Treatment methods for glioblastoma

Abstract

The invention features a method of treating glioblastoma in a subject, the method comprising administering to the subject an effective amount of sepiapterin or a pharma- ceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits and priority of the pending U.S. Provisional Patent Application No. 63 / 147,625, filed on 9 February 2021, the contents of which are expressly incorporated into this application by reference in their entirety. [Background technology]

[0002] Glioblastoma, also known as glioblastoma multiforme (GBM), is an aggressive cancer that originates in the brain. Treating GBM is difficult because many drugs cannot cross the blood-brain barrier, and conventional treatments are prone to damaging the brain. Radiation therapy is frequently used to treat GBM, but it often causes side effects such as fatigue, headaches, memory and speech impairments, seizures, stroke-like symptoms, and cognitive decline. Furthermore, GBM tumors may be resistant to radiation therapy.

[0003] Sepiapterin, a metabolic precursor of the enzyme cofactor tetrahydrobiopterin (BH4), has good oral bioavailability and a favorable safety profile in humans, and is currently being tested as a treatment for certain metabolic disorders. Sepiapterin has also been shown to cross the blood-brain barrier and affect neurotransmitter production. Once in the brain, separatepitterin is converted to BH4.

[0004] What is needed is a method to treat GBM. Furthermore, what is needed are drugs that are effective in treating GBM that can cross the blood-brain barrier. Additionally, methods to radiosensitize GBM tumors are needed. Furthermore, radioprotective agents for treating GBM are needed. [Overview of the project]

[0005] A method for treating glioblastoma in a subject is provided, comprising administering an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is about 10 mg / kg to about 60 mg / kg per dose. In some embodiments, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is about 20 mg / kg to about 60 mg / kg per dose. In some embodiments, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is about 20 mg / kg per dose. In some embodiments, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is about 40 mg / kg per dose. In some embodiments, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is about 60 mg / kg per dose. In some embodiments, including any of the above embodiments, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments including any of the above embodiments, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments including any of the above embodiments, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered in two equivalents. In some embodiments including any of the above embodiments, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered with food. In some embodiments including any of the above embodiments, administration to the subject is performed before or within 30 minutes after food intake. In some embodiments including any of the above embodiments, administration to the subject is performed substantially simultaneously with food. In some embodiments including any of the above embodiments, the food is a high-protein and / or high-fat food. In some embodiments including any of the above embodiments, the food is a low-fat food. In some embodiments including any of the above embodiments, the food is a high-calorie food. In some embodiments including any of the above embodiments, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered without food. In some embodiments, including any of the above embodiments, administration to the subject is performed at least 30 minutes before food intake, or at least 2 hours after food intake.In some embodiments including any of the above embodiments, administration to the subject is performed at least 30 minutes before food intake or at least 3 hours after food intake. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is formulated as an oral powder for suspension. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered as a suspension in a flavored suspension vehicle. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered as a suspension in water or juice (e.g., apple, orange, grape). In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is formulated as an oral tablet, capsule, or caplet. In some embodiments including any of the above embodiments, the method further includes treating the subject with therapeutic radiation. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered during the course of therapeutic radiotherapy. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered before therapeutic radiation. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered after therapeutic radiation. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 5 days. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 6 days. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 10 days. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 14 days. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 15 days.In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 14 days. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered at least 6 days, or at least 10 days, or at least 14 days, or at least 30 days before radiation therapy. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered at least 6 days, or at least 10 days, or at least 14 days, or at least 30 days after therapeutic radiation. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered continuously concurrently with therapeutic radiation. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered daily in a 28-day treatment cycle. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered daily during a continuous 28-day treatment cycle. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered daily for at least six 28-day treatment cycles. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered daily in consecutive 28-day treatment cycles until progressive disease (PD) develops. In some embodiments including any of the above embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered daily in consecutive 28-day treatment cycles until death. In some embodiments including any of the above embodiments, the method further includes treating the subject with temozolomide (TMZ). In some embodiments including any of the above embodiments, the subject is human.

[0006] In some embodiments of any of the methods described herein, administration of sepiapterin or a pharmaceutically acceptable salt thereof results in 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, or 50 ng / ml to 100 ng / ml, 60 ng / ml to 400 ng / ml, and 200 ng / ml to 600 ng / ml, 400 ng / ml to 1000 ng / ml, or 600 ng / ml to 1500 ng / ml) in the plasma of the subject within 10 hours after administration.

[0007] In some embodiments of the methods described herein, the effective dose is an amount 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, or 50 ng / ml to 100 ng / ml, 60 ng / ml to 400 ng / ml, 200 ng / ml to 600 ng / ml, 400 ng / ml to 1000 ng / ml, or 600 ng / ml to 1500 ng / ml) in the plasma of the subject within 10 hours of administration of sepiapterin or a pharmaceutically acceptable salt thereof (e.g., 2.5 mg / kg to 100 mg / kg per single dose).

[0008] In some embodiments of any of the methods described herein, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is about 2.5 mg / kg to about 100 mg / kg per single dose (for example, about 20 mg / kg to about 60 mg / kg, or about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg).

[0009] In some embodiments of any of the methods described herein, an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof is administered with food. In some embodiments of any of the methods described herein, the effective amount is 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, or 50 ng / ml to 100 ng / ml, 60 ng / ml to 400 ng / ml, 200 ng / ml to 600 ng / ml, 400 ng / ml to 1000 ng / ml, or 600 ng / ml to 1500 ng / ml) in the plasma of the subject within 10 hours after administration with food (e.g., 1 mg / kg to 100 mg / kg per dose, or 2.5 mg / kg to 100 mg / kg per dose). In some embodiments, the effective dose includes a dose at least 5% lower (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, or 50 ng / ml to 100 ng / ml, 60 ng / ml to 400 ng / ml, 200 ng / ml to 600 ng / ml, 400 ng / ml to 1000 ng / ml, or 600 ng / ml to 1500 ng / ml) than the dose sufficient to produce a maximum BH4 plasma concentration (Cmax) of at least 50 ng / ml in the subject's plasma within 10 hours of administration of sepiapterin or a pharmaceutically acceptable salt thereof without food.

[0010] In some embodiments of the methods described herein, administration to the subject is performed less than 30 minutes before or after the intake of food, for example, immediately before or within 1 hour after the intake of food. In some embodiments, administration to the subject is substantially simultaneous with the food. In some embodiments of the methods described herein, the food is a high-protein food. In some embodiments of the methods described herein, the food is a high-fat food (for example, at least 25, 30, 40, or 50% of the calories are from fat). In some embodiments of the methods described herein, the food is a high-protein and high-fat food. In some embodiments, the food is a high-calorie food (for example, the food contains at least 100 calories, for example, at least 200 calories, at least 300 calories, at least 400 calories, at least 500 calories, for example, 500-1500 or 800-1000 calories). In some embodiments of the methods described herein, the food is a meal, for example, breakfast, lunch, or dinner. In some embodiments of any of the methods described herein, the food is a low-fat food (for example, less than 25% of the calories come from fat).

[0011] In some embodiments of any of the methods described herein, administration with food (e.g., less than 30 minutes before food intake, or after food intake, e.g., immediately before food intake to 1 hour after food intake) results in an increase in BH4 Cmax (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%) compared to administration without food (e.g., at least 2 hours after food intake and up to 30 minutes before food intake).

[0012] In some embodiments of the methods described herein, administration with food (e.g., less than 30 minutes before food intake, or after food intake, e.g., immediately before food intake to 1 hour after intake) compared to administration without food (e.g., less than 30 minutes before food intake, or after food intake, e.g., immediately before food intake to 1 hour after intake) results in a greater degree of BH4 production and the resulting plasma exposure (AUC). 0-last This results in an increase (for example, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%).

[0013] In some embodiments of the methods described herein, the sepiapterin or a pharmaceutically acceptable salt thereof is provided in a composition separate from the ingested food (for example, the sepiapterin or a pharmaceutically acceptable salt thereof is not incorporated into the food product). In some embodiments of the methods described herein, the food is taken before the administration of the sepiapterin or a pharmaceutically acceptable salt thereof (for example, the food is taken between one hour before and immediately before the administration of the sepiapterin or a pharmaceutically acceptable salt thereof). In some embodiments of the methods described herein, the food is taken after the administration of the sepiapterin or a pharmaceutically acceptable salt thereof (for example, the food is taken between immediately after and 30 minutes after administration).

[0014] In some embodiments of any of the above methods, the effective dose is an amount sufficient to produce a sepiapterin plasma concentration of at least 0.5 ng / mL (e.g., at least 1 ng / mL, at least 1.5 ng / mL, at least 2.5 ng / mL, or at least 3.5 ng / mL) in the subject's plasma within one hour after administration without food (e.g., 2.5 mg / kg to 100 mg / kg per dose). For example, the effective dose includes a dose at least 10% (e.g., at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, or at least 120%) lower than the dose sufficient to produce a maximum plasma concentration (Cmax) of at least 0.5 ng / mL (e.g., at least 1 ng / mL, at least 1.5 ng / mL, at least 2.5 ng / mL, or at least 3.5 ng / mL) in the subject's plasma within one hour after administration of sepiapterin with food. In some embodiments, administration (e.g., more than 30 minutes before food intake or at least 2 hours after food intake) results in an increase in maximum plasma, CSF, and / or brain concentration (Cmax) of sepiapterin (e.g., at least 10% (at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, or at least 120%) compared to administration with food (e.g., administration within 30 minutes up to 2 hours after food intake). In some embodiments, administration (e.g., more than 30 minutes before food intake or at least 2 hours after food intake) results in an increase in the degree of absorption (AUC) of sepiapterin compared to administration with food. 0-last This results in an increase (for example, at least 10% (at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, or at least 120%) (for example, administration to the subject is performed less than 30 minutes before food intake and less than 2 hours after food intake).

[0015] In some embodiments of the methods described herein, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered in two equal doses (e.g., two doses at different times of the day). In some embodiments of the methods described herein, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments of the methods described herein, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered in two 60 mg / kg doses (e.g., one 60 mg / kg dose in the morning and one 60 mg / kg dose in the evening). In some embodiments of the methods described herein, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered in two 40 mg / kg doses (e.g., one 40 mg / kg dose in the morning and one 40 mg / kg dose in the evening). In some embodiments of the methods described herein, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered in two 30 mg / kg doses (e.g., one 30 mg / kg dose in the morning and one 30 mg / kg dose in the evening). In some embodiments of the methods described herein, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered in two 20 mg / kg doses (e.g., one 20 mg / kg dose in the morning and one 20 mg / kg dose in the evening). In some embodiments of the methods described herein, an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is administered in two 10 mg / kg doses (e.g., one 10 mg / kg dose in the morning and one 10 mg / kg dose in the evening).

[0016] In any embodiment of the method described herein, the method comprises administering to a subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof once daily with food. In any embodiment of the method described herein, the method comprises administering to a subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof more than once daily with food, for example twice daily. In any embodiment of the method described herein, the method comprises administering to a subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof once daily without food. In any embodiment of the method described herein, the method comprises administering to a subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof more than once daily without food, for example twice daily.

[0017] In some embodiments of any of the methods described herein, the subjects are children (for example, the subjects are under 18, under 17, under 16, under 15, under 14, under 13, under 12, under 11, under 10, under 9, under 8, under 7, under 6, under 5, under 4, under 3, under 2, under 1). In some embodiments of any of the methods described herein, the subjects are adults (for example, the subjects are over 18). In some embodiments, the subjects are over 20, over 30, over 40, over 50, over 60, over 70, over 80, over 90.

