WO2024256964A1 - (s)-2-hydroxy-6-((4-(2-(2-hydroxyéthyl)nicotinoyl)morpholin-3-yl) méthoxy)benzaldéhyde destiné à être utilisé dans le traitement de la drépanocytose - Google Patents

(s)-2-hydroxy-6-((4-(2-(2-hydroxyéthyl)nicotinoyl)morpholin-3-yl) méthoxy)benzaldéhyde destiné à être utilisé dans le traitement de la drépanocytose Download PDF

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WO2024256964A1
WO2024256964A1 PCT/IB2024/055707 IB2024055707W WO2024256964A1 WO 2024256964 A1 WO2024256964 A1 WO 2024256964A1 IB 2024055707 W IB2024055707 W IB 2024055707W WO 2024256964 A1 WO2024256964 A1 WO 2024256964A1
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compound
dose
pharmaceutically acceptable
acceptable salt
per day
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Aline BERGESCH BARTH
Kenneth Leslie DUCHIN
Eleanor Allen LISBON
Arthur Chi Hang LO
Eric Iredell ZIMMERMAN
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Global Blood Therapeutics Inc
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Global Blood Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent.
  • the basis for SCD is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin A (HbA).
  • Hemoglobin transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes.
  • Sickle hemoglobin contains a point mutation where glutamic acid is replaced with valine, making HbS susceptible to polymerization under hypoxic conditions to give the HbS containing red blood cells (RBCs) their characteristic sickle shape.
  • RBCs red blood cells
  • the sickled cells are also more rigid than normal RBCs, and their lack of flexibility can lead to blockage of blood vessels.
  • the present disclosure provides for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I of formula: or a pharmaceutically acceptable salt thereof, followed by a second dose of Compound I, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides for a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of Compound I, or a pharmaceutically acceptable salt thereof, wherein the administrations of the first dose and the second dose provide about 25% to about 60% hemoglobin occupancy of Compound I.
  • the present disclosure provides for a method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg per day to about 1600 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of about 25 mg per day to about 500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides for a method of treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 300 mg once daily (QD) of Compound I, or a pharmaceutically acceptable salt thereof, for fourteen days, followed thereafter by a second dose of about 200 mg once daily (QD) of Compound I, or a pharmaceutically acceptable salt thereof.
  • FIG. 1 shows the Study Schema for Part A of the study described in Example 1.
  • FIG. 2 shows the Study Schema for Part B of the study described in Example 1.
  • FIG. 3 shows the Study Schema for Part C of the study described in Example 1.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • to the term “about X” includes description of “X”.
  • Forms of Compound I or salts or solvates thereof are provided herein.
  • reference to a form of Compound I or a salt or a solvate thereof means that at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I or a salt or a solvate thereof present in a composition is in the designated form.
  • solid form refers to a type of solid-state material that includes amorphous as well as crystalline forms.
  • crystalline form refers to polymorphs as well as solvates, etc.
  • polymorph refers to a particular crystal structure having particular physical properties such as X-ray diffraction, melting point, and the like.
  • solvate refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • solvents include, but are not limited to, methanol, N,N- dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
  • the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.
  • amorphous refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (glass transition).
  • any formula or stmcture given herein, including Compound I, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. It is understood that for any given atom, the isotopes may be present essentially in ratios according to their natural occurrence, or one or more particular atoms may be enhanced with respect to one or more isotopes using synthetic methods known to one skilled in the art.
  • hydrogen includes for example 1H, 2H, 3H; carbon includes for example 11C, 12C, 13C, 14C; oxygen includes for example 160, 170, 180; nitrogen includes for example 13N, 14N, 15N; sulfur includes for example 32S, 33S, 34S, 35S, 36S, 37S, 38S; fluoro includes for example 17F, 18F, 19F; chloro includes for example 350, 360, 370, 380, 390; and the like.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to forms as described herein, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluene-sulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines.
  • suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.
  • a pharmaceutically acceptable salt does not include a salt of a primary amine.
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • a) inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition
  • prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • a compound described herein, solid form described herein, or a salt or a solvate thereof may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • terapéuticaally effective amount or “effective amount” of a compound or solid form described herein, or a salt or a solvate thereof, means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a sickle cell disease.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.
  • a therapeutically effective amount can also be ascertained by evaluating biomarkers of the disease or disorder to be treated.
  • biomarkers may include measuring blood Hb levels, hemolysis (e.g., via blood bilirubin levels), percent Hb occupancy by compound, partial pressure of 02 at which Hb is 20% saturated (p20) or 50% saturated (p50) with 02, and RBC deformability as a function of oxygen tension (pO2) including determination of maximum RBC deformability under normoxic conditions (Elmax), minimum RBC deformability under hypoxic conditions (Elmin), and the specific pO2 level at which RBC sickling occurs, i.e., the point of sickling (PoS).
