonia levels were 23 micromol/L and 24 micromol/L, respectively, after a mean treatment duration of 8 years. 1
  • The mean plasma ammonia level at baseline and the decline that is observed after treatment with CARBAGLU in 13 evaluable patients with NAGS deficiency is illustrated below.

Mean Plasma Ammonia levels in 13 evaluable NAGS deficiency patients at baseline and after treatment with CARBAGLU1

Safety

Adverse Reactions Reported in ≥ 2 Patients with NAGS deficiency in the Retrospective Case Series

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 1


This table summarizes adverse reactions occurring in 2 or more patients treated with CARBAGLU in the retrospective case series (≥ 9%). The most common adverse reactions (≥ 13%) in this study, regardless of causality, were:1

  • Vomiting
  • Abdominal Pain
  • Pyrexia
  • Tonsillitis
  • Anemia
  • Diarrhea
  • Ear infection
  • Infections
  • Nasopharyngitis
  • Hemoglobin decreased
  • Headache

REFERENCES

  1. CARBAGLU [Package Insert]. Lebanon, NJ: Recordati Rare Diseases; 2021
  2. Orphan Europe, data on file, 2009.
  3. Recordati Rare Diseases, data on file.
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