Sepiapterin

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 of water or apple juice. Daily Dose (mg) Number of 1,000 mg packets a Number of 250 mg packets a Volume of water or apple juice (mL) 250 mg or less 0 1 9 mL 251 mg to 500 mg 0 2 18 mL 501 mg to 750 mg 0 3 27 mL 751 mg to 999 mg 1 0 36 mL Calculate the prescribed dose volume to the nearest 0.2 mL. Divide the calculated daily dose (mg) by the final concentration (25 mg/mL) of SEPHIENCE liquid mixture for doses less than 1,000 mg. Prescribed dose volume (mL) = SEPHIENCE calculated dose (mg)) 25 mg/mL Prepare a liquid mixture. Open and empty the entire content of each SEPHIENCE packet into an appropriate-size container and mix with the required volume of water or apple juice per Table 2 . Stir the contents for 30 seconds or more until the mixture is uniformly mixed. Using a graduated oral dosing syringe, draw up the prescribed dose volume to the nearest 0.2 mL. Administer the prescribed dose volume (mL). Administer immediately. If particles are remaining in the syringe, draw up additional water or apple juice and administer the contents immediately. Repeat if particles still remain. Discard unused portion of SEPHIENCE mixture remaining in the container. Consume additional food after administration of the prescribed dose volume. Doses 1,000 mg or Greater ( whole packet administration ) Determine the required number of SEPHIENCE packets and the required volume of water, apple juice, strawberry jam, or applesauce (see Table 3 ). Table 3: Number of SEPHIENCE Packets and Volume to Prepare a SEPHIENCE Mixture for Doses of 1,000 mg or Greater Abbreviations: mg, milligrams; mL, milliliters; Tbsp, tablespoons a For calculated daily doses 1,000 mg or greater, round the dose to the nearest 250 mg to determine the number of SEPHIENCE packets required. b For each 1,000 mg packet, add 2 Tbsp (30 mL) of water, apple juice, strawberry jam, or applesauce, and then add an additional quantity of 2 Tbsp (30 mL) for up to three 250 mg packet(s) and then mix. Daily Dose (mg) Number of 1,000 mg packets a Number of 250 mg packets a Volume of water, apple juice, strawberry jam, or applesauce b 1,000 mg to 1,124 mg 1 0 2 Tbsp or 30 mL 1,125 mg to 1,374 mg 1 1 4 Tbsp or 60 mL 1,375 mg to 1,624 mg 1 2 1,625 mg to 1,874 mg 1 3 1,875 mg to 2,124 mg 2 0 2,125 mg to 2,374 mg 2 1 6 Tbsp or 90 mL 2,375 mg to 2,624 mg 2 2 2,625 mg to 2,874 mg 2 3 2,875 mg to 3,124 mg 3 0 3,125 mg to 3,374 mg 3 1 8 Tbsp or 120 mL 3,375 mg to 3,624 mg 3 2 3,625 mg to 3,874 mg 3 3 3,875 mg to 4,124 mg 4 0 4,125 mg to 4,374 mg 4 1 10 Tbsp or 150 mL 4,375 mg to 4,624 mg 4 2 4,625 mg to 4,874 mg 4 3 4,875 mg to 5,124 mg 5 0 5,125 mg to 5,374 mg 5 1 12 Tbsp or 180 mL 5,375 mg to 5,624 mg 5 2 5,625 mg to 5,874 mg 5 3 5,875 mg to 6,124 mg 6 0 Prepare a liquid or soft food mixture. Open and empty the entire content of each SEPHIENCE packet into a container. Mix with the required amount of water, apple juice, strawberry jam, or applesauce per Table 3 . Stir the contents for 30 seconds or more when mixing SEPHIENCE with water or apple juice or 60 seconds or more when mixing SEPHIENCE with strawberry jam or applesauce until the mixture is uniform. Administer the dose. Consume the entire mixture immediately. If particles are remaining in the container, add additional water or juice to the container and administer the contents immediately. Repeat if particles still remain. Consume additional food after administration of the entire mixture.

2.4 Storage Instructions for the Liquid and Soft Food Mixtures If the SEPHIENCE liquid or soft food mixture is not administered immediately, cover and store the mixture at controlled room temperature between 20°C to 25°C (68°F to 77°F) for up to 6 hours or refrigerate between 2°C to 8°C (36°F to 46°F) for up to 24 hours. If the liquid or soft food mixture is stored, stir for at least 30 or 60 seconds, respectively, prior to administration of the prescribed dose. Discard unused SEPHIENCE mixture after 6 hours at controlled room temperature or after 24 hours if refrigerated.

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

12.2 Pharmacodynamics Cardiac Electrophysiology At the recommended SEPHIENCE dose of 60 mg/kg orally once daily, clinically significant QTc interval prolongation was not observed.