  • Therapeutic efficacy in SCD may also include measuring oxygen deliver to tissues including, e.g., microvasculature oxygen saturation, cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate for oxygen, which may be measured by, e.g., diffuse correlation spectroscopy (DSC) and/or frequency -domain near-infrared spectroscopy (FDNIRS).
  • tissues including, e.g., microvasculature oxygen saturation, cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate for oxygen, which may be measured by, e.g., diffuse correlation spectroscopy (DSC) and/or frequency -domain near-infrared spectroscopy (FDNIRS).
  • DSC diffuse correlation spectroscopy
  • FDNIRS frequency -domain near-infrared spectroscopy
  • the therapeutically effective amount is determined by measuring the percent of hemoglobin occupied by the compound, i.e., the percent Hb occupancy.
  • the percent Hb occupancy is a measure of target engagement defined as the percentage of hemoglobin bound by a compound (e.g., Compound I) calculated as the molar concentration of the compound (e.g., Compound I) in RBCs divided by the molar concentration of hemoglobin in RBCs (the mean corpuscular hemoglobin concentration calculated from the hematology panel).
  • concentration of a compound (e.g., Compound I) in RBCs is calculated from the concentrations in whole blood and plasma, and the hematocrit.
  • the methods described herein may be applied to cell populations in vivo or ex vivo.
  • “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual.
  • “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the forms described herein and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the forms described herein and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a form of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the forms described herein and compositions described herein may be suited are described below or will become apparent to those skilled in the art.
  • the selected forms described herein may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • hemoglobin refers to any hemoglobin protein, including normal hemoglobin (HbA) and abnormal hemoglobin, such as sickle hemoglobin (HbS).
  • HbA normal hemoglobin
  • HbS sickle hemoglobin
  • sickle cell disease refers to diseases mediated by sickle hemoglobin (HbS) that results from a single point mutation in the hemoglobin (Hb).
  • Sickle cell diseases include sickle cell anemia (HbSS), hemoglobin SC disease (HbSC), hemoglobin S beta-plus-thalassemia (HbS/ +) and hemoglobin S beta-zero-thalassemia (HbS/ 0).
  • First dose refers to an initial dose of a compound as described herein, or series of such doses, given to achieve a target therapeutic level in the subject in a desired amount of time.
  • a “first dose” refers to a “loading dose”.
  • a “loading dose” refers to a “first dose”.
  • “Second dose” refers to a dose of a compound as described herein, or series of such doses, administered to maintain a desired therapeutic level of the compound in the subject.
  • a “second dose” refers to a “maintenance dose”.
  • a “maintenance dose” refers to a “second dose”.
  • a target therapeutic level can be assessed based on the percent hemoglobin occupancy or on parameters related thereto such as concentration of Compound I in the subject’s blood relative to the subject’s hematocrit.
  • Sickle hemoglobin contains a point mutation where glutamic acid is replaced with valine, making HbS susceptible to polymerization under hypoxic conditions to give the HbS containing red blood cells their characteristic sickle shape.
  • the sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. It is contemplated that an approach to therapy would be to maintain the HbS in the oxygenated state, as polymerization occurs only in the deoxygenated state under hypoxic conditions.
  • SCD sickle cell disease
  • Methods for treating sickle cell disease comprising administering (S)- 2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3-yl)methoxy)benzaldehyde (Compound I) or a pharmaceutically acceptable salt thereof.
  • Compound I has the following formula:
  • Compound I is a modulator of hemoglobin, and its synthesis and method of use thereof is described in U.S. Patent No. 10,683,285.
  • Compound I is a solid form.
  • Compound I is a crystalline form.
  • Compound I is a crystalline form characterized by an X-ray powder diffractogram comprising the following peaks: 18.3, 23.4, and 26.1 °20 ⁇ 0.2 °20 (Compound I Form I), as determined on a diffractometer using Cu-Ka radiation.
  • the diffractogram further comprises one or more peaks at: 10.8 or 17.3 °20 ⁇ 0.2 °20.
  • the crystalline form is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 111 °C (onset temperature).
  • DSC differential scanning calorimetry
  • Amorphous Compound I may be made according to methods known in the art. A solution of amorphous Compound I in acetonitrile (>540 mg/mL) was refrigerated for 4 days and then placed in a freezer for 1 day. The solids were filtered and dried under nitrogen to provide Compound I Form I. [0042] Compound I Form I was also prepared as follows: Amorphous Compound I was slurried in ether with seeding with Compound I Form I from another experiment (prepared as described herein) at ambient temperature for 1 day, providing Compound I Form I.
  • X-ray Powder Diffraction XRPD figures were generated using SSCI Pattern Match 3.0.4, unvalidated software. XRPD patterns were collected with a PANalytical X'Pert PRO MPD or a PANalytical Empyrean diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kot X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e or NIST SRM 640f) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST- certified position.
  • a specimen of the sample was sandwiched between 3-pm-thick films and analyzed in transmission geometry.
