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WO2025207563A1 - Utilisation d'un activateur de pk dans le traitement de la drépanocytose - Google Patents

Utilisation d'un activateur de pk dans le traitement de la drépanocytose

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Publication number
WO2025207563A1
WO2025207563A1 PCT/US2025/021249 US2025021249W WO2025207563A1 WO 2025207563 A1 WO2025207563 A1 WO 2025207563A1 US 2025021249 W US2025021249 W US 2025021249W WO 2025207563 A1 WO2025207563 A1 WO 2025207563A1
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WIPO (PCT)
Prior art keywords
compound
solvate
pharmaceutically acceptable
acceptable salt
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/US2025/021249
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English (en)
Inventor
Michael Urban CALLAGHAN
Peter F. HAWKINS
Rolandas URBSTONAITIS
Michael Cooper
Varsha Venkatachalam IYER
Sebastien Jacques Rene RONSEAUX
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Agios Pharmaceuticals Inc
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Agios Pharmaceuticals Inc
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Publication of WO2025207563A1 publication Critical patent/WO2025207563A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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 monogenetic red blood disorder that is characterized by hemolytic anemia and vaso-occlusive crises (VOCs), which may also be referred to as sickle cell pain crises (SCPCs).
  • VOCs hemolytic anemia and vaso-occlusive crises
  • SCPCs sickle cell pain crises
  • RBCs red blood cells
  • Sickling is one of the core factors that cause vaso-occlusion and sickling is modulated by glycolytic intermediates such as 2,3- diphosphoglycerate (2,3 -DPG) and adenosine triphosphate (ATP).
  • red blood cell pyruvate kinase PLR
  • PK Pyruvate Kinase
  • SCD red blood cell pyruvate kinase
  • PK Pyruvate Kinase
  • allosteric activators of PK increases enzymatic activity and thermostability, reduces 2,3 -DPG levels, decreases hemoglobin oxygen affinity (p50,) and subsequently reduced sickling
  • p50 hemoglobin oxygen affinity
  • AG-946 was also investigated in a Phase 1 study to assess its safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers, and then subsequently tested in the same Phase 1 trial to determine its safety, tolerability, pharmacokinetics and pharmacodynamics in subjects with sickle cell disease. See e.g., U.S. clinical trials identifiers NCT05490446 and NCT04536792, respectively. It is important to note that the Phase 1 trial of AG-946 in healthy volunteers and the Phase lb study in SCD patients, like most Phase 1 trials, were designed to determine the safety not the efficacy of AG-946. The efficacy of AG-946 in patients with SCD will be investigated in a future Phase 2 clinical trial.
  • SCPC sickle cell pain crisis
  • ATP adenosine triphosphate
  • a pharmaceutical composition comprising Compound 1 is used in any of the provided methods and/or uses described herein.
  • a solvate of Compound 1, a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 is used in any of the provided methods and/or uses described herein.
  • the amount of a solvate of Compound 1, the amount of a pharmaceutically acceptable salt of Compound 1 or the amount of a solvate of a pharmaceutically acceptable salt of Compound 1 used in any of the provided methods and/or uses described herein is a dose that is equivalent to a dose of about 1 mg to about 30 mg of Compound 1.
  • FIG. 1A depicts the hemoglobin change in patients (cohort 1) after a 2 mg daily dose of Compound 1.
  • FIG. IB depicts the hemoglobin change in patients (cohort 2) after a 5 mg daily dose of Compound 1.
  • FIG. 2A depicts the percent (%) change in lactate dehydrogenase (LDH), indirect bilirubin, reticulocytes, and erythropoietin in patients (cohort 1) after a 2 mg daily dose of Compound 1.
  • FIG. 2B depicts the percent change in lactate dehydrogenase (LDH), indirect bilirubin, reticulocytes, and erythropoietin in patients (cohort 2) after a 5 mg daily dose of Compound 1.
  • FIG. 3 shows the change in hemoglobin in patients (cohort 2) after a 5 mg daily dose of Compound 1 for 28 days, and a follow up period of 28 days where no drug is administered.
  • FIG. 4 shows the percent (%) change in the % of reticulocytes (% reticulocyte) in patients (cohort 2) after a 5 mg daily dose of Compound 1 for 28 days, and a follow up period of 28 days where no drug is administered.
