Levacetylleucine

12.1 Mechanism of Action The distinct molecular target for levacetylleucine in the treatment of NPC is unknown.

1 INDICATIONS AND USAGE 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. ( 1 )

2 DOSAGE AND ADMINISTRATION • For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. ( 2.1 ) • Recommended dosage ( 2.2 ) Patient Body Weight Morning Dose Afternoon Dose Evening Dose 15 to <25 kg 1 g No Dose 1 g 25 to <35 kg 1 g 1 g 1 g 35 kg or more 2 g 1 g 1 g • See the full prescribing information for administration instructions. ( 2.3 ) 2.1 Important Recommendation Prior to AQNEURSA Treatment Initiation For females of reproductive potential, verify that the patient is not pregnant [see Use in Specific Populations ( 8.1 , 8.3 )]. 2.2 Recommended Dosage The recommended dosage of AQNEURSA is based on the patient’s actual body weight (kg) to be administered orally up to three times daily. See Table 1 . AQNEURSA can be taken with or without food [see Clinical Studies ( 14 )] . For 2 gram levacetylleucine doses, prepare two AQNEURSA packets individually [see Dosage and Administration ( 2.3 )] . Table 1 Recommended Dosage of Levacetylleucine Based on Body Weight (kg) Patient’s Body Weight Morning Dose Afternoon Dose Evening Dose 15 kg to less than 25 kg 1 gram No Dose 1 gram 25 kg to less than 35 kg 1 gram 1 gram 1 gram 35 kg or more 2 gram 1 gram 1 gram One AQNEURSA packet contains 1 gram levacetylleucine. Missed Dose If a dose of AQNEURSA is missed, skip the missed dose and take the next dose at the scheduled time. Do not take 2 doses at the same time to make up for a missed dose. 2.3 Preparation and Administration Instructions Oral Administration For oral administration, administer AQNEURSA as follows: 1. Obtain the required number of AQNEURSA packets for the prescribed dose (one or two packets). 2. Open and empty the entire contents of one AQNEURSA packet into a container with 40 mL of water, orange juice, or almond milk. Do not use hot liquid. 3. Stir to form a suspension. 4. Swallow the suspension immediately (within 30 minutes). 5. For doses requiring two AQNEURSA packets, repeat steps 2 to 4. 6. Discard unused AQNEURSA suspension if not administered within 30 minutes. Use of Gastrostomy Tube (G-Tube) for Feeding Tube Administration For patients who have a G-tube (French size 18 or larger) in place, administer AQNEURSA as follows: 1. Prepare AQNEURSA suspension immediately before administration via gastrostomy tube. 2. Obtain the required number of AQNEURSA packets for the prescribed dose (one or two packets). 3. Open and empty the entire contents of one AQNEURSA packet into a container with 40 mL of water ONLY. Do not use hot liquid. 4. Stir to form a suspension. 5. Draw up the suspension into a catheter tip syringe. 6. Administer the suspension immediately through the G-tube. 7. Flush any residual suspension in the catheter tip syringe with an additional 20 mL of water. 8. Flush the G-tube again, as needed, until no residual suspension is left in the syringe or feeding tube. 9. For doses requiring two AQNEURSA packets, repeat steps 3 to 8. 10. Discard unused AQNEURSA suspension if not administered immediately.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5% and greater than placebo) are abdominal pain, dysphagia, upper respiratory tract infections, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact IntraBio Inc. at 1-833-306-9677 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 [see Clinical Studies ( 14 )] . The mean (SD) treatment duration of AQNEURSA was 86.2 (4.7) days (69 min, 97 max); the mean (SD) treatment duration on placebo was 87.3 (4.8) 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 (17) 1 (3) Abdominal pain 2 (7) 0 (0) Dysphagia 2 (7) 0 (0) Vomiting 2 (7) 0 (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.

7 DRUG INTERACTIONS • 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.