  • a beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening and asymmetry from axial divergence.
  • Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b or v. 5.5.
  • Some embodiments provide for methods for treating sickle cell disease by administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein the administration provides about 30% to about 50% hemoglobin occupancy.
  • the present disclosure provides for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I of formula: or a pharmaceutically acceptable salt thereof, for eight or more days, followed by a second dose of Compound I, or a pharmaceutically acceptable salt thereof, wherein the administration of the first dose and the second dose provide about 30% to about 50% hemoglobin occupancy by Compound I.
  • the percent hemoglobin occupancy, as provided by the administration of Compound I is about 25% to about 80%. In some embodiments, the percent hemoglobin occupancy, as provided by the administration of Compound I, is about 25% to about 75%. In some embodiments, the percent hemoglobin occupancy, as provided by the administration of Compound I, is about 25% to about 70%. In some embodiments, the percent hemoglobin occupancy, as provided by the administration of Compound I, is about 25% to about 65%. In some embodiments, the percent hemoglobin occupancy, as provided by the administration of Compound I, is about 25% to about 60%. In some embodiments, the percent hemoglobin occupancy is about 25% to about 55%.
  • the percent hemoglobin occupancy (as provided by the administration of Compound I) is about 25% to about 50%. In some embodiments, the percent hemoglobin occupancy is about 25% to about 45%. In some embodiments, the percent hemoglobin occupancy is about 30% to about 60%. In some embodiments, the percent hemoglobin occupancy is about 30% to about 55%. In some embodiments, the percent hemoglobin occupancy is about 30% to about 50%. In some embodiments, the percent hemoglobin occupancy is about 30% to about 45%. In some embodiments, the percent hemoglobin occupancy is about 30% to about 40%. In some embodiments, the percent hemoglobin occupancy is about 30% to about 35%. In some embodiments, the percent hemoglobin occupancy is about 35% to about 60%.
  • the percent hemoglobin occupancy is about 35% to about 55%. In some embodiments, the percent hemoglobin occupancy is about 35% to about 50%. In some embodiments, the percent hemoglobin occupancy is about 35% to about 40%. In some embodiments, the percent hemoglobin occupancy is about 40% to about 60%. In some embodiments, the percent hemoglobin occupancy is about 40% to about 55%. In some embodiments, the percent hemoglobin occupancy is about 40% to about 50%. In some embodiments, the percent hemoglobin occupancy is about 40% to about 45%.
  • the percent hemoglobin occupancy may be calculated as described herein. In some embodiments, percent hemoglobin occupancy is the molar ratio of Compound I concentration to the Hb concentration in red blood cells.
  • the present disclosure provides methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days to achieve a target therapeutic level in the subject, followed thereafter by a second dose of Compound I, or a pharmaceutically acceptable salt thereof, to maintain the target therapeutic level in the subject, wherein on a daily dose basis the first dose is greater than the second dose (i.e. the first dose per day is greater than the second dose per day).
  • the ratio of first dose to second dose is about 88: 1 to about 2: 1. In some embodiments, the ratio of first dose to second dose is about 60: 1 to about 2:1. In some embodiments, the ratio of first dose to second dose is about 40:1 to about 2: 1. In some embodiments, the ratio of first dose to second dose is about 20:1 to about 2: 1. In some embodiments, the ratio of first dose to second dose is about to second dose 10: 1 to about 2: 1.
  • the ratio of first dose per day to second dose per day is about 88: 1 to about 1 : 1. In some embodiments, the ratio of first dose per day to second dose per day is about 60: 1 to about 1 : 1. In some embodiments, the ratio of first dose per day to second dose per day is about 40: 1 to about 1 : 1. In some embodiments, the ratio of first dose per day to second dose per day is about 20: 1 to about 1 : 1. In some embodiments, the ratio of first dose per day to second dose per day is about 10: 1 to about 1 : 1. In some embodiments, the ratio of first dose per day to second dose per day is about 4: 1 to about 1: 1.
  • the ratio of first dose per day to second dose per day is about 2: 1 to 1: 1.
  • Some embodiments provide for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 100 mg per day to about 2200 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of about 25 mg per day to about 500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg per day to about 1600 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of about 25 mg per day to about 500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 300 mg per day to about 900 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of about 25 mg per day to about 250 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg per day to about 900 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed by a second dose of about 25 mg per day to about 250 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, thereafter.