[0018] In some embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is formulated as an oral powder for suspension. In some embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered as a suspension in a flavored vehicle for suspension (e.g., MEDISCA® Oral Mix). In some embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered as a suspension in water or juice (e.g., apple juice). In some embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered as a suspension in foods such as applesauce or pudding. In some embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is formulated as a tablet, capsule, or caplet.

[0019] Definitions In this application, unless the context clearly dictates otherwise: (i) the term "a" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and / or"; (iii) the terms "comprising" and "comprise" may be understood to include the listed elements or steps, whether presented by themselves or in conjunction with one or more additional elements or steps; and (iv) the term "about" may be understood to allow for standard variation as understood by one of ordinary skill in the art, and (v) when ranges are provided, endpoints are included.

[0020] The descriptions of the compounds, compositions, formulations, and treatment methods described herein are to be understood to include the embodiments "comprising," "consisting of," and "consisting essentially of." In some embodiments, for all of the compositions described herein and all of the methods of using the compositions described herein, the compositions can include the recited ingredients or steps, or can "consist essentially of" the recited ingredients or steps. When a composition is described as "consisting essentially of" the recited ingredients, the composition includes the recited ingredients and may include other ingredients that do not substantially affect the condition being treated, but does not include any other ingredients, other than those specifically recited, that substantially affect the condition being treated; or, if the composition actually includes additional ingredients that substantially affect the condition being treated, other than the recited ingredients, the composition does not include the additional ingredients at a concentration or amount sufficient to substantially affect the condition being treated. When a method is described as "consisting essentially of" the recited steps, the method includes the recited steps and may include other steps that do not substantially affect the condition being treated, but the method does not include any other steps, other than those specifically recited, that substantially affect the condition being treated. By way of non-limiting specific example, when a composition is described as "consisting essentially of" a certain ingredient, the composition can further include any amount of a pharmaceutically acceptable carrier, vehicle, or diluent and other such ingredients that do not substantially affect the condition being treated.

[0021] Unless otherwise apparent from the context, all references to sepiapterin herein refer to sepiapterin or a pharmaceutically acceptable salt of sepiapterin.

[0022] As used herein, the term "about" represents a value that is within ±10% of the value that follows the term "about." In this specification, referring to a value or parameter as "about" includes (and describes) variations that are directed to that value or parameter itself. For example, a description that refers to "about X" includes a description of "X."

[0023] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound described herein or a preparation containing the same) to a subject or system. Administration to an animal subject (e.g., administration to a human) may be by any suitable route. For example, in some embodiments, administration includes bronchial (including bronchial infusion), oral, enteral, interdermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), percutaneous, vaginal, and vitreous.

[0024] The "effective dose" of a compound may vary depending on factors such as the individual's medical condition, age, sex, and weight, as well as the compound's ability to induce the desired response. A therapeutically effective dose encompasses the amount in which the therapeutically beneficial effect outweighs any toxic or harmful effects of the compound. The effective dose also includes an amount sufficient to provide a benefit, such as a clinical benefit.

[0025] As used herein, the term “food” refers to solid food having sufficient bulk and fat content so that it is not rapidly dissolved and absorbed in the stomach. For example, a meal such as breakfast, lunch, or dinner. As used herein, the term “with food” refers to administering the composition between approximately 30 minutes before eating (for example, food) and approximately 2 hours after eating. The terms “without food,” “fasting,” or “hunger” further refer to a state in which solid food has not been consumed up to approximately 30 minutes before ingesting solid food and at least approximately 2 hours (at least 3 hours) afterward.

[0026] "Low-fat foods" refer to meals in which calories from fat account for 25% or less. In some embodiments, low-fat foods contain approximately 11-14g of fat. In some embodiments, low-fat foods contain approximately 400-500 calories in total.

[0027] "Natural protein" refers to protein derived from natural sources (e.g., animals, plants, or fungi).

[0028] As used herein, the term “pharmaceutical composition” refers to a composition comprising the compounds described herein, formulated with pharmaceutically acceptable excipients. Pharmaceutical compositions may be formulated, for example, for oral administration of unit formulations (e.g., tablets, capsules, caplets, gel caps, suspensions, solutions, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as sterile solutions of granular embolism-free solvent systems suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0029] As used herein, the term “pharmaceutically acceptable salt” means any salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977, and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting a free base group with a suitable organic acid.

[0030] In many cases, compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acids and methods for preparing suitable salts are well known in the art. Salts may be prepared from pharmaceutically acceptable, non-toxic acids, including inorganic and organic acids.

[0031] Typical acid addition salts include acetate, adipate, alginate, ascorbate, aspatate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butylate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, gentisate, glucoheptate, glycerophosphate, glycolate, hemisulfate, heptonate, hexanate, hydrobromide, hydrochloride, hydroiodide, and 2 This includes hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, parsulfates, 3-phenylpropionates, phosphates, picates, pivalates, propionates, stearates, succinates, sulfates, tarates, thiocyanates, toluenesulfonates, undecanoates, and valverate salts.

[0032] As used herein, the term “substantially free” means a qualitative state indicating the absence of all or nearly all ranges or degrees of a compound or type of compound of interest. Any ordinary technician in the field of biology will understand that biological and chemical phenomena are rarely determined to be absolutely zero, for example, due to inherent errors in any measurement. Therefore, the term “substantially free” is used herein to capture the potential lack of completeness inherent in many biological and chemical measurements.

[0033] As used herein, the terms “subject,” “participant,” or “patient” refer to any organism to which a compound or composition according to the present invention may be administered, for example, for experimental, diagnostic, preventive, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). Subjects may be humans or animals that require treatment, are receiving treatment, may receive treatment in the future, or are being cared for by a specialist trained for a particular disease or condition.

[0034] As used herein, the terms “treat,” “treated,” or “treatment process” mean both therapeutic measures and preventive or inhibitory measures, the purpose of which is to suppress or slow (reduce) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desirable clinical outcome. Beneficial or desirable clinical outcomes include, but are not limited to, relief of symptoms, reduction in the severity of a condition, disorder, or disease, stabilization (i.e., non-worsening) of a condition, disorder, or disease, onset or delay of progression of a condition, disorder, or disease, improvement (partial or overall) of a condition, disorder, or disease, whether detectable or undetectable, improvement of at least one measurable physical parameter, which is not necessarily identifiable by the subject, or improvement or enhancement of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes extending survival compared to the expected survival without treatment.

[0035] "Progressive disease (PD)" refers to one or more of the following: (1) the appearance of one or more new lesions; (2) an increase of at least 20% in the total diameter of target lesions, using the minimum total in the study as a reference (the minimum in the study includes the baseline total). In addition to a relative increase of 20%, the total must demonstrate an absolute increase of at least 5 mm. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumors: revised RECIST guideline (versions 1.1). Eur J Cancer. 2009;45:228-247.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which this invention pertains. Methods and materials are described herein for use in the disclosure herein, and other suitable methods and materials known in the art may also be used. Materials, methods and examples are illustrative and not intended to limit. All publications, patent applications, patents, sequences, database entries and other references referenced herein are incorporated in their entirety by reference. In case of any conflict, this specification, including definitions, shall prevail.

[0037] Details of one or more embodiments of the present invention are described below. Other features, purposes, and advantages of the present invention will become apparent from this specification and the claims. [Brief explanation of the drawing]

[0038] [Figure 1] This graph shows the survival rate of nude (U87) mice with glioblastoma tumors treated with a combination of sepiapterin and radiation, or radiation alone, compared to a control group.

[0039] [Figure 2]This graph shows the survival rates of syngeneic (GL261) mice treated with sepiapterin (SP) alone, sepiapterin in combination with radiation (IR), or radiation alone, compared to a control group.

[0040] [Figure 3] This graph shows the survival rate of mice with glioblastoma tumors treated with temozolomide (TMZ) alone or sepiapterin, compared to a control group.

[0041] [Figure 4] This graph shows the novel object recognition (NOR) discrimination index of mice treated with either radiation or radiation and sepiapterin, compared to the control group (naive).

[0042] [Figure 5] This is a schematic diagram of a phase 2 study of temozolomide and sepiapterin combined with therapeutic radiation in newly diagnosed or recurrent glioblastoma. [Modes for carrying out the invention]

[0043] The inventors have discovered that sepiapterin is effective in treating patients with glioblastoma. In some embodiments, sepiapterin is administered with food. In some embodiments, sepiapterin is administered without food. While not intended to be bound by theory, sepiapterin may not only sensitize glioblastoma to therapeutic radiation and / or chemotherapeutic agents, but also protect the brain from side effects of therapeutic radiation and / or chemotherapeutic agents. In some embodiments, sepiapterin prevents, delays, and / or mitigates cognitive decline caused by therapeutic radiation and / or chemotherapeutic agents. Accordingly, the present invention features a method for treating a target glioblastoma by administering sepiapterin or a pharmaceutically acceptable salt thereof. The method herein may further include treatment with chemotherapeutic agents and / or therapeutic radiation.

[0044] Sepiaapterin Sepiapterin ((S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridine-4(3H)-one) passes into the cell and is converted to 7,8-dihydrobiopterin by sepiapterin reductase. 7,8-dihydrobiopterin is further converted to BH4 via reduction by dihydrofolate reductase.

[0045] Sepiapterin or a pharmaceutically acceptable salt thereof may be incorporated into the pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention contains 20-30% of sepiapterin or a salt thereof by total weight, for example, about 20%, 22%, 25%, 27%, or 30%. In some embodiments, the pharmaceutical composition contains more than 20% of sepiapterin by total weight, for example, more than 25%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90%. In some embodiments, the pharmaceutical composition contains less than 20% of sepiapterin by total weight, for example, less than 20%, less than 15%, less than 10%, or less than 5%.

[0046] In some embodiments, the present invention features a pharmaceutical composition comprising sepiapterin or a pharmaceutically acceptable salt thereof, and an antioxidant in less than 10% by total weight (e.g., about 9%, 7%, 5%, 3%, 1%, 0.5%, 0.25%, 0.1%, or no antioxidant). The antioxidant may be ascorbic acid. In some embodiments, the ratio of sepiapterin or a pharmaceutically acceptable salt thereof to the antioxidant is 1:1 by weight, or greater than 1:1, for example, 2:1, 5:1, 7:1, or 10:1. The pharmaceutical composition may contain sepiapterin or a pharmaceutically acceptable salt thereof in an amount of 20-30% by total weight, for example, about 20%, 22%, 25%, 27%, or 30%. The pharmaceutical composition may further contain a dispersant, for example, crocamerose sodium. The pharmaceutical composition may contain a dispersant in an amount of 0.1 to 1.5% of the total weight, for example, 0.1%, 0.5%, 1%, or 1.5%. In some embodiments, the pharmaceutical composition contains at least one anticaking agent, for example, colloidal silicon dioxide or microcrystalline cellulose. The pharmaceutical composition may contain an anticaking agent in an amount of 65 to 75% of the total weight, for example, about 65%, 67%, 70%, 73%, or 75%. In some embodiments, the pharmaceutical composition contains both colloidal silicon dioxide and microcrystalline cellulose. In some embodiments, the pharmaceutical composition contains 60 to 65% microcrystalline cellulose and 5 to 7% colloidal silicon dioxide by weight. In some embodiments, the crystalline form of sepiapterin is formulated as particles less than 140 μm in size (e.g., about 120 μm, 110 μm, 100 μm, 90 μm, 80 μm, 70 μm, 60 μm, 50 μm, 40 μm, 30 μm, 20 μm, 10 μm, or 5 μm). In some embodiments, the pharmaceutical composition contains impurities such as lactoylpterin in amounts less than 1% of the total weight, e.g., less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, or less than 0.2%.

