Sephience

1 INDICATIONS AND USAGE SEPHIENCE is indicated for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU). SEPHIENCE is to be used in conjunction with a phenylalanine (Phe)-restricted diet. SEPHIENCE is a phenylalanine hydroxylase (PAH) activator indicated for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU). SEPHIENCE is to be used in conjunction with a phenylalanine (Phe)- restricted diet. ( 1 )

2 DOSAGE AND ADMINISTRATION Patients treated with SEPHIENCE should be on a dietary protein and a Phe-restricted diet. ( 2.1 ) Administer SEPHIENCE orally once daily with food. ( 2.2 ) The recommended starting dosage of SEPHIENCE is: ( 2.2 ) Age SEPHIENCE (mg/kg) per day Less than 6 months 7.5 mg/kg 6 months to less than 1 year 15 mg/kg 1 year to less than 2 years 30 mg/kg 2 years and older 60 mg/kg Important Administration Information: prepare SEPHIENCE calculated daily doses of < 1,000 mg as a liquid mixture (25 mg/mL), and administer exact prescribed dose volume (mL). ( 2.2 , 2.3 ) See full prescribing information for complete preparation and administration instructions. ( 2.3 ) 2.1 Important Recommendation Prior to SEPHIENCE Treatment Treatment with SEPHIENCE should be directed by physicians knowledgeable in the management of PKU. Biochemical response to SEPHIENCE treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic evaluation of SEPHIENCE [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.1 )]. Obtain baseline blood Phe concentration before initiating treatment. All patients with PKU who are treated with SEPHIENCE should be on a dietary protein and Phe-restricted diet that is based on blood Phe levels. Patients should undergo regular dietary assessments, including protein and Phe intake, by their healthcare provider [see Dosage and Administration ( 2.2 )]. 2.2 Recommended Dosage and Administration The recommended starting dosage of SEPHIENCE is based on the patient’s age and is administered orally once daily (see Table 1 ). Administer SEPHIENCE with food [see Clinical Pharmacology ( 12.3 )] . Table 1: Recommended Starting Dosage of SEPHIENCE * in Pediatric and Adult Patients * For calculated daily doses less than 1,000 mg, the final concentration of prepared SEPHIENCE liquid mixture is 25 mg/mL [see Dosage and Administration ( 2.3 )] . ** 60 mg/kg is the maximum daily dose for all patients. Age SEPHIENCE (mg/kg) per day ** Less than 6 months 7.5 mg/kg 6 months to less than 1 year 15 mg/kg 1 year to less than 2 years 30 mg/kg 2 years and older 60 mg/kg Evaluation Period Dosage Titration in Patients Less than 2 Years of Age After initiating treatment at the starting dosage by age ( Table 1 ), check blood Phe levels to determine response to treatment within 2 weeks. If blood Phe does not decrease, SEPHIENCE dosage may be titrated incrementally based on blood Phe levels to a maximum daily dosage of 60 mg/kg. Existing dietary protein and Phe intake should not be modified during the evaluation period. Discontinuation for Lack of Biochemical Response Discontinue SEPHIENCE in patients whose blood Phe does not decrease after 2 weeks of treatment at the maximum daily dosage of 60 mg/kg. Dosage Modification and Monitoring Monitor blood Phe levels during treatment, and if needed, modify the daily dosage of SEPHIENCE within the range of 7.5 mg/kg to 60 mg/kg and/or dietary protein and Phe intake to ensure adequate blood Phe level control. Frequent blood Phe monitoring is recommended in the pediatric population [see Warnings and Precautions ( 5.2 )] . Missed Dose A missed dose should be taken as soon as possible but 2 doses should not be administered on the same day. Resume the normal dosing schedule the following day. 2.3 Preparation and Administration Instructions Doses Less Than 1,000 mg ( administration based on 25 mg/mL concentration ) Determine the required number of SEPHIENCE packets and the required volume of water or apple juice to achieve a concentration of 25 mg/mL mixture (see Table 2 ). Table 2: Number of SEPHIENCE Packets and Volume to Prepare a SEPHIENCE Mixture of 25 mg/mL for Doses Less than 1,000 mg Abbreviations: mg, milligrams; mL, milliliters a For calculated daily doses less than 1,000 mg, round the dose up to the nearest 250 mg to determine the number of SEPHIENCE packets and prepare each 250 mg packet with 9 mL o …