  • Some embodiments provide for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg per day to about 900 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of about 25 mg per day to about 200 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 200 mg per day to about 900 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of about 25 mg per day to about 150 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide for methods for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a first dose of about 300 mg per day to about 900 mg per day of Compound I, or a pharmaceutically acceptable salt thereof, for fourteen days, followed by a second dose of about 50 mg per day to about 250 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • the first dose comprises about 200 mg per day to about 1600 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 300 mg per day to about 1500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 1500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 1000 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day to about 900 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • the first dose comprises about 1500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 1400 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 1300 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 1200 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 1100 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 1000 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • the first dose comprises about 900 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 800 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 700 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 600 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 400 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • the first dose comprises about 300 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 200 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose comprises about 100 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. [0071] In some embodiments, the first dose is administered for eight to fourteen days. In some embodiments, the first dose is administered for eight to thirteen days. In some embodiments, the first dose is administered for eight to twelve days. In some embodiments, the first dose is administered for eight to eleven days. In some embodiments, the first dose is administered for eight to ten days. In some embodiments, the first dose is administered for eight to nine days.
  • the first dose is administered for eight days. In some embodiments, the first dose is administered for nine days. In some embodiments, the first dose is administered for ten days. In some embodiments, the first dose is administered for eleven days. In some embodiments, the first dose is administered for twelve days. In some embodiments, the first dose is administered for thirteen days. In some embodiments, the first dose is administered for fourteen days.
  • the second dose is about 175 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the second dose is about 200 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the second dose is about 225 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the second dose is about 250 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the second dose is about 275 mg per day of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the second dose is about 300 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • the second dose is administered once daily (QD).
  • the first dose is administered for fourteen days. In some embodiments, the first dose is administered for thirteen days. In some embodiments, the first dose is administered for twelve days. In some embodiments, the first dose is administered for eleven days. In some embodiments, the first dose is administered for ten days. In some embodiments, the first dose is administered for nine days.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered once daily (QD). In some embodiments, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID). In some embodiments, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered three times daily (TID). In some embodiments, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered four times daily (QID). In some embodiments, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered every six hours (Q6H). [0081] In some embodiments, the first dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily (QD), and the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily (QD) thereafter.
  • the second dose is administered for as long as the patient requires or benefits from the therapeutic effect provided by such administration.
  • the second dose is administered for one to four weeks. In some embodiments, the second dose is administered for one to five weeks. In some embodiments, the second dose is administered for one to six weeks. In some embodiments, the second dose is administered for one to seven weeks. In some embodiments, the second dose is administered for one to eight weeks. In some embodiments, the second dose is administered for one to nine weeks. In some embodiments, the second dose is administered for one to ten weeks. In some embodiments, the second dose is administered for one to twenty weeks. In some embodiments, the second dose is administered for one to thirty weeks.
  • the second dose is administered for at least one week. In some embodiments, the second dose is administered for at least two weeks. In some embodiments, the second dose is administered for at least three weeks. In some embodiments, the second dose is administered for at least four weeks. In some embodiments, the second dose is administered for at least five weeks. In some embodiments, the second dose is administered for at least six weeks. In some embodiments, the second dose is administered for at least seven weeks. In some embodiments, the second dose is administered for at least eight weeks. In some embodiments, the second dose is administered for at least nine weeks. In some embodiments, the second dose is administered for at least ten weeks. In some embodiments, the second dose is administered for at least fifteen weeks.
  • the second dose is administered for at least twenty weeks. In some embodiments, the second dose is administered for at least thirty weeks. In some embodiments, the second dose is administered for at least forty weeks. In some embodiments, the second dose is administered for at least fifty weeks. In some embodiments, the second dose is administered for at least sixty weeks. In some embodiments, the second dose is administered for at least seventy weeks. In some embodiments, the second dose is administered for at least eight weeks. In some embodiments, the second dose is administered for at least ninety weeks. In some embodiments, the second dose is administered for at least one hundred weeks.
  • the second dose is administered for at least one year. In some embodiments, the second dose is administered for at least two years. In some embodiments, the second dose is administered for at least three years. In some embodiments, the second dose is administered for at least four years. In some embodiments, the second dose is administered for at least five years. In some embodiments, the second dose is administered for at least six years. In some embodiments, the second dose is administered for at least seven years. In some embodiments, the second dose is administered for at least eight years. In some embodiments, the second dose is administered for at least nine years. In some embodiments, the second dose is administered for at least ten years. [0086] In some embodiments, the second dose is administered for the lifetime of the subject. In some embodiments, the second dose is administered until the subject dies.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% after about 8 hours to about 24 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the percent hemoglobin occupancy in the subject, as provided by the administration of Compound I, or a pharmaceutically acceptable salt thereof, reaches about 25% to about 60% after 8 hours to about 20 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% after 8 hours to about 16 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the percent hemoglobin occupancy in the subject, as provided by the administration of Compound I, or a pharmaceutically acceptable salt thereof, reaches about 25% to about 60% after 8 hours to about 12 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 55% after about 8 hours to about 24 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the percent hemoglobin occupancy in the subject, as provided by the administration of Compound I, or a pharmaceutically acceptable salt thereof, reaches about 25% to about 50% after about 8 hours to about 24 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 45% after about 8 hours to about 24 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the percent hemoglobin occupancy in the subject, as provided by the administration of Compound I, or a pharmaceutically acceptable salt thereof, reaches about 25% to about 40% after about 8 hours to about 24 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 35% after about 8 hours to about 24 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% following a loading dose regimen as described herein.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% following a loading dose regimen that comprises administration of 300 mg of Compound I, or a pharmaceutically acceptable salt thereof, once daily (QD) for fourteen days.