[0047] In some embodiments, sepiapterin is a salt of sepiapterin, for example, a salt with sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid, tartaric acid (e.g., L-tartaric acid), phosphoric acid, gentisic acid, fumaric acid, glycolic acid, acetic acid, or nicotinic acid.

[0048] In some embodiments, sepiapterin or its pharmaceutically acceptable salts are in crystalline form. The crystalline form of crystalline sepiapterin-free base or salts of sepiapterin may occur as anhydrous (e.g., without any bound water or solvent or hydration or solvation), or as hydrates, partial hydrates (e.g., hemihydrate, sesquihydrate, etc.), dihydrates, trihydrates, etc., where the crystalline form binds the hydration water or solvent molecules associated with the crystalline form of sepiapterin or its salts. In one embodiment, crystalline sepiapterin occurs as a monohydrate or hemihydrate.

[0049] Exemplary salts, cocrystals, and crystalline forms of sepiapterin are described in WO2018 / 102314, WO2018 / 102315, WO2019 / 232120, and WO2019 / 046849. These crystalline forms, salts, and cocrystals are incorporated herein by reference in their entirety.

[0050] In some embodiments, the crystalline form of the free sepiapterin base is crystalline form F of the free sepiapterin base, and is characterized by a powder X-ray diffraction pattern obtained by irradiation with CuKα X-rays having peaks represented by 2θ at 9.7°±0.5, e.g., 9.7°±0.2, 10.2°±0.5, e.g., 10.2°±0.2, and 11.3°±0.5, e.g., 11.3°±0.2. In other embodiments, the sepiapterin crystalline form is characterized by a powder X-ray diffraction pattern obtained by irradiation with CuKα X-rays having peaks represented by 2θ at 9.7°±0.5, e.g., 9.7°±0.2; 10.2°±0.5, e.g., 10.2°±0.2; 11.3°±0.5, e.g., 11.3°±0.2; 14.0°±0.5, e.g., 14.0°±0.2; 14.6°±0.5, e.g., 14.6°±0.2; 19.9°±0.5, e.g., 19.9°±0.2; 22.2°±0.5, e.g., 22.2°±0.2; 25.3°±0.5, e.g., 25.3°±0.2; and 32.4°±0.5, e.g., 32.4°±0.2. In the essentially pure form of this crystal structure, a peak at the refraction angle 2θ may be observed, as shown in Table 1. Alternatively or additionally, this crystal structure is characterized by two DSC curves showing endothermic activity at 71.6°C and 233.4°C.

[0051] [Table 1] In some embodiments, the crystalline form of the free sepiapterin base is crystalline form B of the free sepiapterin base, and has peaks at diffraction angles 2θ(°) of 8.4°±0.5, e.g., 8.4°±0.2, 16.9°±0.5, e.g., 16.9°±0.2, and 25.4°±0.5, e.g., 25.4°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, crystalline form B of the free sepiapterin base has peaks at diffraction angles 2θ(°) of 8.4°±0.5, e.g., 8.4°±0.2, 14.9°±0.5, e.g., 14.9°±0.2, 16.9°±0.5, e.g., 16.9°±0.2, 25.4°±0.5, e.g., 25.4°±0.2, and 34.1°±0.5, e.g., 34.1°±0.2, measured by X-ray diffraction upon irradiation with CuKα X-rays, or calculated from X-ray diffraction. In essentially pure materials of this crystalline form, a peak at the refraction angle 2θ may be observed as shown in Table 2. Alternatively or additionally, this crystalline form is characterized by a DSC curve showing a melting event at 195.2°C.

[0052] [Table 2] In some embodiments, the crystalline form of the free sepiapterin base is the crystalline form C of the free sepiapterin base, which has peaks at diffraction angles 2θ(°) of 5.7°±0.5, e.g., 5.7°±0.2, 7.8°±0.5, e.g., 7.8°±0.2, and 25.4°±0.5, e.g., 25.4°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the crystalline form C of the sepiapterin free base has peaks at diffraction angles 2θ(°) of 5.7°±0.5, e.g., 5.7°±0.2, 7.8°±0.5, e.g., 7.8°±0.2, 9.1°±0.5, e.g., 9.1°±0.2, 11.5°±0.5, e.g., 11.5°±0.2, 15.3°±0.5, e.g., 15.3°±0.2, 16.0°±0.5, e.g., 16.0°±0.2, 20.1°±0.5, e.g., 20.1°±0.2, 25.4°±0.5, e.g., 25.4°±0.2, and 26.6°±0.5, e.g., 26.6°±0.2. In the essentially pure material of this crystal form, a peak at the refraction angle 2θ may be observed, as shown in Table 3. Alternatively or additionally, this crystal form is characterized by a DSC curve showing five endothermic peaks at 58.3°C, 101.8°C, 129.8°C, 156.5°C, and 168.3°C.

[0053] [Table 3] In some embodiments, the crystalline form of the free sepiapterin base is crystalline form D of the free sepiapterin base, and is measured by X-ray diffraction induced by CuKα X-ray irradiation or calculated from X-ray diffraction, having peaks at diffraction angles 2θ(°) of 8.9°±0.5, e.g., 8.9°±0.2, 10.3°±0.5, e.g., 10.3°±0.2, and 26.0°±0.5, e.g., 26.0°±0.2. In some embodiments, the crystalline form D of the free sepiapterin base is measured by X-ray diffraction induced by CuKα X-ray irradiation or calculated from X-ray diffraction, and has peaks at diffraction angles 2θ(°) of 8.9°±0.5, e.g., 8.9°±0.2, 10.3°±0.5, e.g., 10.3°±0.2, 10.9°±0.5, e.g., 10.9°±0.2, 17.8°±0.5, e.g. For example, it has peaks at diffraction angles 2θ(°) of 17.8°±0.2, 24.9°±0.5, 24.9°±0.2, 26.0°±0.5, 26.0°±0.2, 26.7°±0.5, 26.7°±0.2, 26.8°±0.5, 26.8°±0.2, and 28.3°±0.5, for example, 28.3°±0.2. In essentially pure materials of this crystalline form, peaks at refraction angles 2θ may be observed as shown in Table 4. Alternatively or additionally, this crystalline form is characterized by three endothermic DSC curves at 42.7°C, 66.3°C, and 232.9°C.

[0054] [Table 4] In some embodiments, the crystalline form of the free sepiapterin base is crystalline form A of the free sepiapterin base, and has peaks at diffraction angles 2θ(°) of 4.7°±0.5, e.g., 4.7°±0.2, 7.4°±0.5, e.g., 7.4°±0.2, and 26.2°±0.5, e.g., 26.2°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, crystalline form A of the free sepiapterin base has peaks at diffraction angles 2θ(°) of 4.7°±0.5, e.g., 4.7°±0.2, 7.4°±0.5, e.g., 7.4°±0.2, 9.5°±0.5, e.g., 9.5°±0.2, 11.3°±0.5, e.g., 11.3°±0.2, 15.6°±0.5, e.g., 15.6°±0.2, 16.4°±0.5, e.g., 16.4°±0.2, 26.2°±0.5, e.g., 26.2°±0.2, and 27.2°±0.5, e.g., 27.2°±0.2, as measured by X-ray diffraction induced by CuKα X-ray irradiation or calculated from X-ray diffraction. In essentially pure materials of this crystalline form, peaks at refraction angles 2θ may be observed as shown in Table 5. Alternatively or additionally, this crystal form is characterized by DSC curves showing endothermic peaks at 82.8°C and 179.8°C.

[0055] [Table 5] In some embodiments, the crystalline form of the free sepiapterin base is crystalline form E of the free sepiapterin base, and has peaks at diffraction angles 2θ(°) of 6.0°±0.5, 6.0°±0.2, 10.6°±0.5, 10.6°±0.2, 12.1°±0.5, e.g., 12.1°±0.2, 15.9°±0.5, e.g., 15.9°±0.2, 20.9°±0.5, e.g., 20.9°±0.2, and 24.6°±0.5, e.g., 24.6°±0.2. In some embodiments, the crystalline form E of the free sepiapterin base is measured by X-ray diffraction induced by CuKα X-ray irradiation, or calculated from X-ray diffraction, e.g., 6.0°±0.5, e.g., 6.0°±0.2, 10.6°±0.5, e.g., 10.6°±0.2, 12.1°±0.5, e.g., 12.1°±0.2, 15.9°±0.5, e.g., 15.9°±0.2, 18.1°±0.5, e.g., 18.1°±0.2, 20.9°±0.5, e.g. For example, it has peaks at diffraction angles 2θ(°) at 20.9°±0.2, 22.1°±0.5, 22.1°±0.2, 24.6°±0.5, 24.6°±0.2, 26.1°±0.5, 26.1°±0.2, 28.1°±0.5, 28.1°±0.2, 28.9°±0.5, 28.9°±0.2, 32.1°±0.5, 32.1°±0.2, and 37.0°±0.5, for example, 37.0°±0.2. In the essentially pure form of this crystal, a peak at the refraction angle 2θ may be observed as shown in Table 6. Alternatively or additionally, this crystal form is characterized by a DSC curve showing two endothermic peaks at 112.9°C and 195.8°C.

[0056] [Table 6] In some embodiments, the crystalline form of the free sepiapterin base is crystalline form G of the free sepiapterin base, and has peaks at diffraction angles 2θ(°) of 10.0°±0.5, e.g., 10.0°±0.2, 10.6°±0.5, e.g., 10.6°±0.2, and 25.7°±0.5, e.g., 25.7°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the crystalline form G of the free sepiapterin base is measured by X-ray diffraction induced by CuKα X-ray irradiation, or calculated from X-ray diffraction, such as 10.0°±0.5, e.g., 10.0°±0.2; 10.6°±0.5, e.g., 10.6°±0.2; 11.2°±0.5, e.g., 11.2°±0.2; and 15.3°±0.5, e.g., 15.3°±0. It has peaks at diffraction angles 2θ(°) of 2, 15.9°±0.5, e.g., 15.9°±0.2, 22.8°±0.5, e.g., 22.8°±0.2, 24.4°±0.5, e.g., 24.4°±0.2, 25.0°±0.5, e.g., 25.0°±0.2, 25.7°±0.5, e.g., 25.7°±0.2, and 26.6°±0.5, e.g., 26.6°±0.2. In essentially pure materials of this crystal form, peaks at refractive angles 2θ may be observed as shown in Table 7.

[0057] [Table 7] In some embodiments, the crystalline form of sepiapterin hydrochloride has peaks at diffraction angles 2θ(°) of 7.8°±0.5, e.g., 7.8°±0.2, 12.9°±0.5, e.g., 12.9°±0.2, and 26.2°±0.5, e.g., 26.2°±0.2, measured by X-ray diffraction induced by CuKα X-ray irradiation, or calculated from X-ray diffraction. In some embodiments, the strongest peak in the X-ray diffraction pattern of the crystalline form of sepiapterin hydrochloride is observed at a refractive angle 2θ of 7.8°±0.5, e.g., 7.8°±0.2. The essentially pure material of this crystalline sepiapterin hydrochloride may show a peak at refractive angle 2θ as shown in Table 8. Alternatively or additionally, the crystalline sepiapterin hydrochloride is characterized by a DSC curve that exhibits endothermic effects at 225.9°C.