  • FIG. 5 shows the percent (%) reduction in LDH in patients (cohort 2) after a 5 mg daily dose of Compound 1 for 28 days, and a follow up period of 28 days where no drug is administered.
  • FIG. 6A depicts the change in Pyruvate Kinase R (PKR) activation after ex vivo treatment with Compound 1 or another PK activator (mitapivat).
  • PSR Pyruvate Kinase R
  • FIG. 6B depicts the change in PKR thermostability after ex vivo treatment with Compound 1 or mitapivat.
  • FIG. 7A depicts the reduction in 2,3 diphosphoglyceric acid (2,3 DPG) after ex vivo treatment with Compound 1 or mitapivat.
  • FIG. 7B depicts the change in adenosine triphosphate (ATP)/2,3 DPG ratio after ex vivo treatment with Compound 1 or mitapivat.
  • ATP adenosine triphosphate
  • FIG. 8A depicts the reduction in p50 after ex vivo treatment with Compound 1 or mitapivat.
  • FIG. 8B depicts the reduction in PoS after ex vivo treatment with Compound 1 or mitapivat.
  • provided herein are methods of treating sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising a dose of about 1 mg to about 30 mg of Compound 1) to a subject.
  • methods of treating sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to a subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods of treating sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to a subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods of treating sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to a subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the methods of treating sickle cell disease in a subject comprise orally administering a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the methods for treating sickle cell disease in a subject comprise orally administering a dose of about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for treating sickle cell disease in a subject.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for treating sickle cell disease in a subject wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for treating sickle cell disease in a subject, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1) for the manufacture of an oral medicament for treating sickle cell disease in a subject, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • the use of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for treating sickle cell disease in a subject wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for treating sickle cell disease in a subject, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for treating sickle cell disease in a subject, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1 or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg, or about 5 mg or about 7.5 mg of Compound 1.
  • provided herein are methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject.
  • methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the dose for increasing hemoglobin concentration in a subject with sickle cell disease is about 1 mg to about 10 mg of Compound 1, or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the dose for increasing hemoglobin concentration in a subject with sickle cell disease is about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or a dose of a pharmaceutically acceptable salt of Compound 1, or a dose of a solvate of Compound 1, or a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the concentration of hemoglobin in a subject prior to orally administering any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the any of the foregoing).
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the dose for increasing the concentration of hemoglobin in a subject is about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the dose for increasing the concentration of hemoglobin in a subject is about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the concentration of hemoglobin in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the use of Compound 1 (or a pharmaceutical composition comprising Compound 1 for the manufacture of an oral medicament for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein are methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising Compound 1) to the subject.
  • methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for reducing hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the methods for reducing hemolysis in a subject comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the methods for reducing hemolysis in a subject comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the level of hemolysis in a subject prior to orally administering any dose of Compound 1, or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the use of a dose for reducing hemolysis in a subject comprises about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • a dose for reducing hemolysis in a subject comprises about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • compositions comprising Compound 1 for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1.
  • LDH lactate dehydrogenase
  • reducing lactate dehydrogenase (LDH) in a subject comprises the use of a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising the any of the foregoing).
  • Compound 1 or a pharmaceutical composition comprising Compound 1 for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • LDH lactate dehydrogenase
  • an amount of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing lactate dehydrogenase (LDH) as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament for reducing lactate dehydrogenase is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • the medicament for reducing lactate dehydrogenase is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1.
  • baseline refers to the level of LDH in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein are methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject.
  • methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for reducing cell-free heme as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the methods for reducing cell-free heme comprises administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the methods for reducing cell -free heme comprises administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the level of cell-free heme in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing cell-free heme as compared to baseline in a subject with sickle cell disease.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing cell-free heme as compared to baseline in a subject with sickle cell disease wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • reducing cell-free heme in a subject comprises the use of a dose of about 1 mg to about 10 mg of Compound 1, or the use of an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the level of cell-free heme in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • an amount of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing cell- free heme as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing cell-free heme as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament for reducing cell-free heme in a subject is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • an amount of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing the number or frequency of VOC (vaso-occlusive crisis) events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • baseline refers to the number or frequency of VOC events in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • SCPC sickle cell pain crisis
  • provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • SCPC sickle cell pain crisis
  • the use for reducing the number or frequency of sickle cell pain crisis (SCPC) events comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • SCPC sickle cell pain crisis
  • the use for reducing the number or frequency of sickle cell pain crisis (SCPC) events comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • SCPC sickle cell pain crisis
  • baseline refers to the number or frequency of SCPC events in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • Compound 1 or a pharmaceutical composition comprising Compound 1 for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • an amount of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing the number or frequency of sickle cell pain crisis events as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1.