  • the hemoglobin occupancy in the subject reaches about 25% to about 60% prior to administration of the second dose (or maintenance dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject, as provided by the administration of Compound I, or a pharmaceutically acceptable salt thereof reaches about 25% to about 60% following a first dose (loading dose) regimen that comprises administration of 300 mg of Compound I, or a pharmaceutically acceptable salt thereof, once daily for fourteen days, and prior to administration of the second dose (or maintenance dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a hematocrit value of about 20% to about 50% in the subject.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a hematocrit value of at least about 20% in the subject. In some embodiment, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a hematocrit value of at least about 30% in the subject. In some embodiment, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a hematocrit value of about 40% in the subject. In some embodiment, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a hematocrit value of about 45% in the subject.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a blood concentration of Compound I of about 50 pg/mL to about 800 pg/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 95 pg/mL to about 775 pg/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 95 pg/mL to about 750 pg/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a blood concentration of Compound I of about 140 pg/mL to about 700 pg/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 190 pg/mL to about 650 pg/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 250 pg/mL to about 475 pg/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a blood concentration of Compound I of about 300 pg/mL to about 450 pg/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 300 pg/mL to about 475 pg/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of about 1,200 pg*h/mL to about 19,200 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 2,280 pg*h/mL to about 18,600 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 2,280 pg*h/mL to about 18,000 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of about 3,360 pg*h/mL to about 16,800 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 4,560 pg*h/mL to about 15,600 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 6,000 pg*h/mL to about 11,400 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of about 7,200 pg*h/mL to about 10,800 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 7,200 pg*h/mL to about 11,400 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of more than about 1,200 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 2,280 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 3,360 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 4,560 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of more than about 6,000 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 7,200 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 10,800 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 11,400 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of more than about 15,600 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 16,800 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 18,000 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 18,600 pg*h/mL. In some embodiments, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 19,000 pg*h/mL.
  • Compound I is administered as a pharmaceutical composition. In some embodiments, Compound I is administered as a pharmaceutical composition.
  • Compound I is administered orally.
  • Some embodiments provided herein further comprise administering an additional therapeutic agent.
  • the additional therapeutic agent is a modulator of hemoglobin. In some embodiments, the additional therapeutic agent is useful for treating sickle cell disease. In some embodiments, the additional therapeutic agent is useful for treating a complication of sickle cell disease. Non-limiting examples of a complication of sickle cell disease include iron overload, pain, infections, acute chest syndrome, stroke, and pulmonary hypertension. In some embodiments, the additional therapeutic agent is hydroxyurea, L-glutamine, crizanlizumab, or deferiprone. In some embodiments, the additional therapeutic agent is hydroxyurea.
  • the present disclosure provides a compound for use in a method of treating sickle cell disease in a subject in need thereof, wherein the compound is Compound I, or a pharmaceutically acceptable salt thereof, and wherein the method is as described herein.
  • Some embodiments of the present disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, wherein the compound is Compound I of formula: or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a first dose of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of Compound I, or a pharmaceutically acceptable salt thereof, wherein the administrations of the first dose and the second dose provide about 25% to about 60% hemoglobin occupancy by Compound I.
  • the administration of the first dose and the second dose of Compound I, or a pharmaceutically acceptable salt thereof provide about 30% to about 50% hemoglobin occupancy by Compound I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments of the present disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, wherein the compound is Compound I of formula: or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a first dose of Compound I, or a pharmaceutically acceptable salt thereof, for eight or more days, followed thereafter by a second dose of about 25 mg per day to about 500 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • Some embodiments of the present disclosure provide a compound for use in a method of treating sickle cell disease in a subject in need thereof, wherein the compound is Compound I of formula:
  • Compound I or a pharmaceutically acceptable salt thereof
  • the method comprises administering to the subject a first dose of about 300 mg once daily (QD) of Compound I, or a pharmaceutically acceptable salt thereof, for fourteen days, followed thereafter by a second dose of 200 mg per day of Compound I, or a pharmaceutically acceptable salt thereof.
  • QD once daily
  • the first dose of Compound I, or a pharmaceutically acceptable salt thereof is administered once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), or every six hours (Q4H).
  • the first dose of Compound I, or a pharmaceutically acceptable salt thereof is administered once daily (QD).
  • the first dose of Compound I, or a pharmaceutically acceptable salt thereof is administered twice daily (BID).
  • the first dose of Compound I, or a pharmaceutically acceptable salt thereof is administered three times daily (TID). In some embodiments of the methods described herein, or some embodiments of the compound for use, the first dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered four times daily (QID). In some embodiments of the methods described herein, or some embodiments of the compound for use, the first dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered every six hours (Q4H).