[0058] [Table 8] In some embodiments, crystalline form 1 of the methanesulfonate of sepiapterin has peaks at refraction angles 2θ(°) of 7.8°±0.5, e.g., 7.8°±0.5, e.g., 7.8°±0.2, 23.5°±0.5, e.g., 23.5°±0.2, and 29.0°±0.5, e.g., 29.0°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 23.5°±0.5, e.g., 23.5°±0.2. In essentially pure materials of crystalline form 1 methanesulfonate of sepiapterin, a peak at refraction angle 2θ may be observed as shown in Table 9. Alternatively or additionally, the crystalline form 1-methanesulfonate of sepiapterin is characterized by two endothermic DSC curves at 186.0°C and 229.1°C.

[0059] [Table 9] In some embodiments, crystalline form 2 of the methanesulfonate of sepiapterin has peaks at refraction angles 2θ(°) of 7.8°±0.5, e.g., 7.9°±0.5, e.g., 7.9°±0.2, 23.4°±0.5, e.g., 23.4°±0.2, and 28.9°±0.5, e.g., 28.9°±0.2, as measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 7.9°±0.5, e.g., 7.9°±0.2. In essentially pure materials of crystalline form 2 methanesulfonate of sepiapterin, a peak at a refraction angle 2θ may be observed as shown in Table 10. Alternatively or additionally, the crystalline form 2-methanesulfonate of sepiapterin is characterized by three endothermic DSC curves at 75.5°C, 182.6°C, and 234.9°C.

[0060] [Table 10] In some embodiments, crystalline form 3 of the methanesulfonate of sepiapterin has peaks at refraction angles 2θ(°) of 7.8°±0.5, e.g., 21.7°±0.5, e.g., 21.7°±0.2, 26.0°±0.5, e.g., 26.0°±0.2, and 28.9°±0.5, e.g., 28.9°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 26.1°±0.5, e.g., 26.1°±0.2. In essentially pure materials of crystalline form 3 methanesulfonate of sepiapterin, a peak at a refraction angle 2θ may be observed as shown in Table 11. Alternatively or additionally, the crystalline form 3-methanesulfonate of sepiapterin is characterized by two endothermic DSC curves at 195.1°C and 240.1°C.

[0061] [Table 11] In some embodiments, crystalline sepiapterin nicotinates have peaks at refraction angles 2θ(°) of 9.5°±0.5, e.g., 9.5°±0.2, 9.9°±0.5, e.g., 9.9°±0.2, and 24.5°±0.5, e.g., 24.5°±0.2, measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at refraction angle 2θ of 24.5°±0.5, e.g., 24.5°±0.2. In essentially pure materials of crystalline sepiapterin nicotinates, a peak at refraction angle 2θ may be observed as shown in Table 12. Alternatively or additionally, crystalline sepiapterin nicotinates are characterized by a DSC curve that exhibits endothermic properties at 221.9°C.

[0062] [Table 12] In some embodiments, crystalline p-toluenesulfonate of sepiapterin has peaks at refraction angles 2θ(°) of 6.5°±0.5, e.g., 6.5°±0.2, 15.1°±0.5, e.g., 15.1°±0.2, and 23.4°±0.5, e.g., 23.4°±0.2, as measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 6.5°±0.5, e.g., 6.5°±0.2. In essentially pure materials of p-toluenesulfonate of sepiapterin, a peak at a refraction angle 2θ may be observed as shown in Table 13. Alternatively or additionally, the crystalline p-toluenesulfonate of sepiapterin is characterized by three endothermic DSC curves at 77.2°C, 202.4°C, and 260.2°C.

[0063] [Table 13] In some embodiments, crystalline sepiapterin benzenesulfonates have peaks at refraction angles 2θ(°) of 6.5°±0.5, e.g., 6.5°±0.2, 14.8°±0.5, e.g., 14.8°±0.2, and 19.6°±0.5, e.g., 19.6°±0.2, as measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 6.5°±0.5, e.g., 6.5°±0.2. In essentially pure materials of sepiapterin benzenesulfonates, a peak at refraction angle 2θ may be observed as shown in Table 14. Alternatively or additionally, crystalline sepiapterin benzenesulfonates are characterized by DSC curves showing two endothermic peaks at 202.3°C and 265.5°C.

[0064] [Table 14] In some embodiments, crystalline sepiapterin phosphates have peaks at refraction angles 2θ(°) of 16.6°±0.5, e.g., 16.6°±0.2, 22.2°±0.5, e.g., 22.2°±0.2, and 25.6°±0.5, e.g., 25.6°±0.2, as measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 25.6°±0.5, e.g., 25.6°±0.2. In essentially pure materials of crystalline sepiapterin phosphate, a peak at refraction angle 2θ may be observed as shown in Table 15. Alternatively or additionally, the crystalline phosphate of sepiapterin is characterized by three endothermic DSC curves at 125.9°C, 152.1°C, and 157.6°C.

[0065] [Table 15] In some embodiments, crystalline sepiapterin malonates have peaks at refraction angles 2θ(°) of 6.9°±0.5, e.g., 6.9°±0.2, 22.7°±0.5, e.g., 22.7°±0.2, and 23.8°±0.5, e.g., 23.8°±0.2, measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 6.9°±0.5, e.g., 6.9°±0.2. In essentially pure materials of crystalline sepiapterin malonates, a peak at refraction angle 2θ may be observed as shown in Table 16. Alternatively or additionally, crystalline sepiapterin malonates are characterized by a DSC curve showing a melting event at 115.8°C.

[0066] [Table 16] In some embodiments, the crystalline L-tartrate of sepiapterin has peaks at refraction angles 2θ(°) of 7.4°±0.5, e.g., 7.4°±0.2, 14.2°±0.5, e.g., 14.2°±0.2, and 21.8°±0.5, e.g., 21.8°±0.2, measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 7.4°±0.5, e.g., 7.4°±0.2. In essentially pure materials of crystalline L-tartrate of sepiapterin, a peak at refraction angle 2θ may be observed as shown in Table 17. Alternatively or additionally, crystalline L-tartrate of sepiapterin is characterized by DSC curves showing two endothermic values ​​at 97.2°C and 160.6°C.

[0067] [Table 17] In some embodiments, crystalline sepiapterin gentisic acid has peaks at refraction angles 2θ(°) of 7.1°±0.5, e.g., 7.1°±0.2, 8.7°±0.5, e.g., 8.7°±0.2, and 26.7°±0.5, e.g., 26.7°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 7.1°±0.5, e.g., 7.1°±0.2. In essentially pure materials of crystalline sepiapterin gentisic acid, a peak at refraction angle 2θ may be observed as shown in Table 18. Alternatively or additionally, the crystalline gentisic acid salt of sepiapterin is characterized by three endothermic DSC curves at 70.5°C, 128.2°C, and 184.7°C.

[0068] [Table 18] In some embodiments, crystalline sepiapterin fumarate has peaks at refraction angles 2θ(°) of 11.4°±0.5, e.g., 11.4°±0.2, 24.0°±0.5, e.g., 24.0°±0.2, and 28.2°±0.5, e.g., 28.2°±0.2, measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of at least 24.0°±0.5, e.g., 24.0°±0.2. In essentially pure materials of crystalline sepiapterin fumarate, a peak may be observed at a refraction angle 2θ as shown in Table 19. Alternatively or additionally, crystalline sepiapterin fumarate can be characterized by DSC curves showing two endothermic values ​​at 114.3°C and 229.7°C.

[0069] [Table 19] In some embodiments, crystalline sepiapterin glycolate has peaks at refraction angles 2θ(°) of 7.6°±0.5, e.g., 7.6°±0.2, 10.7°±0.5, e.g., 10.7°±0.2, and 24.0°±0.5, e.g., 24.0°±0.2, measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at refraction angle 2θ of 7.6°±0.5, e.g., 7.6°±0.2. In essentially pure materials of crystalline sepiapterin glycolate, a peak at refraction angle 2θ may be observed as shown in Table 20. Alternatively or additionally, crystalline sepiapterin glycolate is characterized by DSC curves showing two endothermic peaks at 133.9°C and 147.7°C.

[0070] [Table 20] In some embodiments, crystalline sepiapterin acetate has peaks at refraction angles 2θ(°) of 6.2°±0.5, e.g., 6.2°±0.2, 12.0°±0.5, e.g., 12.0°±0.2, and 18.1°±0.5, e.g., 18.1°±0.2, measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of at least 6.2°±0.5, e.g., 6.2°±0.2. In the essentially pure material of crystalline sepiapterin acetate, a peak may be observed at a refraction angle 2θ as shown in Table 21. Alternatively or additionally, crystalline sepiapterin acetate is characterized by DSC curves showing two endothermic peaks at 146.1°C and 175.4°C.

[0071] [Table 21] In some embodiments, crystalline form 1 of sepiapterin sulfate has peaks at refraction angles 2θ(°) of 5.1°±0.5, e.g., 5.1°±0.2, 7.8°±0.5, e.g., 7.8°±0.2, and 23.0°±0.5, e.g., 23.0°±0.2, as measured by or calculated from X-ray diffraction induced by CuKα X-ray irradiation. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at refraction angle 2θ of 5.1°±0.5, e.g., 5.1°±0.2. In essentially pure material of crystalline form 1 sulfate of sepiapterin, a peak at refraction angle 2θ may be observed as shown in Table 22. Alternatively or additionally, crystalline form 1 sulfate of sepiapterin is characterized by three DSC curves showing endothermic reactions at 94.5°C, 158.3°C, and 209.9°C.

[0072] [Table 22] In some embodiments, crystalline form 2 of sepiapterin sulfate has peaks at refraction angles 2θ(°) of 7.8°±0.5, e.g., 7.8°±0.2, 8.8°±0.5, e.g., 8.8°±0.2, and 24.1°±0.5, e.g., 24.1°±0.2, as measured by or calculated from X-ray diffraction irradiated with CuKα X-rays. In some embodiments, the strongest peak in the X-ray diffraction pattern is observed at a refraction angle 2θ of 8.8°±0.5, e.g., 8.8°±0.2. In essentially pure materials of crystalline form 2 sulfate of sepiapterin, a peak at a refraction angle 2θ may be observed as shown in Table 23.

[0073] [Table 23] The present invention may employ a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof. Examples of pharmaceutical compositions of sepiapterin and its salts can be found in WO2019 / 046849 and WO2019 / 232120, and such compositions are incorporated herein by reference in their entirety.

[0074] Pharmaceutically acceptable excipients may be any of those conventionally used, and are limited only by physicochemical considerations such as solubility and route of administration. Those skilled in the art will understand that, in addition to the pharmaceutical compositions described below, sepiapterin can be formulated as inclusion complexes such as cyclodextrin inclusion complexes, or as liposomes.

[0075] The pharmaceutically acceptable excipients described herein, such as vehicles, adjuvants, excipients, or diluents, are well known to those skilled in the art and readily available. Preferably, the pharmaceutically acceptable excipients are chemically inert to sepiapterin and do not have adverse side effects or toxicity under the conditions of use.