12.3 Pharmacokinetics Following oral administration, sepiapterin reached the maximum concentration in plasma at 2 hours post-treatment and converted to pharmacologically active metabolite BH 4 with the exposures of sepiapterin generally less than 2% of those of BH 4 ( Table 5 ). There was no accumulation for BH 4 following repeated once daily dose up to 60 mg/kg administered in adult healthy volunteers. When administered with a high-fat, high-calorie meal in adult healthy volunteers, BH 4 exposures increased less than dose proportionally (with slopes 0.87 and 0.84 for C max and AUC 0-last , respectively) in the dose range 5 to 20 mg/kg and less than dose proportionally (with slopes 0.1957 and 0.3189 for C max and AUC 0-last , respectively) in the dose range 20 to 60 mg/kg. The pharmacokinetics of sepiapterin and its active metabolite BH 4 following oral administration of sepiapterin at 60 mg/kg with food in adult patients with PKU are summarized in Table 5 . Table 5: Summary of Pharmacokinetic Parameters of Sepiapterin and BH 4 Following Oral Administration of Sepiapterin at 60 mg/kg with Food a in Adult Patients (Age ≥17 Years) with PKU a Sepiapterin was administered with dietary Phe restriction. NC: not calculated. Sepiapterin plasma concentration quickly declines to below lower limit of quantitation by 12 hours post dose and AUCinf were not estimable for the majority of patients. Analyte T max (hr) Median (Range) C max (ng/mL) Mean (SD) AUC inf ng*hr/mL) Mean (SD) AUC 24 (ng*hr/mL) Mean (SD) Sepiapterin N Results 29 2 (0.5, 6.1) 29 2.9 (1.6) NC 27 19.9 (18.3) BH 4 N Results 30 4 (2, 8) 30 432 (177) 19 3,626 (1267) 30 3,618 (1,699) Absorption The time to maximum plasma concentration (T max ) of sepiapterin is approximately 1 to 3 hours after oral administration. Plasma sepiapterin is rapidly metabolized to BH 4 and peak BH 4 concentrations are achieved approximately 4 hours after the oral administration of sepiapterin. Effect of Food Administration of SEPHIENCE with food results in increased exposure to sepiapterin and BH 4 . When SEPHIENCE was administered at 20 or 60 mg/kg daily with a low-fat meal in healthy adult subjects, BH 4 exposures were 169% to 172% higher for C max and 162% to 173% higher for AUC 0-24h compared to administration under fasted conditions. When sepiapterin at 20 or 60 mg/kg was administered with a high-fat, high-calorie meal, BH 4 exposures were 221% to 226% higher for C max and 251% to 284% higher for AUC 0-24h compared to administration under fasted conditions [see Dosage and Administration ( 2.2 )] . Distribution Sepiapterin mean human plasma protein binding was 15.4% in the presence of 0.1% dithiothreitol (DTT) in the concentration range of 0.1 to 10 μM. BH 4 mean human plasma protein binding was between 24.1% and 41.3% in the concentration range 2 to 15 μM in the presence of 0.5% β-mercaptoethanol. Sepiapterin apparent volume of distribution could not be estimated reliably as sepiapterin is converted to BH 4 post oral administration and plasma concentration declines to below lower limit of quantitation generally by 12 hours postdose. BH 4 apparent volume of distribution is 11433 (5790) L in adult patients with PKU. Increase of BH 4 in cerebrospinal fluid was detected after oral administration of sepiapterin 60 mg/kg QD for 7 days in healthy adult subjects. Elimination Following oral administration, sepiapterin is quickly absorbed and converted to BH 4 . Sepiapterin plasma concentration is remarkably lower than BH 4 and declines rapidly to below the limit of quantitation generally by 12 hours post dose. The terminal half-life of BH 4 is approximately 5 hours and the apparent clearance is 1498 (848) L/h in adult patients with PKU. Metabolism Sepiapterin is metabolized by SR/carbonyl reductase (CR) and DHFR in a 2-step unidirectional process to form pharmacologically active metabolite BH 4 . BH 4 is further metabolized non-enzymatically or enzymatically mediated by aromatic amino acid hydroxylases, such as PAH, tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), pterin-4α-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR), xanthine oxidase (XO), and nitric oxide synthase (NOS) in various tissues. Extensive metabolism of sepiapterin was observed in humans following a single oral dose of 14 C-sepiapterin. Absorbed sepiapterin was converted to the active metabolite BH 4 , with C max and AUC 0-24h of sepiapterin generally less than 2% of those of BH 4 . Excretion Following a single oral dose of radiolabeled sepiapterin 4,000 mg to healthy adult subjects, a mean of 6.7% was recovered in