3 DOSAGE FORMS AND STRENGTHS Oral powder: 250 mg or 1,000 mg sepiapterin as yellow to orange powder in a unit-dose packet. Oral Powder: 250 mg ( 3 ) Oral Powder: 1000 mg ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Increased Bleeding [see Warnings and Precautions ( 5.1 )] . Hypophenylalaninemia [see Warnings and Precautions ( 5.2 )] . Most common adverse reactions with SEPHIENCE (≥2% and greater than placebo) were diarrhea, headache, abdominal pain, hypophenylalaninemia, feces discoloration, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PTC Therapeutics, Inc. at 1-866-562-4620 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 SEPHIENCE was evaluated in Trial 1 [Part 1 (open label); Part 2, (placebo-controlled)]; and Trial 2 (open-label). The two trials included a total of 215 SEPHIENCE-treated patients with PKU: 10 (5%) were <2 years old, 118 (55%) were ≥2 and <17 years old, and 87 (40%) were ≥17 years old. All patients received SEPHIENCE from 7.5 mg/kg/day up to 60 mg/kg/day and the median duration of treatment (in weeks) was 25.5 [see Clinical Studies ( 14.1 )] . Trial 1 Trial 1 included a total of 157 patients (85 male and 72 female, aged 1 year to 61 years old) with PKU across both parts of the trial. The patients received dosages from 20 mg/kg up to 60 mg/kg daily and the median duration of treatment was 8 weeks. Table 4 lists the most common adverse reactions that were reported in ≥2% of patients treated with SEPHIENCE and greater than that of the placebo group in Part 2 of Trial 1. Table 4: Adverse Reactions for SEPHIENCE in Adult and Pediatric Patients with PKU that Occurred in ≥2% of Sepiapterin-Treated Patients and Greater than Placebo (Trial 1 Part 2) a Includes Abdominal pain; Abdominal pain upper, Abdominal discomfort. Adverse Reaction SEPHIENCE N=56 N (%) Placebo N=54 N (%) Diarrhea 4 (7) 1 (2) Headache 4 (7) 1 (2) Abdominal pain a 3 (5) 1 (2) Hypophenylalaninemia 2 (4) 0 Feces discoloration 2 (4) 0 Oropharyngeal pain 2 (4) 1 (2) Adverse reactions were similar across both adult and pediatric populations except for hypophenylalaninemia ( see Description of Selected Adverse Reactions ). Description of Selected Adverse Reactions Increased Bleeding In Trial 1 Part 2, a case of heavy menstrual bleeding was reported in a SEPHIENCE-treated patient. Less than 2% of patients in Trial 2 experienced increased bleeding, which included heavy menstrual bleeding, non-traumatic superficial hematomas, and prolonged bleeding. Hypophenylalaninemia In Trial 1 Part 2, hypophenylalaninemia was seen in 5% (2/37) of sepiapterin-treated pediatric patients and in no adult patients. Some pediatric patients in Trial 2 had multiple low blood Phe levels.