  • baseline refers to the number or frequency of SCPC events in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • VOCs vaso-occlusive crisis
  • SCPC sickle cell pain crisis
  • provided herein are methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • VOCs vaso-occlusive crisis
  • SCPC sickle cell pain crisis
  • provided herein are methods for reducing the number or frequency of hospitalization visits for treatment of VOCs (vaso-occlusive crisis) or sickle cell pain crisis (SCPC) events per year as compared to baseline or for reducing the number of prescriptions for opioids or other pain medications per year as compared to baseline or for reducing the number of days of opioid use or use of other pain medications per year as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • VOCs vaso-occlusive crisis
  • SCPC sickle cell pain crisis
  • baseline refers to the number of days of opioid use or use of other pain medications for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the number of days of opioid use or use of other pain medications for the treatment of VOCs or SCPC events per year in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the use for reducing fatigue comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the level of fatigue in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing fatigue as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • provided herein are methods for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the solvate of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the methods for reducing one or more markers of hemolysis comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the methods for reducing one or more markers of hemolysis comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the level of one or more markers of hemolysis in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • baseline refers to the level of one or more markers of hemolysis in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • baseline refers to the level of one or more markers of hemolysis in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein are methods for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject.
  • methods for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for reducing erythropoietin as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the methods for reducing erythropoietin comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the methods for reducing erythropoietin comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the level of erythropoietin in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the use for reducing erythropoietin comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the use for reducing erythropoietin comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the level of erythropoietin in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • Compound 1 or a pharmaceutical composition comprising Compound 1 for the manufacture of an oral medicament for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for reducing erythropoietin as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • baseline refers to the level of erythropoietin in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • ATP adenosine triphosphate
  • adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease
  • methods for increasing adenosine triphosphate (ATP) concentration comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • ATP adenosine triphosphate
  • adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease
  • methods for increasing adenosine triphosphate (ATP) concentration comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • ATP adenosine triphosphate
  • adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease
  • methods for increasing adenosine triphosphate (ATP) concentration comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • ATP adenosine triphosphate
  • the methods for increasing adenosine triphosphate (ATP) concentration comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • ATP adenosine triphosphate
  • the methods for increasing adenosine triphosphate (ATP) concentration comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • ATP adenosine triphosphate
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the use for increasing adenosine triphosphate (ATP) concentration is a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the use for increasing adenosine triphosphate (ATP) concentration is a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the ATP concentration in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • Compound 1 or a pharmaceutical composition comprising Compound 1 for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • ATP adenosine triphosphate
  • an amount of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1.
  • baseline refers to the ATP concentration in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • kits for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) to the subject.
  • provided herein are methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of Compound 1 (or a pharmaceutical composition comprising a solvate of Compound 1) to the subject, wherein the pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein are methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease comprising orally administering a dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) to the subject, wherein the solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprise administering a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the methods for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprise administering a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the 2,3 DPG concentration in a subject prior to the oral administration of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • provided herein is the oral use of a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising about 1 mg to about 30 mg of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease.
  • a dose of an amount of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease wherein the amount of the pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • a dose of an amount of a solvate of Compound 1 (or a pharmaceutical composition comprising an amount of a solvate of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease wherein the amount of the solvate of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • provided herein is the oral use of a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a solvate of a pharmaceutically acceptable salt of Compound 1) for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the amount of the solvate of a pharmaceutically acceptable salt of Compound 1 used is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the use for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprises a dose of about 1 mg to about 10 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the use for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration comprises a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • baseline refers to the 2,3 DPG concentration in a subject prior to the oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • Compound 1 or a pharmaceutical composition comprising Compound 1 for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of about 1 mg to about 30 mg of Compound 1.
  • an amount of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of Compound 1 for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 for the manufacture of an oral medicament for decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease, wherein the medicament is formulated to comprise a dose of an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 1 mg to about 10 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 1 mg to about 10 mg of Compound 1.
