Aqneursa Drug Information

AQNEURSA™ is indicated for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adults and pediatric patients weighing ≥15 kg. AQNEURSA is indicated for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adults and pediatric patients weighing ≥15 kg.

Clinical Trials Experience

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. The safety of AQNEURSA was evaluated in Trial 1, which included a total of 60 patients with Niemann-Pick disease Type C (NPC), in a placebo-controlled, randomized, crossover trial . The mean (SD) treatment duration of AQNEURSA was 86.2 days (69 min, 97 max); the mean (SD) treatment duration on placebo was 87.3 days (78 min, 113 max). Table 2 summarizes adverse reactions that occurred in patients who were treated with AQNEURSA in Treatment Period I of Trial 1. Table 2 Adverse Reactions that Occurred in Adult and Pediatric Patients with NPC at an Incidence of ≥5% in Treatment Period I of Trial 1 Adverse Reaction AQNEURSA N=30 n (%) Placebo N=30 n (%) Upper respiratory tract infection 5 1 Abdominal pain 2 0 Dysphagia 2 0 Vomiting 2 0 Rosacea One patient experienced an exacerbation of rosacea during Trial 1 that responded to treatment. AQNEURSA was not discontinued.

Laboratory Findings Thrombocytopenia with platelets < 100 10^3 cells/µL was observed in four patients during Treatment Period 1, all of whom were receiving miglustat for 42 days or longer at the time of enrollment. In two of these patients, the thrombocytopenia was present at baseline. In the other two patients, the thrombocytopenia developed during the trial.

• N-acetyl-DL-leucine or N-acetyl-D-leucine : Avoid concomitant use with AQNEURSA. ( 7.1 )
• P-glycoprotein (P-gp) Transporter Substrates : Monitor for adverse reactions if used with AQNEURSA. ( 7.2 ) 7.1 Effect of Other Drugs on AQNEURSA N-acetyl-DL-leucine and N-acetyl-D-leucine Avoid concomitant use of AQNEURSA with N-acetyl-DL-leucine and N-acetyl-D-leucine. The D-enantiomer, N-acetyl-D-leucine, competes with levacetylleucine for monocarboxylate transporter uptake, which may reduce the levacetylleucine efficacy. 7.2 Effect of AQNEURSA on Other Drugs P-glycoprotein (P-gp) Transporter Substrates Monitor more frequently for P-gp substrate related adverse reactions when used concomitantly with AQNEURSA. Levacetylleucine inhibits P-gp [see Clinical Pharmacology ( 12.3 )] . However, the clinical significance of this finding has not been fully characterized.

Pregnancy Risk Summary Based on findings from animal reproduction studies, AQNEURSA may cause embryo-fetal harm when administered during pregnancy. In animal reproduction studies, an increase in embryo-fetal death (post implantation loss/resorption), decrease in fetal body weight, and increase in external and skeletal malformations were observed in rats and rabbits when levacetylleucine was administered in pregnant rats and rabbits during the period of organogenesis. These effects were observed in rats and rabbits at the doses that were approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose (MRHD) in patients taking 4 grams of AQNEURSA per day ( see Data ). There are no available data on AQNEURSA use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

Advise a pregnant female of the potential risk to the fetus. The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the female’s need for AQNEURSA, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal disease. The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a dose-range finding rat embryo-fetal development study, doses of up to 1000 mg/kg/day oral levacetylleucine were administered daily to pregnant females during organogenesis (Gestation Day 6 through GD 17). Increases in the mean number of resorptions, mean post-implantation losses and skeletal malformations (thoracic arch of the vertebra-fused thoracic arch, misaligned thoracic arch, hemicentric thoracic centrum, and misaligned thoracic centrum; vertebral column-scoliosis, and ribs-absent costal cartilage and short rib) were observed at a dose of 600 mg/kg/day, which is 1.4-fold the 4 g/day MRHD of levacetylleucine based on body surface area.

In a dose-range finding rabbit embryo-fetal development study, doses of up to 2500 mg/kg/day oral levacetylleucine were administered daily to pregnant females during organogenesis (GD 7 through GD 19). Increased embryo-fetal death (post-implantation loss/resorption), decreased fetal body weight, and increase in external (open or partially open eyes, hyperflexion of limbs) and skeletal malformations (misshapen maxillae and premaxillae, and small interparietal bones) were observed at the dose of 1250 mg/kg/day, which is 6-fold the MRHD of levacetylleucine based on body surface area.

Pediatric Use The safety and effectiveness of AQNEURSA for the treatment of NPC have been established in 23 pediatric patients weighing ≥15 kg in Trial 1. Use of AQNEURSA for this indication is supported by evidence from one adequate and well-controlled study in adults and pediatric patients weighing ≥15 kg with additional pharmacokinetic data from 40 adults and 17 pediatric patients who participated in two open-label studies . The safety and effectiveness of AQNEURSA have not been established in pediatric patients weighing <15 kg.