  • the first dose of Compound I, or a pharmaceutically acceptable salt thereof is administered for fourteen days.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered for at least one week, at least ten weeks, or at least fifty weeks.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered for at least one week.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered for at least ten weeks.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered for at least fifty weeks.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered for at least one year, at least five years, or at least ten years. In some embodiments of the compound for use, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered for at least one year. In some embodiments of the compound for use, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered for at least five years. In some embodiments of the compound for use, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered for at least ten years.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered for the lifetime of the subject. In some embodiments of the compound for use, the second dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered until the subject dies.
  • the second dose of Compound I, or a pharmaceutically acceptable salt thereof is administered once daily (QD).
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% after about 8 hours to about 24 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% after 8 hours to about 20 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% after 8 hours to about 16 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments of the compound for use, the percent hemoglobin occupancy in the subject, as provided by the administration of Compound I, or a pharmaceutically acceptable salt thereof, reaches about 25% to about 60% after 8 hours to about 12 hours following the completion of the first dose (or loading dose) of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments of the compound for use, the administration of the first dose and the second dose of Compound I provide about 30% to about 50% hemoglobin occupancy by Compound I
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% following a loading dose regimen as described herein.
  • the percent hemoglobin occupancy in the subject, as provided by administration of Compound I, or a pharmaceutically acceptable salt thereof reaches about 25% to about 60% following a loading dose regimen that comprises administration of 300 mg of Compound I, or a pharmaceutically acceptable salt thereof, once daily (QD) for fourteen days.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% prior to administration of the second dose (or maintenance dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the percent hemoglobin occupancy in the subject reaches about 25% to about 60% following a loading dose regimen that comprises administration of 300 mg of Compound I, or a pharmaceutically acceptable salt thereof, once daily (QD) for fourteen days, and prior to administration of the second dose (or maintenance dose) of Compound I, or a pharmaceutically acceptable salt thereof.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a hematocrit value of about 20% to about 50% in the subject.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a hematocrit value of at least about 20% in the subject. In some embodiment, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a hematocrit value of at least about 30% in the subject. In some embodiment of the compound for use, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a hematocrit value of about 40% in the subject. In some embodiment, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a hematocrit value of about 45% in the subject.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a blood concentration of Compound I of about 50 pg/mL to about 800 pg/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 95 pg/mL to about 775 pg/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a blood concentration of Compound I of about 95 pg/mL to about 750 pg/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 140 pg/mL to about 700 pg/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a blood concentration of Compound I of about 190 pg/mL to about 650 pg/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 250 pg/mL to about 475 pg/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides a blood concentration of Compound I of about 300 pg/mL to about 450 pg/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides a blood concentration of Compound I of about 300 pg/mL to about 475 pg/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of about 1,200 pg*h/mL to about 19,200 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of about 2,280 pg*h/mL to about 18,600 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of about 2,280 pg*h/mL to about 18,000 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 3,360 pg*h/mL to about 16,800 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 6,000 pg*h/mL to about 11,400 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of about 7,200 pg*h/mL to about 10,800 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of about 7,200 pg*h/mL to about 11,400 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of more than about 1,200 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 2,280 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 3,360 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of more than about 4,560 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 6,000 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 7,200 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of more than about 10,800 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 11,400 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 15,600 pg*h/mL.
  • the administration of Compound I, or a pharmaceutically acceptable salt thereof provides an AUCO-24 of Compound I of more than about 16,800 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 18,000 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 18,600 pg*h/mL. In some embodiments of the compound for use in a method of treating sickle cell disease, the administration of Compound I, or a pharmaceutically acceptable salt thereof, provides an AUCO-24 of Compound I of more than about 19,000 pg*h/mL.
  • Compound I is administered orally.
  • Compound I is a crystalline form characterized by an X-ray powder diffractogram comprising the following peaks: 18.3°, 23.4°, and 26.1 °20 ⁇ 0.2 °20 (Compound I Form I), as determined on a diffractometer using Cu-Ka radiation.
  • the diffractogram further comprises one or more peaks at: 10.8° or 17.3 °20 ⁇ 0.2 °20.
  • the crystalline form is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 111 °C (onset temperature).
  • DSC differential scanning calorimetry
  • the use in treating sickle cell disease further comprises administering an additional therapeutic agent.
  • the additional therapeutic agent is a modulator of hemoglobin.
  • the additional therapeutic agent is useful for treating sickle cell disease.
  • the additional therapeutic agent is useful for treating a complication of sickle cell disease.
  • Non-limiting examples of a complication of sickle cell disease include iron overload, pain, infections, acute chest syndrome, stroke, and pulmonary hypertension.
  • the additional therapeutic agent is hydroxyurea, L- glutamine, crizanlizumab, or deferiprone. In some embodiments, the additional therapeutic agent is hydroxyurea.