[0076] Preparations that increase gastric and / or foregut retention time Gastric-retaining drug delivery is an approach designed to keep drug formulations in the stomach longer until drug release is complete.

[0077] Bioadhesive formulations utilize polymers that can adhere to surfaces and provide controlled release of the drug. The bioadhesive polymer may be anionic (e.g., carboxymethylcellulose, alginic acid, polyacrylic acid, pectin, carrageenan, polycarbophil, or carbomer), cationic (e.g., chitosan, polylysine, or polyblen), or nonionic (e.g., polyethylene glycol, polyvinylpyrrolidone, dextran, or hydroxypropyl methylcellulose).

[0078] High-density formulations are designed to be present in the stomach at a level lower than the pyloric sphincter, thus avoiding emptying the stomach. Suitable excipients for high-density formulations include iron powder, barium sulfate, zinc oxide, and titanium dioxide.

[0079] Bulk-forming formulations are designed to expand in the stomach to become larger than the pyloric sphincter, thus helping to avoid hunger. For example, formulations containing a drug core, a swellable hydrocolloid, and an outer semipermeable polymer are suitable for bulk-forming formulations.

[0080] Hyperporous hydrogel formulations, like bulk-forming formulations, are designed to expand beyond the pyloric sphincter in the stomach. Hyperporous hydrogel formulations may contain polymers such as croscarmellose sodium.

[0081] Floating formulations are designed to have a density lower than that of gastric juice. Floating formulations may include compositions comprising ion exchange resins, raft systems, inflatable chambers, effervescent mixtures, swellable hydrocolloids, or multi-particle systems.

[0082] Antioxidants Sepiapterin tends to oxidize rapidly when exposed to air. Therefore, the pharmaceutical composition of the present invention may contain antioxidants. The antioxidants may minimize the oxidative degradation of sepiapterin. Examples of antioxidants, but not limited to, include 4-chloro-2,6-di-tert-butylphenol, tocopherol, α-tocopherol, alkylated diphenylamine, ascorbic acid, ascorbyl myristate, ascorbyl palmitate, ascorbyl stearate, β-carotene, butylhydroxyanisole, butylhydroxytoluene, citric acid, cysteine, D-α-tocopheryl polyethylene glycol 1000 succinate, deferoxamine methanesulfonate, dodecyl gallate, ethylenediaminetetraacetic acid, ethylparaben, folic acid, fumaric acid, gallic acid, glutathione, lecithin, malic acid, This includes methylparaben, monothioglycerol, N-acetylcysteine, nordihydroguaiaretinic acid, octyl gallate, p-phenylenediamine, potassium ascorbate, potassium metabisulfite, potassium sorbate, propionic acid, propyl gallate, retinol, sorbic acid, sodium ascorbate, sodium bisulfite, sodium hydrosulfite, sodium isoascorbate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, tartaric acid, tert-butylhydroquinone, thiourea, tocopherol acetate, vitamin A, vitamin B6, vitamin B12, or vitamin E. Examples of antioxidants, but not limited to, include ascorbic acid, tocopherol, retinol, ascorbyl palmitate, N-acetylcysteine, glutathione, ethylenediaminetetraacetic acid, sodium bisulfite, sodium metabisulfite, thiourea, butylated hydroxytoluene, butylated hydroxyanisole, and vitamin E. Examples of antioxidants include, but are not limited to, ascorbic acid, tocopherol, retinol, ascorbyl palmitate, N-acetylcysteine, glutathione, ethylenediaminetetraacetic acid, sodium bisulfite, sodium metabisulfite, thiourea, butylated hydroxytoluene, butylated hydroxyanisole, and vitamin E.In some embodiments, the pharmaceutical composition of the present invention comprises ascorbic acid, tocopherol, retinol, ascorbyl palmitate, N-acetylcysteine, glutathione, butylated hydroxytoluene, and / or butylated hydroxyanisole as antioxidants.

[0083] In some embodiments, the pharmaceutical composition contains less than 10% by weight of the antioxidant, for example, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or substantially no antioxidant. In some embodiments, the pharmaceutical composition contains 2 to 9% of the antioxidant by weight, for example, 2 to 4%, 3 to 5%, 4 to 6%, 5 to 7%, 6 to 8%, or 7 to 9%. In some embodiments, the pharmaceutical composition contains 5 to 100% of the USP maximum daily dose of the antioxidant, for example, in some embodiments, the pharmaceutical composition contains about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the USP maximum daily dose of the antioxidant. In some embodiments, the ratio of sepiapterin to antioxidant is at least 1:1 by weight, for example, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1.

[0084] Dispersant In some embodiments, the pharmaceutical composition of the present invention comprises at least one dispersant. The dispersant may separate particles in the formulation and, for example, release its active ingredient upon contact with water. Examples of dispersants include, but are not limited to, cross-linked polyvinylpyrrolidone, carboxymethylcellulose (e.g., croscarmellose salt, e.g., croscarmellose sodium), starch (e.g., sodium starch glycolate), or alginic acid. In some embodiments, the dispersant in the pharmaceutical composition is carboxymethylcellulose, such as a pharmaceutically acceptable salt of croscarmellose. In some embodiments, the pharmaceutical composition may contain 0.1 to 1.5% (e.g., about 0.1%, 0.5%, 1%, or 1.5%) of the dispersant based on the total weight. In some embodiments, the pharmaceutical composition may contain less than 1.5% (e.g., less than 1%, less than 0.5%, or less than 0.1%) of the dispersant based on the total weight.

[0085] Anti-caking agent In some embodiments, the pharmaceutical composition of the present invention comprises at least one anticaking agent. In some embodiments, the pharmaceutical composition of the present invention comprises at least two anticaking agents. Exemplary anticaking agents include colloidal silicon dioxide, microcrystalline cellulose, tricalcium phosphate, microcrystalline cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, colloidal silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, and polydimethylsiloxane. In some embodiments, at least one anticaking agent is colloidal silicon dioxide or microcrystalline cellulose. In some embodiments, the pharmaceutical composition may contain 65-75% (e.g., about 65%, 67%, 70%, 73%, or 75%) of the anticaking agent based on the total weight. In some embodiments, the pharmaceutical composition contains both colloidal silicon dioxide and microcrystalline cellulose. In some embodiments, the pharmaceutical composition contains 60-65% microcrystalline cellulose and 5-7% colloidal silicon dioxide by weight.

[0086] Administration vehicle In some embodiments, the pharmaceutical composition of the present invention is combined with an administration vehicle before administration (e.g., an administration vehicle having a viscosity of about 50 to 1750 centipoise (cP)). One type of suspension that can be used is a combination of glycerin and sucrose in water (e.g., MEDISCA containing 2.5% glycerin and 27% sucrose in water). (R) (Oral mix). An appropriate amount of the composition can be added to the administration vehicle mixture and stirred to suspend the composition immediately before administration.

[0087] Other suspensions may also be used as administration vehicles. Exemplary suspensions include water, agar, alginic acid, sodium carboxymethylcellulose, carrageenan, dextrin, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypermellose, methylcellulose, polyethylene glycol, povidone, tragacanth, xanthan gum, or other suspensions known in the art.

[0088] dose Sepiapterin or its pharmaceutically acceptable salts can be used in any appropriate dose. Appropriate doses and dose regimens can be determined within the scope of the prior art. Generally, treatment is initiated with a dose lower than the optimal dose. The dose is then gradually increased until the optimal effect is achieved under the circumstances. For convenience, the total daily dose can be divided and administered throughout the day if desired. With appropriate doses and appropriate administration of specific compounds, the present invention provides a wide range of responses. Typically, doses range from about 1 to about 150 mg / kg or about 2.5 to about 150 mg / kg body weight / day (e.g., 60 mg / kg / day) to the subject being treated. For example, in the embodiment, sepiapterin, or a pharmaceutically acceptable salt thereof, can be administered once or more times a day at doses of approximately 10 mg / kg to approximately 150 mg / kg, approximately 20 mg / kg to approximately 150 mg / kg, approximately 10 mg / kg to approximately 60 mg / kg, approximately 20 mg / kg to approximately 60 mg / kg, approximately 40 mg / kg to approximately 100 mg / kg, approximately 100 mg / kg to approximately 150 mg / kg, approximately 60 mg / kg to approximately 120 mg / kg, approximately 80 mg / kg to approximately 100 mg / kg, approximately 40 mg / kg to approximately 60 mg / kg, approximately 2.5 mg / kg to approximately 20 mg / kg, approximately 2.5 mg / kg to approximately 10 mg / kg, or approximately 2.5 mg / kg to approximately 5 mg / kg of target body weight / day, in order to obtain the desired therapeutic effect.

[0089] In some embodiments, sepiapterin or a pharmaceutically acceptable salt thereof can be formulated as a unit solid oral dosage form, such as particles. In these embodiments, each unit solid oral dosage form, for example, a sachet, may contain any appropriate amount of sepiapterin or a pharmaceutically acceptable salt thereof. For example, each solid oral formulation may contain approximately 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 750 mg, 1 g, 1.25 g, or 1.5 g.

[0090] Sepiapterin or a pharmaceutically acceptable salt thereof can be used to prepare liquid formulations such as solutions, suspensions, or emulsions. Formulations suitable for oral administration include, but are not limited to, (a) solid or granular formulations, each containing a predetermined amount of the active ingredient, such as capsules, sachets, tablets, lozenges, and troches; (b) powders; (c) liquid formulations such as an effective amount of the compound dissolved in a diluent such as water, saline, or orange juice; (d) suspensions in a suitable liquid; and (e) suitable emulsions. Preferably, solid oral formulations are available, such as capsules, tablets, and powders. Capsules may be of the usual hard or soft shell-like gelatin type, containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. The tablet form may contain lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and one or more other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings, and pharmacologically suitable excipients. The lozenge form may contain the active ingredient in addition to a flavor (usually sucrose and acacia or tragacanth), and similarly, pastilles may contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia, emulsion, or gel, and such excipients are known in the art.

[0091] Formulations suitable for oral and / or parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostags, and solutes and suspensions that make the formulation isotonic with the recipient's blood, as well as aqueous and non-aqueous sterile suspensions, solubilizers, thickeners, stabilizers, and preservatives. The compounds of the present invention can be administered in a physiologically acceptable diluent in a sterile liquid or mixture of liquids containing pharmaceutical excipients, such as water, physiological saline, glucose aqueous solution and related sugar solutions, alcohols such as ethanol, benzyl alcohol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol and polyethylene alcohol, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of pharmaceutically acceptable surfactants such as soap or detergent, suspending agents such as pectin, carbohydrates, methylcellulose, hydroxypropyl methylcellulose, or carboxymethylcellulose, or emulsifiers, and other pharmaceutical adjuvants.

[0092] The present invention features pharmaceutical compositions of orally acceptable formulations comprising a therapeutically effective amount of sepiapterin and less than 10% of an antioxidant. In some embodiments, the pharmaceutical composition is a granular formulation dispersed in a pharmaceutically acceptable excipient, for example, the composition can be mixed with water and ingested by a subject (e.g., within 5 to 10 minutes). Preferred formulations for use in the present invention are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA 22nd ed., 2010. Unless any conventional excipient is incompatible with the active ingredient, its use in the pharmaceutical compositions of the present invention is intended. Furthermore, for animal (e.g., human) administration, it will be understood that the formulation should meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA Office's biological standards.

