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JP-7855033-B2 - Compositions and methods for increasing tetrahydrobiopterin plasma exposure

JP7855033B2JP 7855033 B2JP7855033 B2JP 7855033B2JP-7855033-B2

Inventors

  • スミス， ニール
  • レイス， ジョナサン

Dates

Publication Date
20260507
Application Date
20240828
Priority Date
20190528

Claims (11)

  1. A composition comprising sepiapterin or a pharmaceutically acceptable salt thereof for use in the treatment of a tetrahydrobiopterin (BH4)-related disorder selected from BH4 deficiency or phenylketonuria in a subject requiring such treatment, wherein the treatment comprises orally administering an effective amount of the composition to the subject once daily with food, the administration to the subject less than 30 minutes before or concurrently with food intake.
  2. The composition for use according to claim 1 , wherein the effective amount is sufficient to produce a BH4 concentration of at least 50 ng/mL in the target plasma within 10 hours of administration.
  3. The composition for use according to claim 1 or 2 , wherein the effective amount is 2.5 mg/kg to 100 mg/kg.
  4. The composition for use according to claim 3, wherein the effective amount is 2.5 mg/kg to 20 mg/kg.
  5. The composition for use according to claim 3, wherein the effective amount is 40 mg/kg to 60 mg/kg.
  6. The composition for use according to claim 3, wherein the effective amount is 60 mg/kg.
  7. A composition for use according to any one of claims 1 to 6 , wherein administration to the subject is carried out simultaneously with food.
  8. The composition for use according to any one of claims 1 to 7 , wherein the effective amount results in an increase in the maximum plasma concentration (Cmax) of BH4 compared to administration without food.
  9. The composition for use according to any one of claims 1 to 8 , wherein the effective amount results in an increase in the area under the concentration-time curve from time zero to the final concentration (AUC0-last) of BH4 compared to administration without food.
  10. The composition for use according to any one of claims 1 to 9, wherein the food contains at least 300 calories.
  11. The composition for use according to any one of claims 1 to 10, wherein the food is a high-fat food and at least 25% of the calories come from fat.

Description

Sepiapterin is a naturally occurring precursor of tetrahydrobiopterin (BH4), a naturally occurring essential cofactor for important intracellular enzymes (including, but not limited to, phenylalanine hydroxylase (PAH) (Kaufman, 1958), tyrosine hydroxylase (TH) (Nagatsu et al, 1964), tryptophan hydroxylase (TPH) (Ichiyama et al, 1970), nitrile oxide synthase (NOS) (Kwon et al, 1989), (Mayer et al, 1991), and alkylglycerol monooxygenase (AGMO) (Tietz et al, 1964). The rapid conversion of sepiapterin to BH4 occurs via a two-step reduction in the salvage pathway for BH4 synthesis (Sawabe, 2008). Synthetic forms of BH4 (e.g., sapropterin dihydrochloride) are used as a therapy for hyperplasmic phenylalanine-related disorders such as phenylketonuria (PKU). PKU is a congenital metabolic disorder primarily caused by mutations in the PAH gene. BH4 has also been tested as a treatment for various central nervous system symptoms and other disorders associated with PKU, but its efficacy has been limited, possibly due to its inability to effectively cross the blood-brain barrier (Klaiman et al, 2013; Grant et al, 2015). Recent studies suggest that, compared to BH4, peripherally administered sepiapterin has higher membrane permeability, resulting in easier access to liver, kidney, and brain cells. Sepiapterin has been reported to be rapidly converted to BH4 intracellularly, thereby increasing BH4 levels in the liver, kidney, and brain (Sawabe, 2008). Consequently, sepiapterin may serve as a useful therapeutic agent for diseases associated with low intracellular BH4 levels or dysfunction of various BH4-dependent metabolic pathways. This invention is directed toward the discovery that when sepiapterin is administered to a subject with food, the production of BH4 unexpectedly increases, and further, the subject's BH4 plasma (plasma) exposure, CSF exposure, and/or brain exposure occur. While not bound by theory, the increased BH4 plasma exposure may result from delayed absorption of sepiapterin due to increased gastric residence time, or prolonged absorption rate of sepiapterin due to increased foregut residence time, or prolonged intracellular concentration of sepiapterin below, equal to, or slightly above the maximum rate of enzymatic activity (V max ) of sepiapterin reductase or dihydrofolate reductase, or a combination of the above, resulting in a greater proportion of administered sepiapterin being converted to BH4 before passive or active transport into the circulation for excretion and/or elimination. This invention features compositions comprising sepiapterin or salts thereof, and methods for treating BH4-related diseases. In some embodiments, this composition and method result in increased plasma exposure of BH4. As is known in this art, food can affect the absorption of compounds. Absorption may be delayed but not reduced, or the total amount of drug absorbed may be reduced. The effects of food can stem from delaying gastric retention time, delaying foregut retention time, reducing access of the compound to the absorption site, altering the dissolution rate of the compound, or altering gastric pH. Because of these effects, it is important to establish specific administration schedules for drugs that should be administered separately from or with food. In one embodiment, the present invention is characterized by a method for treating BH4-related diseases in subjects requiring such treatment, by administering an effective amount of sepiapteprine or a pharmaceutically acceptable salt thereof together with food. In another embodiment, the present invention is characterized by a method for increasing BH4 plasma exposure in subjects receiving sepiapterin therapy by administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof to the subjects together with food. In a further embodiment, the present invention features a method for reducing the absorption rate of an oral formulation of sepiapterin, as measured by the BH4 concentration that reaches the plasma over time in a subject requiring its therapeutic effect. The method comprises administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof to the subject together with food. In some embodiments of any of the methods described above, the effective dose is a dose sufficient to produce a BH4 concentration of at least 50 ng/mL (e.g., at least 60 ng/mL, at least 100 ng/mL, at least 200 ng/mL, at least 400 ng/mL, at least 600 ng/mL, at least 1000 ng/mL, or at least 2000 ng/mL) in the target plasma within 10 hours after administration with food (e.g., 2.5 mg/kg to 100 mg/kg per administration). The effective dose may include a dose that is at least 5% (at least 10%, at least 20%, at least 50%, at least 70%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%) less than the dose sufficient to produce a maximum BH4 plasma concentration (Cmax) of at least 50 ng/m