  • the additional therapeutic agent is hydroxyurea.
  • compositions comprising one or more of the forms of Compound I described herein, or salts or solvates thereof, and one or more pharmaceutically acceptable vehicles such as carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fdlers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art.
  • compositions may be administered alone or in combination with other therapeutic agents.
  • the pharmaceutical compositions may be administered in either single or multiple first and/or second doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • Oral administration may be another route for administration of the compounds described herein, solid forms described herein, or salts or solvates thereof. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active ingredient, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound or solid form described herein, or salts or solvates thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”).
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds or solid forms described herein, or salts or solvates thereof, in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound or solid form described herein, or salts or solvates thereof.
  • a pharmaceutical excipient When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds or solid forms described herein, or salts or solvates thereof may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • Example 1 A Phase 2/3 Randomized and Multicenter Study of Compound I Administered Orally to Participants with Sickle Cell Disease and an Open-Label Pharmacokinetics Study in Pediatric Participants with Sickle Cell Disease [0139] This example describes a three-part Phase 2/3 study of orally administered Compound I to participants with SCD.
  • Part A of this study is a Phase 2 randomized, open-label, dose-finding study in approximately 60 adult participants with SCD.
  • the primary objective of Part A of this study is to assess the effects of Compound I in adult participants with SCD as measured by change in hemoglobin.
  • a study schema for Part A of the study is shown in FIG. 1.
  • Participants are screened for eligibility in the study from Day -28 through Day -1. Eligible participants are randomized on Day 1 based on a 1:1 (100 mg: 150 mg) allocation and will receive their initial dose (loading dose) of Compound I. After completion of Day 1 assessments and subsequent loading doses, participants will continue with administration of their maintenance dose daily through Week 12.
  • participant enrolled After a determination has been made to include a higher dose treatment arm, participants enrolled thereafter are randomized 1: 1: 1 (100 mg: 150 mg: up to 200 mg of Compound I respectively) or adaptive method to ensure balance and receive a loading dose regimen over 4 days followed by daily maintenance doses through Week 12. Loading doses to be used in this study will not exceed 2200 mg within 24 hours period.
  • the primary endpoint of Part A of the study is to assess the change from baseline in hemoglobin through Week 12.
  • the secondary endpoints of Part A of the study include the effects of Compound I on hemoglobin, hematocrit, clinical measures of hemolysis, and the safety and tolerability, as well as the PK and PD properties of multiple dose Compound I administration. Additional secondary endpoints of Part B of the study also include:
  • the exploratory endpoint of Part A of the study is to evaluate the effects of Compound I on neurocognitive function, erythropoietin (EPO) levels, quality of life (QOL) assessments, RBC deformability, RBC mitochondrial content, VOCs, and other biomarkers. Additional exploratory endpoints of Part A of the study include:
  • Part B is a Phase 3, randomized, double-blind, placebo-controlled study in adult and pediatric participants. Part B will initiate after selection of the optimum dose from Part A of the study. Part B of the study will assess the safety and efficacy of Compound I in increasing the Hb response in approximately 380 adult and pediatric participants with SCD, with approximately 190 participants receiving placebo and approximately 190 participants receiving Compound I optimal dose selected from Part A of the study.
  • a study schema for Part B of the study is shown in FIG. 2.
  • Part B of the study is to assess the effects of an optimum Compound I dose as compared to placebo in adult and pediatric participants with SCD as measured by hemoglobin response.
  • participant are screened for eligibility in the study from Day -28 through Day - 1. Eligible adult participants are randomized on Day 1 based on a 1 : 1 (Compound I : Placebo) allocation and will receive their initial dose (loading dose) at the clinical site. After completion of Day 1 assessments and subsequent loading doses, participants will continue with administration of their maintenance dose daily from Week 1 through Week 48. Participants will return to the clinical site for assessments of safety, efficacy, and PK/PD. The incidence of VOC events will be collected every 4 weeks. After completion of treatment at Week 48 (Day 337), participants will return for final follow-up visit 8 weeks later (Week 56, Day 393), approximately 5 half-lives after the last dose. Participants may choose to emoll in an OLE study under a separate protocol after completing Week 48 visits. Participants not entering the OLE study will be followed for approximately 8 weeks after completing dosing to further assess safety.
  • Compound I Placebo
  • the primary endpoint of Part B of the study is to assess the proportion of participants with an increase from baseline of >1 g/dL in Hb at Week 48.
  • the secondary endpoints of Part B of the study include the effects of Compound I compared to placebo on hemoglobin, hematocrit, clinical measures of hemolysis, and relevant clinical outcomes, and to evaluate the safety and tolerability of 48 weeks of daily administration of Compound I. Additional secondary endpoints also include:
  • the exploratory endpoint of Part B of the study is to evaluate the effects of Compound I as compared to placebo on neurocognitive function, EPO levels, QOL assessments, RBC deformability, RBC mitochondrial content, VOCs, and renal biomarkers. Additional exploratory endpoints also include:
  • Part C of the study is a single arm, open-label, multi-dose PK study in four age-group cohorts of pediatric participants with SCD, and the multi-dose portion of Part C of the study will begin after the dose has been selected for Part B of the study.