[0093] Oral solid dosage form Formulations for oral use comprise particles containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients, and such formulations are known to those skilled in the art (e.g., US Patent Nos.: 5,817,307, 5,824,300, 5,830,456, 5,846,526, 5,882,640, 5,910,304, 6,036,949, 6,036,949, 6,372,218, which are incorporated herein by reference). Excipients include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch containing potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate), granulating and disintegrating agents (e.g., cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginates, or alginic acid), binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pre-gelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyropropylcellulose) The excipients may be lydone (or polyethylene glycol), lubricants, anti-adhesion agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc), and anticaking agents (e.g., colloidal silicon dioxide, microcrystalline cellulose, tricalcium phosphate, microcrystalline cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, colloidal silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, or polydimethylsiloxane). Other pharmaceutically acceptable excipients may be colorants, fragrances, plasticizers, humectants, and buffers. In some embodiments, the excipients (e.g., fragrances) are packaged together with the composition.In some embodiments, excipients (e.g., fragrances) are packaged separately from the composition (e.g., combined with the composition before administration).

[0094] The solid composition of the present invention may include a coating adapted to protect the composition from undesirable chemical changes (e.g., chemical decomposition before the release of the active substance). The coating may be applied to the solid dosage form in a manner similar to that described in the Encyclopedia of Pharmaceutical Technology above.

[0095] Using the above components, powders and granules may be prepared by conventional methods, for example, using a mixer, fluidized bed apparatus, melt-solidification apparatus, rotor granulator, extrusion / spheroidization apparatus, or spray drying apparatus.

[0096] Treatment method Sepiapterin or its pharmaceutically acceptable salts function as useful therapeutic agents for the treatment of glioblastoma. In some embodiments of any of the methods described herein, the method further comprises therapeutic radiotherapy. In some embodiments of any of the methods described herein, the method further comprises the administration of a chemotherapeutic agent (e.g., temozolomide). Accordingly, various forms of sepiapterin or its pharmaceutically acceptable salts according to the present invention can be administered to a subject in an effective amount to obtain treatment or improvement of a disease, disorder or condition.

[0097] In some embodiments of any method described herein, the method further includes therapeutic radiation. In some embodiments of any method described herein, the radiation dose irradiated during a therapeutic cycle may be at least about 1 Gy, at least about 2 Gy, at least about 5 Gy, at least about 10 Gy, at least about 20 Gy, at least about 30 Gy, at least about 40 Gy, at least about 50 Gy, at least about 60 Gy, at least about 70 Gy, at least about 80 Gy, at least about 90 Gy, at least about 100 Gy, at least about 150 Gy, at least about 200 Gy, at least about 300 Gy, at least about 400 Gy, or at least about 500 Gy. In various embodiments, the radiation dose for each therapeutic cycle is divided into multiple divisions, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 or more divisions. In various embodiments, the treatment cycle may be at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or at least about 10 weeks. In various embodiments, one or more treatment cycles (e.g., 2, 3, 4, 5 or more treatment cycles) may be performed.

[0098] In some embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered prior to therapeutic radiation. In some embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered at least 1, 2, 3, 4, 5, 6, 7, 10 days or more prior to therapeutic radiation.

[0099] In some embodiments of any method described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered before therapeutic radiation. In some embodiments of any method described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered at least 1, 2, 3, 4, 5, 6, 7, 10, 20, 30, 60, 90, 120, 150, 180, 210, 300 or more days after therapeutic radiation.

[0100] In some embodiments of any of the methods described herein, the method further comprises administering a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents are temozolomide (TMZ). In various embodiments, the dosage of TMZ, measured by the body surface area of the subject, is about 1 to about 1000 mg / m per day 2 is. In various embodiments, the dosage of TMZ is about 1 to about 500 mg / m per day 2 , about 1 to about 250 mg / m per day 2 , about 1 to about 100 mg / m per day 2 , about 10 to about 500 mg / m per day 2 , about 50 to about 250 mg / m per day 2 , or about 50 to about 100 mg / m per day 2 is. The chemotherapeutic agent (e.g., TMZ) can be administered for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks. In various embodiments, the chemotherapeutic agent (e.g., TMZ) can be administered before, simultaneously with, and / or after the administration of sepiapterin or a pharmaceutically acceptable salt thereof. In various embodiments, the chemotherapeutic agent (e.g., TMZ) is administered before, simultaneously with, and / or after the administration of therapeutic radiation. Further, the chemotherapeutic agent (e.g., TMZ) can be administered in a maintenance cycle. The chemotherapeutic agent (e.g., TMZ) is administered for at least 1 day during, for example, a 28-day treatment cycle, and for at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 days during, for example, a 28-day maintenance treatment cycle.

[0101] Sepiapterin or a pharmaceutically acceptable salt thereof may be administered to a subject before, during, and / or after the administration of therapeutic radiotherapy and / or chemotherapeutic agents. In various embodiments of any of the methods described herein, separatepapterin or a pharmaceutically acceptable salt thereof is administered for at least 1, 2, 3, 5, 6, 10, 14, 21, 28, or 30 days prior to the initiation of radiotherapy. In various embodiments of any of the methods described herein, separatepapterin or a pharmaceutically acceptable salt thereof is administered continuously (e.g., daily) throughout radiotherapy. In various embodiments of any of the methods described herein, separatepapterin or a pharmaceutically acceptable salt thereof is administered for at least 1, 2, 3, 5, 6, 10, 14, 21, 28, 30, 60, 90, 120, 150, 180, 210, 240 days or longer after radiotherapy. In various embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 1, 2, 3, 5, 6, 10, 14, 21, 28, or 30 days prior to the initiation of chemotherapy treatment (e.g., TMZ treatment). In various embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered continuously (e.g., daily) throughout chemotherapy treatment (e.g., TMZ treatment). In various embodiments of any of the methods described herein, sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 1, 2, 3, 5, 6, 10, 14, 21, 28, 30, 60, 90, 120, 150, 180, 210, 240 days or longer after chemotherapy treatment (e.g., TMZ treatment).

[0102] In some embodiments of any of the methods described herein, the treatment schedule for a subject is as follows: (1) an induction period of sepiapterin or a pharmaceutically acceptable salt thereof alone (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or more; sepiapterin or a pharmaceutically acceptable salt thereof alone); (2) a radiotherapy period of sepiapterin or a pharmaceutically acceptable salt thereof + chemotherapeutic agent (e.g., TMZ) + radiotherapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more); (3) a "discontinuation" period of chemotherapy (e.g., sepiapterin (4) A maintenance period comprising one or more 28-day cycles (e.g., 2, 3, 4, 5, 6, 7, 8 or more cycles) (wherein sepiapterin or a pharmaceutically acceptable salt thereof is administered continuously throughout the cycle, while a chemotherapeutic agent (e.g., TMZ) is administered only for the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days of each 28-day cycle.

[0103] In some embodiments, the subjects are children (for example, under 18, under 17, under 16, under 15, under 14, under 13, under 12, under 11, under 10, under 9, under 8, under 7, under 6, under 5, under 4, under 3, under 2, under 1). In some embodiments, the subjects are adults (for example, over 18). In some embodiments, the subjects are at least 20, 20, 30, 40, 50, 60, 70, or 80 years old.

[0104] Sepiapterin or its pharmaceutically acceptable salts may or may not be administered with food. While not theoretically bound, administration of separatepitterin with food increases plasma exposure of BH4 (for example, by reducing the absorption rate of separatepitterin). If administered separatepitterin is rapidly absorbed, for example, by administration on an empty stomach, intracellular separatepitterin reductase and / or dihydrofolate reductase will increase V maxIt is possible that saturation exceeds a certain limit, resulting in at least a portion of the administered sepiapterin being excreted without being reduced to 7,8-dihydrobiopterin followed by BH4. This excess sepiapterin is then excreted without being converted to BH4, which may reduce or prolong the absorption rate of sepiapterin and result in lower plasma BH4 levels compared to when sepiapterin is administered with food, which results in reaction rates below, at or slightly above, the substrate saturation Vmax of sepiapten reductase and / or dihydrofolate reductase. Administration of sepiapterin or its pharmaceutically acceptable salts with food may unexpectedly result in lower maximum BH4 plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of BH4 from time zero to final concentration compared to administration without food. 0-lastThis results in an increased level of exposure as measured by [method / method]. For example, the effective dose of sepiapterin or a pharmaceutically acceptable salt thereof is 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, or 50 ng / ml to 100 ng / ml, 60 ng / ml to 400 ng / ml, 200 ng / ml to 600 ng / ml, 400 ng / ml to 1000 ng / ml, or 600 ng / ml to 1500 ng / ml) in the subject's plasma within 10 hours of administration with food (e.g., 1.0 mg / kg to 100 mg / kg or 2.5 mg / kg to 100 mg / kg per single dose). The effective dose may include a dose at least 5% lower (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, or 50 ng / ml to 100 ng / ml, 60 ng / ml to 400 ng / ml, 200 ng / ml to 600 ng / ml, 400 ng / ml to 1000 ng / ml, or 600 ng / ml to 1500 ng / ml) than the dose sufficient to produce a maximum BH4 plasma concentration (Cmax) of at least 50 ng / ml in the subject's plasma within 10 hours of administration of sepiapterin or a pharmaceutically acceptable salt thereof without food.

[0105] In some embodiments of any of the methods described herein, the food is a high-protein food. In some embodiments of any of the methods described herein, the food is a high-fat food (e.g., at least 25, 30, 40, or 50% of the calories are from fat). In some embodiments of any of the methods described herein, the food is a high-protein and high-fat food. In some embodiments, the food is a high-calorie food (e.g., the food contains at least 100 calories, e.g., at least 200 calories, at least 300 calories, at least 400 calories, at least 500 calories, e.g., 500-1500 or 800-1000 calories). In some embodiments of any of the methods described herein, the food is a meal, e.g., breakfast, lunch, or dinner. Sepiapterin or a pharmaceutically acceptable salt thereof may be provided in a composition separate from the ingested food (e.g., separate pterin or a pharmaceutically acceptable salt thereof is not incorporated into the food product). In some embodiments of any of the methods described herein, the food is a low-fat food.

[0106] The drug may be administered to the subject less than 30 minutes before food intake, or after food intake, for example, from immediately before food intake to 1 hour after, or substantially simultaneously with food intake. Administration with food (for example, less than 30 minutes before food intake, or after food intake, for example, from immediately before food intake to 1 hour after) results in a higher Cmax of BH4 or the degree of BH4 production and the resulting plasma exposure (AUC) compared to administration without food (for example, more than 2 hours after food intake, and up to 30 minutes before food intake). 0-last This could result in an increase (for example, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%).

[0107] Sepiapterin or a pharmaceutically acceptable salt thereof may be administered to a subject without food, for example, at least 30 minutes before food intake or at least 2 hours after food intake. In some embodiments of any of the methods described herein, administration is performed at least 30 minutes before food intake or at least 3 hours after food intake. In some embodiments of any of the above methods, separatepapterin or a pharmaceutically acceptable salt thereof is administered without a high-protein food. In some embodiments of any of the above methods, separatepapterin or a pharmaceutically acceptable salt thereof is administered without a high-fat diet (for example, one in which at least 25, 30, 40, or 50% of calories are derived from fat). In some embodiments of any of the above methods, separatepapterin or a pharmaceutically acceptable salt thereof is administered without a high-protein, high-fat diet. In some embodiments, sepiapterin or a pharmaceutically acceptable salt thereof is administered without high-calorie food (for example, food having at least 100 calories, e.g., at least 200 calories, at least 300 calories, at least 400 calories, at least 500 calories, e.g., 500-1500 or 800-1000 calories). In some embodiments of any of the above methods, sepiapterin or a pharmaceutically acceptable salt thereof is administered without food that constitutes a meal such as breakfast, lunch, or dinner.