  • the medicament is formulated to comprise a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 that is equivalent to a dose of about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1.
  • baseline refers to the concentration of 2,3 DPG in a subject prior to the oral administration or oral use of any dose of Compound 1 or any dose of a pharmaceutically acceptable salt of Compound 1, or any dose of a solvate of Compound 1, or any dose of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising any of the foregoing).
  • the provided methods and uses comprise increasing hemoglobin concentration as compared to baseline in a subject with sickle cell disease.
  • the subject increases about 1.0 g/dL (grams per deciliter) or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 1.5 g/dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 2.0 g/dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 2.5 g/dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 3.0 g/dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 3.5 g/dL or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases by an amount of about 1.0 g/dL to about 3.5 g/dL as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 45 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • “after about x days to about y days” refers to the time period between (and including) day x and day y of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 30 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases as compared to baseline after about 1 day to about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 1.0 g/dL or more as compared to baseline after about 1 day to about 45 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 1.0 g/dL or more as compared to baseline after about 8 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 1.5 g/dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 2.0 g/dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s hemoglobin concentration increases about 3.0 g/dL or more as compared to baseline after about 15 days of administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject has a baseline hemoglobin concentration of about 5.0 g/dL to about 11.0 g/dL. In some aspects, the subject has a baseline hemoglobin concentration of about 5.5 g/dL to about 10.5 g/dL. In some aspects, the subject has a baseline hemoglobin concentration of about 5.0 g/dL to about 9.0 g/dL.
  • baseline refers to a level or concentration of a particular analyte or marker that is measured or established prior to treatment with, or prior to administration of, or at a specific time-point or over a certain period of time (e.g., an average of measurements over a certain period of time) during treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a baseline may be a single measurement that is taken prior to treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a baseline may be based on an average of two or more measurements that are taken over a certain period of time, for example, such as one or more weeks apart, prior to treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the hemoglobin concentration of the subject being treated increases as compared to baseline over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks during treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the provided methods and uses comprise reducing one or more markers of hemolysis as compared to baseline in a subject with sickle cell disease.
  • the one or more markers of hemolysis are selected from lactate dehydrogenase (LDH), indirect bilirubin, and percent reticulocyte (% reticulocyte).
  • LDH lactate dehydrogenase
  • % reticulocyte percent reticulocyte
  • a reduction in one or more hemolysis markers is a reduction of the amounts of one or more of these analytes in the blood of the subject as compared to baseline.
  • the subject’s lactate dehydrogenase is reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s lactate dehydrogenase is reduced by about 30% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the provided methods and uses comprise reducing cell-free heme as compared to baseline in a subject with sickle cell disease.
  • free heme or “free hemoglobin” or “naked hemoglobin” are used interchangeably herein and refer to unbound hemoglobin that is not enclosed in a red blood cell. Free heme may be generated by hemolysis as a pathological feature of sickle cell disease. Generated in sufficient enough quantity, free heme can overwhelm protective mechanisms such as haptoglobin and hemopexin. Free heme in excess of what can be scavenged by the body’s protective mechanisms can have serious and deleterious effects on health and well-being (See, Gbotosho et al., Front. Immunol., 26 January 2021, vol. 11).
  • the subject’s cell-free heme concentration is reduced by about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s cell-free heme concentration is reduced by about 30% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the number or frequency of VOCs are reduced by about 40% or more as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the number or frequency of VOCs are reduced by about 50% or more as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the number or frequency of VOCs are reduced by about 30% to about 80% as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the number or frequency of VOCs are reduced by about 50% to about 90% as compared to baseline in a subject following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the number or frequency of the subject’s VOCs are reduced by about 30% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the measurement of the number or frequency of VOC events is measured over the course of one year.
  • a subject may have a VOC baseline of zero (0) VOCs per year.
  • the provided methods and uses comprise reducing the number or frequency of sickle cell pain crisis (SCPC) events as compared to baseline in a subject with sickle cell disease.
  • SCPC sickle cell pain crisis
  • the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the number or frequency of a subject’s sickle cell pain crisis events are reduced by about 30% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the measurement of the number or frequency of SCPC events is measured over the course of one year.
  • a subject may have a SCPC events baseline of zero (0) SCPC events per year.