urine and 26.2% recovered in feces with a combined total recovery of 32.9% by 240 hours. The low total mass recovery is likely due to formation of volatile metabolites in human intestine. Sepiapterin was a minor component in urine and was one of the prominent radioactive components in feces. Specific Populations No clinically significant difference in pharmacokinetics of sepiapterin were observed based on age (range 0.5 to 61 years), sex (female 52%, male 48%), race/ethnicity (White 74%, Asian 16%, Other or not specified 7%, or American Indian or Alaska Native 3%) or ABCG2 genotype (BCRP p.Gln141Lys). The effect of renal impairment, hepatic impairment, or pregnancy on pharmacokinetics of sepiapterin or BH 4 is unknown. Pediatric Patients The pharmacokinetics of sepiapterin and BH 4 following oral administration of sepiapterin at 60 mg/kg with food in PKU patients ≥2 years old are summarized in Table 6 . Table 6: Summary of Pharmacokinetic Parameters of Sepiapterin and BH 4 Following Oral Administration of Sepiapterin at 60 mg/kg with Food a in Pediatric Patients ≥2 Years Old with PKU a Sepiapterin was administered with dietary Phe restriction. Analyte T max (hr) Median (Range) C max (ng/mL) Mean (SD) AUC inf ng*hr/mL) Mean (SD) AUC 24 (ng*hr/mL) Mean (SD) Sepiapterin N Results 19 1.05 (0.5, 4) 19 2.5 (2.1) NA NA 18 13.8 (15.1) BH 4 N Results 21 4 (1.9, 8) 21 350 (191.9) 16 3,466 (1,792) 21 3,023 (1,637) The pharmacokinetics of sepiapterin have not been evaluated in pediatric patients younger than 2 years of age. Drug Interaction Studies Both sepiapterin and BH 4 were a substrate and inhibitor of efflux transporter breast cancer resistance protein (BCRP) in vitro. Oral coadministration of curcumin, a BCRP inhibitor, and sepiapterin in healthy adult subjects resulted in increases in mean AUCs and C max of BH 4 by approximately 20% to 24%, after a single dose. In healthy adult subjects, oral coadministration of sepiapterin and rosuvastatin, a BCRP substrate, had no impact on rosuvastatin exposures. The pharmacokinetics of sepiapterin and BH 4 following sepiapterin oral administration may be affected by inhibitors of SR and/or DHFR [see Drug Interactions ( 7.1 )] . Sepiapterin may increase the availability of tyrosine, a precursor of levodopa [see Drug Interactions ( 7.2 )] .

Following oral administration, sepiapterin reached the maximum concentration in plasma at 2 hours post-treatment and converted to pharmacologically active metabolite BH 4 with the exposures of sepiapterin generally less than 2% of those of BH 4 ( Table 5 ). There was no accumulation for BH 4 following repeated once daily dose up to 60 mg/kg administered in adult healthy volunteers. When administered with a high-fat, high-calorie meal in adult healthy volunteers, BH 4 exposures increased less than dose proportionally (with slopes 0.87 and 0.84 for C max and AUC 0-last , respectively) in the dose range 5 to 20 mg/kg and less than dose proportionally (with slopes 0.1957 and 0.3189 for C max and AUC 0-last , respectively) in the dose range 20 to 60 mg/kg. The pharmacokinetics of sepiapterin and its active metabolite BH 4 following oral administration of sepiapterin at 60 mg/kg with food in adult patients with PKU are summarized in Table 5 . Table 5: Summary of Pharmacokinetic Parameters of Sepiapterin and BH 4 Following Oral Administration of Sepiapterin at 60 mg/kg with Food a in Adult Patients (Age ≥17 Years) with PKU a Sepiapterin was administered with dietary Phe restriction. NC: not calculated. Sepiapterin plasma concentration quickly declines to below lower limit of quantitation by 12 hours post dose and AUCinf were not estimable for the majority of patients. Analyte T max (hr) Median (Range) C max (ng/mL) Mean (SD) AUC inf ng*hr/mL) Mean (SD) AUC 24 (ng*hr/mL) Mean (SD) Sepiapterin N Results 29 2 (0.5, 6.1) 29 2.9 (1.6) NC 27 19.9 (18.3) BH 4 N Results 30 4 (2, 8) 30 432 (177) 19 3,626 (1267) 30 3,618 (1,699) Absorption The time to maximum plasma concentration (T max ) of sepiapterin is approximately 1 to 3 hours after oral administration. Plasma sepiapterin is rapidly metabolized to BH 4 and peak BH 4 concentrations are achieved approximately 4 hours after the oral administration of sepiapterin. Effect of Food Administration of SEPHIENCE with food results in increased exposure to sepiapterin and BH 4 . When SEPHIENCE was administered at 20 or 60 mg/kg daily with a low-fat meal in healthy adult subjects, BH 4 exposures were 169% to 172% higher for C max and 162% to 173% higher for AUC 0-24h compared to administration under fasted conditions. When