[0108] While not theoretically bound, administering sepiapterin or its pharmaceutically acceptable salts without food may increase exposure to sepiapterin in plasma, CSF, and / or brain due to an increased absorption rate of sepiapterin. Because sepiapterin efficiently crosses cell membranes, if sepiapterin is absorbed quickly, such as when administered on an empty stomach, intracellular sepiapterin membrane transporters and / or sepiapterin reductase enzymes may be saturated. As a result, at least some of the administered sepiapterin may not enter the cell and / or may exit the cell without being reduced to 7,8-dihydrobiopterin. This excess sepiapterin in the plasma may cross the blood-brain barrier (BBB) ​​and enter brain cells before being converted to BH4, resulting in higher BH4 levels in the brain (and / or CSF) compared to administration with food. When administered with food, the absorption rate of sepiapterin decreases, and the sepiapterin transporter and intracellular sepiapterin reductase enzyme may not be saturated. Therefore, administering sepiapterin or its pharmaceutically acceptable salt without food may unexpectedly result in higher maximum plasma, CSF, and / or brain concentrations (Cmax) and / or absorption range (AUC) of sepiapterin compared to administration with food. 0-last Increased levels of sepiapterin in plasma, CSF, and / or brain may be beneficial during treatment.

[0109] The actual dose of the composition of the present invention administered to a subject can be determined by physical and physiological factors such as body weight, severity of condition, type of disease being treated, previous or simultaneous therapeutic interventions, subject characteristics, and route of administration. Depending on the dose and route of administration, the preferred dose and / or number of effective doses may vary depending on the subject's response. The physician responsible for administration will determine the concentration of the active ingredient in the composition and the appropriate dose for each individual subject in any event.

[0110] In some embodiments, subjects are administered approximately 1 mg / kg to 120 mg / kg per dose (e.g., approximately 10 mg / kg to approximately 60 mg / kg, approximately 20 mg / kg to approximately 60 mg / kg, or approximately 20 mg / kg, approximately 30 mg / kg, approximately 40 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg). During treatment, subjects may be administered a pharmaceutical composition containing sepiapterin or a pharmaceutically acceptable salt thereof once, twice, or three times daily. In some embodiments, subjects may not be permitted to take drugs known to inhibit folate synthesis (e.g., methotrexate, pemetrexate, or trimethrexate). Sepiapterin or a pharmaceutically acceptable salt thereof may be administered in two equivalents (for example, two doses at different times of the day), such as two 60 mg / kg doses (for example, one 60 mg / kg dose in the morning and one 60 mg / kg dose in the evening), two 40 mg / kg doses (for example, one 40 mg / kg dose in the morning and one 40 mg / kg dose in the evening), two 30 mg / kg doses (for example, one 30 mg / kg dose in the morning and one 30 mg / kg dose in the evening), two 20 mg / kg doses (for example, one 20 mg / kg dose in the morning and one 20 mg / kg dose in the evening), or two 10 mg / kg doses (for example, one 10 mg / kg dose in the morning and one 10 mg / kg dose in the evening).

[0111] Equivalents and scope Those skilled in the art will recognize many equivalents to the specific embodiments of the present invention described herein, or can verify them by routine experimentation alone. The scope of the present invention is not intended to be limited to the foregoing description, but rather as set forth in the appended claims.

[0112] Furthermore, it is understood that any particular embodiment of the present invention that constitutes prior art may be expressly excluded from one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if the exclusion is not expressly provided herein. Any particular embodiment of the composition of the present invention (e.g., any compound, any production method, any use) may be excluded from one or more claims for any reason, whether or not it relates to the existence of prior art.

[0113] Examples Example 1

[0114] Orthotopic glioblastoma tumors were established on day 0 using nude (U87) and syngeneic (GL261) mouse models (N=13 / group). In the U87 mouse model, sepiapterin (SP) was orally administered for 6 days (10 mg / kg sepiapterin) or daily (1 mg / kg sepiapterin) until the end of the experiment (60 days) starting from day 6. In the GL261 mouse model, SP was orally administered daily (10 mg / kg) starting from day 6 until the end of the experiment (60 days). Radiation therapy (IR) (5 fx, 2 Gy) with 3D treatment planning and execution was started on day 13 and ended on day 17.

[0115] The results for U87 mice are shown in Figure 1. As shown in Figure 1, administration of sepiapterin improved survival rates compared to the control (i.e., no IR or SP) or IR alone, as follows: Both the 6d+IR (10 mg / kg) group and the continued+IR (1 mg / kg) group were significantly different from the control group. The difference between the 6d 10 mg / kg group and the IR alone group did not achieve statistical significance. The 1 mg / kg continued group was significantly different from all other groups (control, IR alone, and 6d 10 mg / kg).

[0116] Comparison of survival curves Log-rank (Mantel-Co) test: Chi-squared 34.39, df3, P-value <0.0001, P-value summary****, significant difference in survival curve.

[0117] Log-rank test for trend: Chi-squared 6.590, df1, P-value 0.0103, P-value summary*, significant trend.

[0118] Gehan-Breslow-Wilcoxon test: Chi-squared 28.79, df3, P-value <0.0001, P-value summary****, significant difference in survival curves.

[0119] The results for the GL261 mouse model are shown in Figure 2. As shown in Figure 2, the results of continuous administration of 10 mg / kg of SP differed significantly from those of the control and IR alone.

[0120] Comparison of survival curves Log-rank (Mantel-Co) test: Chi-squared 21.32, df3, P-value <0.0001, P-value summary****, significant difference in survival curve.

[0121] Log-rank test of tendency: Chi-squared 17.42, df1, P-value < 0.0001, P-value summary*, unexpected tendency.

[0122] Gehan-Breslow-Wilcoxon test: Chi-squared 16.37, df3, P-value <0.0010, P-value summary****, significant difference in survival curves.

[0123] Example 2 Orthotopic GL261 tumors were established on day 0. From day 7, mice were treated with 60 mg / kg temozolomide (TMZ) followed by + / - 10 mg / kg SP for 5 days, and then orally administered from day 7 until the end of the study. The results are shown in Figure 3. Figure 3 shows that mice treated with TMZ + SP had a higher survival rate than mice treated with TMZ alone. Subsequent animal experiments will combine this with fractionated radiotherapy.

[0124] Example 3

[0125] A novel object recognition test is a behavioral test in which mice are asked to explore two similar objects during the first (training) session, and after a certain period of time, one of the two training objects is replaced with a new object during a subsequent (test) session. Because mice are naturally drawn to novelty, once they recognize a familiar object, they will spend most of their time with the new object. The time it takes for the mice to explore the new object provides a measure of recognition memory.

[0126] Twenty-four adult female C57BL / 6J mice were treated as follows: (1) Eight mice received IR irradiation (IR) with a total dose of 10 Gy, divided into three sessions with a "rest" day in between, covering approximately 1 mm square of the center of the head. (2) The same eight mice were irradiated and treated with 10 mg / kg / day of sepiapterin (SP) as forced oral administration from day 1 of IR until 6 days after the final fractionation (a total of 11 days). (3) The eight mice were untreated, naive mice.

[0127] One month after treatment, participants were tested on a novel object recognition (NOR) task with a one-hour trial interval (ITI) to assess hippocampal-mediated memory (i.e., the test was conducted one hour after training). Object examination time was measured at 5 minutes in both the training and test phases. Assessment was performed by two independent observers. The discriminant index = (novel - familiar) / (novel + familiar). As shown in Figure 4, SP administration increased the discriminant index compared to the irradiation-only group.

[0128] One-way analysis of variance Normality test (Shapiro-Wilk): Pass (P=0.992) Equal variance test (Brown-Forsythe): Passed (P=0.540) [Table 24] [Table 25]

[0129] All pairwise multiple comparison procedures (Tukey's test) Comparison of factors: Treatment group [Table 26]

[0130] Two months after treatment, spontaneous alternation in a Y-maze will be tested in the mice. Three months after treatment, the mice will be subjected to another NOR test with 1 hour of ITI.

[0131] Example 4: RNA research Progressive, delayed brain damage following high-dose radiation exposure is thought to be caused by radiation-induced long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines, including ICAM-1, TNF-α, IL-1β, and IFN- γ All of these cytokines are upregulated in the brains of mice after whole-brain irradiation and are involved in the development of delayed brain injury. RNA extracts from brain tissue after 10 Gy (3 fxs x 3.3 Gy) of whole-brain irradiation (TBI) were collected at days 8, 30, and 60 in mice treated with 10 mg / kg of SP for 6 days and in mice not treated with SP, and the above cytokines were analyzed. As previously demonstrated in lung tissue, the expression of these pro-inflammatory cytokines is expected to increase after traumatic brain injury, and their expression is expected to normalize with treatment with SP.

[0132] Example 5: Phase 2 study of the combination of sepiapterin and temozolomide in newly diagnosed or recurrent glioblastoma. Summary This is an open-label, randomized, phase 2 clinical trial testing the safety and efficacy of sepiapterin (SP) in the treatment of newly diagnosed or recurrent glioblastoma. The study design is shown in Figure 5. The objective of this study is to test the safety profile and establish a recommended dose (RD) for phase 3 of sepiapterin with standard temozolomide (TMZ) chemoradiotherapy in patients with newly diagnosed or recurrent glioblastoma. This study will test three dose levels of sepiapterin (20, 40, or 60 mg / kg / day) in combination with standard TMZ chemoradiotherapy and standard TMZ chemoradiotherapy alone. Patients randomly assigned to receive sepiapterin will be treated for 6 days with 20 mg / kg / day, 40 mg / kg / day, or 60 mg / kg / day as part of induction therapy ("Induction Therapy" in Figure 5). This will be followed by 6 weeks of radiotherapy at 60 Gy / 30 fractions, with 75 mg / m² daily. 2 Standard treatment consisting of TMZ followed by sepiapterin in the sepiapterin group (Figure 5, "Radiotherapy"). Subsequently, TMZ-only treatment is interrupted for 4 weeks, and sepiapterin treatment is continued (Figure 5, "TMZ Interruption"). Then, sepiapterin and TMZ 150-200 mg / m² are administered daily during each 28-day maintenance chemotherapy cycle. 2 Maintenance therapy (Figure 5, "Maintenance Therapy") includes six maintenance cycles (days 1-5 every 28 days). Patients randomly assigned to TMZ only will receive standard therapy (6 weeks of 60 Gy / 30 fractions of radiotherapy and 75 mg / m² daily). 2 Treatment is administered with TMZ (consisting of TMZ). This is followed by a 4-week TMZ treatment interruption. TMZ 150-200 mg / m² is administered from day 1 to day 5 of each 28-day maintenance chemotherapy cycle. 2 Maintenance therapy will be administered, including six maintenance cycles. The research scheme is shown in Figure 5.

[0133] the purpose Primary outcome measurement • 6-month progression-free survival (PFS) for all participants according to RECIST version 1.1 Secondary outcome measurement • Overall response rate (ORR) for all patients according to RECIST version 1.1 ORR is assessed by performing investigational imaging every 6–9 weeks after the first dose of the investigational treatment. ORR is defined as the proportion of participants in the analysis population who showed a complete response (CR) or a partial response (PR). Complete response (CR) is defined as the disappearance of all target lesions with pathological lymph nodes that have shrunk to less than 10 mm in the short axis. Partial response (PR) is defined as a reduction of at least 30% in the total diameter of target lesions, using the total diameter at baseline as the baseline.

