METHODS FOR TREATING HYPERPHENYLALANINEMIA

1 . A method of treating phenylketonuria in a subject having a blood phenylalanine concentration greater than 120 micromole per liter, the method comprising administering to the subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the subject is on a phenylalanine-restricted diet.

3 . The method of claim 1 or 2 , wherein the subject has a blood phenylalanine concentration greater than 600 micromole per liter.

4 . The method of any one of claims 1 to 3 , wherein the subject failed to respond to treatment with sapropterin, or a pharmaceutically acceptable salt thereof.

5 . The method of any one of claims 1 to 4 , wherein the subject failed to respond to treatment with pegvaliase-pqpz.

6 . The method of any one of claims 1 to 5 , wherein the subject discontinued treatment with pegvaliase-pqpz due to an adverse reaction and/or tolerability.

7 . The method of any one of claims 1 to 6 , wherein the administering reduces the blood phenylalanine concentration of the subject to less than 360 micromole per liter.

8 . The method of claim 7 , wherein the administering reduces the blood phenylalanine concentration of the subject to less than 120 micromole per liter.

9 . The method of any one of claims 1 to 8 , wherein the administering reduces the blood phenylalanine concentration of the subject at least 35% compared to the blood phenylalanine concentration prior to administration of sepiapterin, or a pharmaceutically acceptable salt thereof.

10 . The method of any one of claims 1 to 9 , wherein the administering reduces the blood phenylalanine concentration of the subject to less than 360 micromole per liter with a phenylalanine consumption of at least about 1500 mg/day.

11 . The method of any one of claims 1 to 10 , wherein the administering produces a BH4 concentration of at least 50 ng/mL in the plasma of the subject within 10 hours of administration of sepiapterin, or a pharmaceutically acceptable salt thereof.

12 . The method of any one of claims 1 to 11 , wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is about 20 mg/kg to about 60 mg/kg per dose.

13 . The method of any one of claims 1 to 12 , wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is about 20 mg/kg per dose.

14 . The method of any one of claims 1 to 12 , wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is about 40 mg/kg per dose.

15 . The method of any one of claims 1 to 12 , wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is about 60 mg/kg per dose.

16 . The method of any one of claims 1 to 15 , wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is administered once daily.

17 . The method of any one of claims 1 to 15 , wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is administered twice daily.

18 . The method of claim 17 , wherein the effective amount of sepiapterin, or pharmaceutically acceptable salt thereof, is administered in two equal doses.

19 . The method of any one of claims 1 to 18 , wherein the effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, is administered with food.

20 . The method of claim 19 , wherein administration to the subject occurs less than 30 minutes prior to consuming food or after consuming food.

21 . The method of claim 19 , wherein the administration to the subject is substantially at the same time as food.

22 . The method of any one of claims 19 to 21 , wherein the food is high protein and/or high fat food.

23 . The method of any one of claims 19 to 22 , wherein the food is high calorie food.

24 . The method of any one of claims 1 to 23 , wherein the risk of adverse events is reduced compared to a subject administered at least 10 mg/kg sapropterin, or a pharmaceutically acceptable salt thereof.

25 . The method of any one of claims 1 to 24 , wherein the administering produces an increase in neurocognitive function of the subject.

26 . The method of any one of claims 1 to 25 , wherein the subject is a child.

27 . The method of claim 26 , wherein the child is less than seven years old.

28 . The method of any one of claims 1 to 26 , wherein the subject is more than seven years old.

29 . The method of any one of claims 1 to 28 , wherein the subject has been diagnosed with tetrahydrobiopterin-responsive phenylketonuria.

30 . The method of any one of claims 1 to 29 , wherein the subject has been diagnosed with sepiapterin-responsive phenylketonuria.

31 . The method of any one of claims 1 to 30 , wherein the sepiapterin or a pharmaceutically acceptable salt thereof, is formulated as an oral powder for suspension.

32 . The method of any one of claims 1 to 31 , wherein the sepiapterin or a pharmaceutically acceptable salt thereof, is administered as a suspension in a flavored suspending vehicle.

33 . The method of any one of claims 1 to 32 , wherein the subject has a blood phenylalanine concentration greater than 1200 micromole per liter.