sepiapterin at 20 or 60 mg/kg was administered with a high-fat, high-calorie meal, BH 4 exposures were 221% to 226% higher for C max and 251% to 284% higher for AUC 0-24h compared to administration under fasted conditions [see Dosage and Administration ( 2.2 )] . Distribution Sepiapterin mean human plasma protein binding was 15.4% in the presence of 0.1% dithiothreitol (DTT) in the concentration range of 0.1 to 10 μM. BH 4 mean human plasma protein binding was between 24.1% and 41.3% in the concentration range 2 to 15 μM in the presence of 0.5% β-mercaptoethanol. Sepiapterin apparent volume of distribution could not be estimated reliably as sepiapterin is converted to BH 4 post oral administration and plasma concentration declines to below lower limit of quantitation generally by 12 hours postdose. BH 4 apparent volume of distribution is 11433 (5790) L in adult patients with PKU. Increase of BH 4 in cerebrospinal fluid was detected after oral administration of sepiapterin 60 mg/kg QD for 7 days in healthy adult subjects. Elimination Following oral administration, sepiapterin is quickly absorbed and converted to BH 4 . Sepiapterin plasma concentration is remarkably lower than BH 4 and declines rapidly to below the limit of quantitation generally by 12 hours post dose. The terminal half-life of BH 4 is approximately 5 hours and the apparent clearance is 1498 (848) L/h in adult patients with PKU. Metabolism Sepiapterin is metabolized by SR/carbonyl reductase (CR) and DHFR in a 2-step unidirectional process to form pharmacologically active metabolite BH 4 . BH 4 is further metabolized non-enzymatically or enzymatically mediated by aromatic amino acid hydroxylases, such as PAH, tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), pterin-4α-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR), xanthine oxidase (XO), and nitric oxide synthase (NOS) in various tissues. Extensive metabolism of sepiapterin was observed in humans following a single oral dose of 14 C-sepiapterin. Absorbed sepiapterin was converted to the active metabolite BH 4 , with C max and AUC 0-24h of sepiapterin generally less than 2% of those of BH 4 . Excretion Following a single oral dose of radiolabeled sepiapterin 4,000 mg to healthy adult subjects, a mean of 6.7% was recovered in urine and 26.2% recovered in feces with a combined total recovery of 32.9% by 240 hours. The low total mass recovery is likely due to formation of volatile metabolites in human intestine. Sepiapterin was a minor component in urine and was one of the prominent radioactive components in feces. Specific Populations No clinically significant difference in pharmacokinetics of sepiapterin were observed based on age (range 0.5 to 61 years), sex (female 52%, male 48%), race/ethnicity (White 74%, Asian 16%, Other or not specified 7%, or American Indian or Alaska Native 3%) or ABCG2 genotype (BCRP p.Gln141Lys). The effect of renal impairment, hepatic impairment, or pregnancy on pharmacokinetics of sepiapterin or BH 4 is unknown. Pediatric Patients The pharmacokinetics of sepiapterin and BH 4 following oral administration of sepiapterin at 60 mg/kg with food in PKU patients ≥2 years old are summarized in Table 6 . Table 6: Summary of Pharmacokinetic Parameters of Sepiapterin and BH 4 Following Oral Administration of Sepiapterin at 60 mg/kg with Food a in Pediatric Patients ≥2 Years Old with PKU a Sepiapterin was administered with dietary Phe restriction. Analyte T max (hr) Median (Range) C max (ng/mL) Mean (SD) AUC inf ng*hr/mL) Mean (SD) AUC 24 (ng*hr/mL) Mean (SD) Sepiapterin N Results 19 1.05 (0.5, 4) 19 2.5 (2.1) NA NA 18 13.8 (15.1) BH 4 N Results 21 4 (1.9, 8) 21 350 (191.9) 16 3,466 (1,792) 21 3,023 (1,637) The pharmacokinetics of sepiapterin have not been evaluated in pediatric patients younger than 2 years of age. Drug Interaction Studies Both sepiapterin and BH 4 were a substrate and inhibitor of efflux transporter breast cancer resistance protein (BCRP) in vitro. Oral coadministration of curcumin, a BCRP inhibitor, and sepiapterin in healthy adult subjects resulted in increases in mean AUCs and C max of BH 4 by approximately 20% to 24%, after a single dose. In healthy adult subjects, oral coadministration of sepiapterin and rosuvastatin, a BCRP substrate, had no impact on rosuvastatin exposures. The pharmacokinetics of sepiapterin and BH 4 following sepiapterin oral administration may be affected by inhibitors of SR and/or DHFR [see Drug Interactions ( 7.1 )] . Sepiapterin may increase the availability of tyrosine, a precursor of levodopa [see Drug Interactions ( 7.2 )] .