[0134] • Disease control rate for all patients according to RECIST version 1.1 Disease control rate is defined by RECIST version 1.1 as the proportion of patients who achieved complete remission, partial remission, or maintained disease control for at least four weeks with the best treatment response.

[0135] • Total survival time (OS) of all participants Overall survival (OS) is defined as the time from the first day of research treatment to death from any cause, analyzed using the Kaplan-Meier method for censored data, and reported in months.

[0136] • Median PFS of all participants The median PFS is defined as the median time from the first day of treatment to the first recorded progressive disease (PD) or death from any cause, whichever comes first, according to RECIST version 1.1.

[0137] • The median overall survival (OS) for all participants is defined as the time from the first day of treatment to death from any cause.

[0138] • Safety as measured by adverse events (AEs), including serious adverse events (SAEs)

[0139] standard Inclusion criteria 1. Voluntary participation and written informed consent 2. Target age: ≥18 years old 3. Supratentorial space-occupying lesion diagnosed as glioblastoma by pathology. 4. Patients scheduled for standard radiotherapy and temozolomide concurrent chemotherapy after surgery. 5. MRI confirmed a new diagnosis or clear recurrence of the tumor. Recurrence was defined as a lesion with a diameter exceeding 1 cm, more than two layers (with a layer spacing of 5 mm), or confirmation of recurrence by repeat biopsy or postoperative pathology. 6. According to RECIST version 1.1, there was at least one measurable lesion. 7. Karnofsky Performance Status Scale (KPS) score ≥ 60 points 8. Can swallow SEPIAPTERIN or TMZ normally. 9. The expected survival period is 3 months or more. 10. Sufficient organ and bone marrow function. The definition is as follows:

[0140] a. Neutrophil count (ANC) ≥ 1500 / mm³ 3 (1.5 × 10 9 / L) b. Platelet count (PLT) ≧100000 / mm 3 (100×10 9 / L) c. Hemoglobin (HB) ≥ 9 g / dl (90 g / L) d. Serum albumin ≥ 2.8 g / dl e. Serum creatinine is 1.5 times or less the upper limit of normal (ULN), or the creatinine clearance rate is 60 ml / min or more. f. Total bilirubin (TB) ≤ 1.5 × ULN, or total bilirubin (TB) > 1.5 × ULN, provided that direct bilirubin (DBIL) ≤ 1 × ULN. Patients with liver metastases must have a total bilirubin (TB) of 2 × ULN or less. g. In patients with liver metastases, the levels of aspartate aminotransferase (AST) / serum glutamate oxaloacetate transaminase (SGOT) or alanine transaminase (ALT) / serum glutamate pyruvate transaminase (SGPT) should be ≤2.5 × ULN and ≤5 × ULN, respectively. h. Left ventricular ejection fraction (LVEF) ≥ 50%, corrected QT interval (QTc) < 450 milliseconds for men and < 470 milliseconds for women. 11. In patients not receiving anticoagulant therapy, the international normalized ratio (INR) of prothrombin time is 1.5 or less, and the activated partial thromboplastin time (APTT) is 1.5 times the upper limit of normal or less. Patients receiving full dose anticoagulants or parenteral anticoagulant therapy may participate in the clinical trial if their anticoagulant dosage has been stable for at least two weeks prior to participation and their coagulation test results are within the range of local treatment. 12. Women of childbearing age must have a negative pregnancy test (serum or urine) within 7 days prior to registration and must voluntarily use appropriate contraception during the observation period and within 8 weeks after the last dose of the investigational drug. Men must agree to undergo surgical sterilization or use appropriate contraception during the observation period and within 8 weeks after the last dose of the investigational drug. 13. Good compliance allows for cooperation in research and follow-up in accordance with program requirements.

[0141] Exclusion criteria 1. Previous allergy history to temozolomide or sepiapterin 2. Major surgery (biopsy may be permitted depending on the diagnosis, and tumor resection may be permitted if possible) or severe trauma within 4 weeks prior to the first use of the investigational drug. 3. Currently participating in another clinical study (excluding observational (non-intervention) clinical studies or interventions in follow-up studies of new clinical studies), or participating in another drug clinical study within 4 weeks prior to the first dose, or the half-life from the last investigational drug is 5 or less. 4. Excluding basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder cancer, cervical intraepithelial neoplasia, breast intraepithelial neoplasia, and papillary thyroid carcinoma (if locally treatable and cured within the past 5 years or simultaneously). 5. Patients with advanced disease whose symptoms have spread to internal organs and who are at risk of developing life-threatening complications in a short period of time (including patients with uncontrolled large amounts of exudate [pleural cavity, pericardium, abdominal cavity]). 6. Patients who experience an unexplained fever exceeding 38.5°C during the screening period or before the first dose (at the discretion of the researchers, fever caused by a tumor may be included in this group). 7. Patients who developed a severe infection (CTCAE > Level 2), such as severe pneumonia, bacteremia, or infectious complications, within four weeks prior to the first use of the investigational drug; patients whose baseline chest imaging revealed active pneumonia, symptoms, and signs of infection within two weeks prior to the first use of the investigational drug; or patients who required oral or intravenous antibiotic treatment (excluding prophylactic use of antibiotics). 8. Patients who have experienced any of the following conditions within six months prior to the start of the study: myocardial infarction, severe / unstable angina, New York Heart Association (NYHA) grade 2 or higher heart failure, and clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention, or poorly controlled hypertension (systolic blood pressure continuously elevated by 150 mmHg or more, or diastolic blood pressure continuously elevated by 100 mmHg or more). 9. History of gastrointestinal bleeding or a tendency toward gastrointestinal bleeding within the past 6 months, e.g., esophageal varices, locally active ulcerative lesions, fecal occult blood ≥ (+) (If fecal occult blood is (+), gastroscopy is required). 10. Inability to swallow the investigational drug, chronic diarrhea (including but not limited to irritable bowel syndrome, Crohn's disease, and ulcerative colitis), intestinal obstruction, and other factors affecting drug administration and absorption. 11. The patient has a known history of allogeneic organ transplantation, allogeneic hematopoietic stem cell transplantation, or congenital immunodeficiency. 12. Patients diagnosed with active pulmonary tuberculosis infection based on medical history or CT scan, patients who have had active pulmonary tuberculosis infection within the year prior to registration, or patients with a history of active pulmonary tuberculosis infection within the past year but who have not received regular treatment. 13. Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS); active hepatitis B (defined as hepatitis B virus surface antigen [HBsAg] positive test result, HBV-DNA ≥ 500); hepatitis C (defined as hepatitis C antibody [HCV AB] positive, HCV-RNA exceeding the detection limit of the analytical method, and abnormal liver function); or co-infection with hepatitis B and hepatitis C. 14. The patient had a clear history of neurological or psychiatric disorders such as epilepsy and dementia, and was known to have a history of psychotropic drug abuse, alcohol dependence, and drug abuse. 15. Patients deemed unsuitable for the study 16. Concomitant use of methotrexate or other folic acid antagonists.

[0142] Other embodiments are described in the claims.

Claims

1. A pharmaceutical composition comprising sepiapterin or a pharmaceutically acceptable salt thereof for use in the treatment of a target glioblastoma, wherein the treatment comprises administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof, and the treatment further comprises administering therapeutic radiation and / or temozolomide (TMZ).

2. The pharmaceutical composition for use according to claim 1, wherein the effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is about 10 mg / kg to about 60 mg / kg per dose.

3. The pharmaceutical composition for use according to claim 1, wherein the effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is about 20 mg / kg to about 60 mg / kg per dose.

4. The pharmaceutical composition for use according to claim 1, wherein the effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is about 20 mg / kg per dose.

5. The pharmaceutical composition for use according to claim 1, wherein the effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is about 40 mg / kg per dose.

6. The pharmaceutical composition for use according to claim 1, wherein the effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is about 60 mg / kg per dose.

7. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein an effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is administered once daily.

8. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein an effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is administered twice daily.

9. The pharmaceutical composition for use according to claim 8, wherein an effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is administered in two equivalents.

10. A pharmaceutical composition for use according to any one of claims 1 to 9, wherein an effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is administered together with food.

11. The pharmaceutical composition for use according to claim 10, wherein the administration to the subject is performed less than 30 minutes before or after the intake of food.

12. The pharmaceutical composition for use according to claim 10, wherein the administration to the subject is substantially simultaneous with the food.

13. The pharmaceutical composition for use according to any one of claims 10 to 12, wherein the food is a high-protein and / or high-fat food.

14. The pharmaceutical composition for use according to any one of claims 10 to 12, wherein the food is a low-fat food.

15. The pharmaceutical composition for use according to any one of claims 10 to 12, wherein the food is a high-calorie food.

16. A pharmaceutical composition for use according to any one of claims 1 to 9, wherein an effective amount of the sepiapterin or a pharmaceutically acceptable salt thereof is administered without food.

17. The pharmaceutical composition for use according to claim 16, wherein the administration to the subject is carried out at least 30 minutes before eating or at least 2 hours after eating food.

18. The pharmaceutical composition for use according to claim 16, wherein the administration to the subject is carried out at least 30 minutes before eating or at least 3 hours after eating food.

19. The pharmaceutical composition for use according to any one of claims 1 to 18, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is formulated as an oral powder for suspension.

20. The pharmaceutical composition for use according to any one of claims 1 to 18, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered as a suspension in a flavored suspension vehicle.

21. The pharmaceutical composition for use according to any one of claims 1 to 18, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered as a powder suspended in water or juice.

22. The pharmaceutical composition for use according to any one of claims 1 to 21, wherein the treatment further comprises administering therapeutic radiation.

23. The pharmaceutical composition for use according to claim 22, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered during the period of therapeutic radiation.

24. The pharmaceutical composition for use according to claim 22 or 23, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered prior to therapeutic radiation.

25. The pharmaceutical composition for use according to any one of claims 22 to 24, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered after therapeutic radiation.

26. The pharmaceutical composition for use according to any one of claims 1 to 25, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least six days.

27. The pharmaceutical composition for use according to any one of claims 1 to 25, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 14 days.

28. The pharmaceutical composition for use according to any one of claims 1 to 25, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 30 days.

29. The pharmaceutical composition for use according to any one of claims 1 to 28, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 14 days after therapeutic radiation.

30. The pharmaceutical composition for use according to any one of claims 1 to 28, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered for at least 30 days after therapeutic radiation.

31. The pharmaceutical composition for use according to any one of claims 1 to 30, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered continuously concurrently with therapeutic radiation.

32. The pharmaceutical composition for use according to any one of claims 1 to 31, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered continuously in a 28-day cycle.

33. A pharmaceutical composition for use according to any one of claims 1 to 31, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered in six 28-day cycles.

34. The pharmaceutical composition for use according to claim 33, wherein the sepiapterin or a pharmaceutically acceptable salt thereof is administered in a cycle of more than six 28-day periods.

35. The subject is a human, the pharmaceutical composition for use according to any one of claims 1 to 34.

36. The pharmaceutical composition for use according to any one of claims 1 to 35, wherein the treatment further comprises administering temozolomide (TMZ).

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