  • a study schema for Part B of the study is shown in FIG.
  • Doses given in the MD portion will be informed by emerging clinical trial data and will not exceed dose levels established as safe in adult clinical trials or previous pediatric cohorts. Participants may choose to emoll in an open-label extension (OLE) study under a separate protocol after completing MD Week 2 visits. Participants not entering the OLE study will be followed for approximately 8 weeks after completing dosing to further assess safety.
  • OLE open-label extension
  • Part C is composed of four cohorts:
  • Cohort Cl includes approximately 10 participants aged 12 to less than 18 years, at least 30% of whom must be 12 to less than 15 years old.
  • Cohort C2 includes approximately 10 participants aged 6 to less than 12 years, at least 30% of whom must be 6 to less than 9 years old.
  • Cohort C3 includes approximately 10 participants aged 2 to less than 6 years.
  • Cohort C4 includes approximately 7 participants aged 6 months to less than 2 years.
  • Cohorts C2-C4 will be initiated after completion of 14 days of MD dosing and Data Monitoring Committee (DMC) review of safety, tolerability, and PK data has been evaluated in at least 4 participants of the preceding Cohort. Up to 10 additional participants may be enrolled in each cohort if needed to evaluate additional dose levels and/or to further characterize PK or safety if deemed necessary. Participants from Part C will not be eligible to emoll in Part B of the study.
  • DMC Data Monitoring Committee
  • Parts A, B, and C Key inclusion criteria for Parts A, B, and C include:
  • SCD SCD genotype homozygous for sickle cell allele (HbSS) or double heterozygote for sickle hemoglobin (HbS) and (3-0 thalassemia (HbSB) may be based on history of laboratory testing or must be confirmed by laboratory testing during Screening.
  • HbSS sickle cell allele
  • HbSB double heterozygote for sickle hemoglobin
  • HbSB 3-0 thalassemia
  • the dose must be stable for at least 90 days prior to signing the ICF or assent and with no anticipated need for dose adjustments during the study in the opinion of the Investigator.
  • Female participants of child-bearing potential must agree to use highly effective methods of contraception or practice abstinence from study start to 120 days after the last dose of study drug.
  • Males who are not surgically sterile with partners of childbearing potential must agree to use a highly effective method of birth control during the study and for 120 days after the last dose of study drug.
  • males who are not surgically sterile with a partner who is pregnant must agree to condom use or maintain sexual abstinence during the study and for 120 days after the last dose of study drug.
  • Part A Additional key inclusion criteria for Part A include:
  • Additional key inclusion criteria for Part B include:
  • crizanlizumab Current or recent use of crizanlizumab. Recent use is defined as within 90 days prior to Day 1.
  • cytochrome P450 CYP
  • CYP3A4/CYP3A5 cytochrome P450
  • Recent is defined as within 5 elimination half-lives or 14 days, whichever is longer prior to Day 1.
  • Marijuana use is allowed, except for 24 hours prior to neurocognitive assessments as outlined in the Schedule of Assessments.
  • Dose selection is based on safety and PK results from previous studies as described in Examples 1, 2, and 3.
  • a loading dose is administered followed by daily maintenance dosing for multi-dose regimens.
  • Part A all adult participants will receive maintenance dosing through approximately Week 12.
  • Part B all adult and pediatric participants will receive maintenance dosing for 48 weeks.
  • Part C pediatric participants in Cohort Cl will receive a single dose of 100 mg followed by daily dosing starting at approximately Week 8 continuing for 14 days.
  • the multi-day dosing regimen for all Part C cohorts and single dose levels for Cohorts C2 to C4 will be informed by emerging data. Doses utilized will not exceed doses determined to have acceptable tolerability in adults or older age pediatric cohorts.
  • Part C cohorts C3 and C4 will be administered Compound I as either a powder for oral solution, or a dispersible tablet.
  • Table ! below includes the preliminary blood analysis of Patient A who was administered Compound I according to the dosing regimen described above m Part A Sub Study 2. Patient A is male and 61 years old.
  • Table d below includes preliminary blood analysis of Patient B who was administered
  • Table 4 below includes preliminary blood analysis of Patient C who was administered

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Abstract

L'invention concerne des méthodes de traitement de la drépanocytose comprenant l'administration du composé I, un modulateur de l'hémoglobine, selon certains schémas posologiques.
PCT/IB2024/055707 2023-06-13 2024-06-11 (s)-2-hydroxy-6-((4-(2-(2-hydroxyéthyl)nicotinoyl)morpholin-3-yl) méthoxy)benzaldéhyde destiné à être utilisé dans le traitement de la drépanocytose Pending WO2024256964A1 (fr)

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