7 DRUG INTERACTIONS Dihydrofolate Reductase (DHFR) Inhibitors : Avoid concomitant use (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, or piritrexim). ( 7.1 ) Sepiapterin Reductase (SR) Inhibitors : Avoid concomitant use (e.g. sulfasalazine or sulfamethoxazole). ( 7.1 ) Interaction with Levodopa : Monitor patients for a change in neurologic status. ( 7.2 ) Drugs Affecting Nitric Oxide-Mediated Vasorelaxation : Potential for vasorelaxation; monitor blood pressure (e.g., PDE-5 inhibitors). ( 7.2 ) 7.1 Effects of Other Drugs on SEPHIENCE Avoid concomitant use of drugs known to inhibit folate synthesis dihydrofolate reductase (DHFR) (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, and piritrexim) while taking SEPHIENCE. Concomitant administration of such drugs may reduce sepiapterin metabolism to tetrahydrobiopterin (BH 4 ). If concomitant use is not avoidable, monitor blood Phe levels. Avoid concomitant use of sepiapterin reductase (SR) inhibitors with SEPHIENCE. Concomitant administration of such drugs may reduce sepiapterin metabolism to BH 4 . If concomitant use is not avoidable, monitor blood Phe levels. 7.2 Effects of SEPHIENCE on Other Drugs SEPHIENCE may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported postmarketing in patients receiving another PAH activator and levodopa concomitantly for a non-PKU indication. Monitor patients for a change in neurologic status when levodopa is administered with SEPHIENCE [see Warnings and Precautions ( 5.3 )] . 7.3 Drugs Affecting Nitric Oxide-Mediated Vasorelaxation SEPHIENCE and PDE-5 inhibitors induce vasorelaxation, thus concomitant use of SEPHIENCE with PDE-5 inhibitors may reduce blood pressure even further. Monitor for signs and symptoms of hypotension with concomitant use of SEPHIENCE with drugs that affect nitric oxide-mediated vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data on the use of SEPHIENCE during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Uncontrolled blood Phe concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects ( see Clinical Considerations ) . In animal reproduction studies, oral administration of sepiapterin to pregnant rats and rabbits during organogenesis at dose exposures up to 9- and 6- times the human exposure at the maximum recommended human dose (MRHD) of 60 mg/kg, respectively, resulted in no adverse developmental effects ( see Data ). All pregnancies have a background risk of birth defects, loss, 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. The background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood Phe concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk Uncontrolled blood Phe concentrations before and during pregnancy are associated with an increased risk of adverse outcomes and fetal adverse effects ( see Data ). To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood Phe concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration ( 2.2 )] . Data Human Data Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in pregnant women with PKU demonstrated that uncontrolled Phe concentrations above 600 micromol/L are associated with an increased risk for major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ. Animal Data In an embryo-fetal development study in rats, SEPHIENCE was administered at dose levels of 100, 300, or 1,000 mg/kg/day via oral gavage to pregnant rats during the period of organogenesis from gestation day (GD) 7 to GD 17. There were no maternal or embryo-fetal developmental toxicities noted at doses up to 1,000 mg/kg/day (9-fold the human AUC 0-24 at the MRHD). In an embryo-fetal development study in pregnant rabbits, SEPHIENCE was administered at dose levels of 100, 300, or 1,000 mg/kg/day via oral gavage to pregnant rabbits during the period of organogenesis from gestation day (GD) 7 to GD 19. There were no maternal or embryo-fetal developmental toxicities at doses up to 1,000 mg/kg/day (6-fold the human AUC 0-24 at the MRHD). In the pre- and post-natal development study in rats, SEPHIENCE was administered at dose levels of 30, 100, and 300 mg/kg/day via oral gavage once daily to pregnant rats from GD 6 to lactation day 20. SEPHIENCE did not induce effects on maternal reproductive function or on developmental and reproductive parameters of male and female offspring up to 300 mg/kg (7-fold the human AUC 0-24 at the MRHD). 8.2 Lactation Risk Summary There are no data on the presence of sepiapterin in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SEPHIENCE and any potential adverse effects on the breastfed infant from SEPHIENCE or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SEPHIENCE have been established in pediatric patients 1 month of age and older. Use of SEPHIENCE for this indication is supported by evidence from one adequate and well-controlled …

12.1 Mechanism of Action SEPHIENCE is a precursor of the enzymatic co-factor tetrahydrobiopterin (BH 4 ) which activates PAH.

11 DESCRIPTION SEPHIENCE (sepiapterin) contains the drug substance sepiapterin, a PAH activator. Sepiapterin is a yellow to orange powder. Sepiapterin is slightly soluble in water with the solubility at 1.4 mg/mL. The chemical name of sepiapterin is (S) -2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4 (3H) -one. The molecular formula is C 9 H 11 N 5 O 3 and the molecular weight is 237.22 g/mol. The structural formula is: SEPHIENCE oral powder contains either 250 mg or 1,000 mg of sepiapterin to be administered orally. The inactive ingredients are: colloidal silicon dioxide, croscarmellose sodium, isomalt, magnesium stearate, mannitol, microcrystalline cellulose, sucralose, and xanthan gum. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied SEPHIENCE (sepiapterin) oral powder is supplied as a yellow to orange powder in a unit-dose heat-sealed laminated aluminum foil packet. Each packet contains: 250 mg sepiapterin per packet: NDC 52856-201-03 Carton of 30-unit dose packets NDC 52856-201-01 Single unit dose packet 1,000 mg sepiapterin per packet: NDC 52856-301-03 Carton of 30-unit dose packets NDC 52856-301-01 Single unit dose packet Storage and Handling Store SEPHIENCE at room temperature between 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store SEPHIENCE liquid or soft food mixture either refrigerated or at controlled room temperature [see Dosage and Administration ( 2.4 )] .