  • a subject may have a SCPC events baseline of zero (0) or one (1) SCPC events per year (e.g., zero (0) or one (1) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a SCPC events baseline of at least one (1) SCPC event per year (e.g., at least one (1) SCPC in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a SCPC events baseline of at least two (2) SCPC events per year (e.g., at least two (2) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a SCPC events baseline of zero (0) to three (3) SCPC events per year (e.g., zero (0) to three (3) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a SCPC events baseline of one (1) to three (3) SCPC events per year (e.g., one (1) to three (3) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of less than six (6) sickle cell pain crisis events per year (e.g., less than six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of at least six (6) sickle cell pain crisis events per year (e.g., at least six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a sickle cell pain crisis events baseline of at least six (6) sickle cell pain crisis events per year (e.g., at least six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of no more than six (6) sickle cell pain crisis events per year (e.g., no more than six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a sickle cell pain crisis events baseline of no more than six (6) sickle cell pain crisis events per year (e.g., no more than six (6) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of no more than eight (8) sickle cell pain crisis events per year (e.g., no more than eight (8) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a sickle cell pain crisis events baseline of no more than eight (8) sickle cell pain crisis events per year (e.g., no more than eight (8) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of no more than ten (10) sickle cell pain crisis events per year (e.g., no more than ten (10) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a sickle cell pain crisis events baseline of no more than ten (10) sickle cell pain crisis events per year (e.g., no more than ten (10) SCPC events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of at least ten (10) sickle cell pain crisis events per year (e.g., at least ten (10) sickle cell pain crisis events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of between ten (10) sickle cell pain crisis events to twelve (12) sickle cell pain crisis events per year (e.g., between ten (10) sickle cell pain crisis events to twelve (12) sickle cell pain crisis in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of at least twelve (12) sickle cell pain crisis events per year (e.g., at least twelve (12) sickle cell pain crisis events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject may have a sickle cell pain crisis events baseline of twelve (12) sickle cell pain crisis events or more per year (e.g., twelve (12) sickle cell pain crisis events in the 12 months prior to treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a two-year period.
  • the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a three-year period.
  • the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a five-year period. In another aspect the sickle cell pain crisis events baseline is an average of the sickle cell pain crisis events per year over a ten-year period.
  • a subject has a reduction in the number or frequency of opioid prescriptions requested or filled per year as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • a subject has a reduction in the number of days taking an opioid medication per year as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • VOC(s) and/or sickle cell pain crisis events or SCPC(s) are all used interchangeably herein and any of these terms may be freely substituted for any of the others.
  • the provided methods and uses comprise treating anemia in a subject with sickle cell disease comprising administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • anemia refers to a deficiency of red blood cells (RBCs) and/or hemoglobin.
  • RBCs red blood cells
  • anemia may be diagnosed using a complete blood count (CBC).
  • CBC complete blood count
  • anemia may be diagnosed by measuring the amount of red blood cells in the blood, called hematocrit, and the level of hemoglobin in the blood.
  • anemia may be diagnosed by measuring and/or analyzing one or more of the following: red blood cell count, hemoglobin concentration, iron, ferritin, reticulocytes and a blood smear.
  • anemia may be diagnosed based on the measurement of one or more markers of hemolysis (e.g., RBC count, hemoglobin, reticulocytes, schistocytes, Lactate Dehydrogenase (LDH), haptoglobin, indirect bilirubin, erythropoietin and ferritin) and/or via hemosiderinuria (the presence of hemosiderin in urine), mean corpuscular volume (MCV) and/or red cell distribution width (RDW).
  • the anemia treated by the described methods and uses is dyserythropoietic anemia.
  • the anemia treated by the described methods and uses is hemolytic anemia.
  • the reduction of or improvement in a subject s anemia following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is compared to baseline.
  • the provided methods and uses comprise improving the quality of life (QoL) of a subject with sickle cell disease as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • improving the quality of life of a subject comprises improving the overall feeling and function of the subject as compared to baseline.
  • improving the quality of life of a subject may include improvements in the six minute walking test (6MWT) as compared to baseline following treatment with or administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the 6MWT is one method available in clinical practice to assess physical capacity of a patient or subject with SCD.
  • the main response variable of the 6MWT is the maximum walking distance (6MWD), and cardiopulmonary stress test.
  • the 6MWT is a simple and inexpensive test that is widely used in chronic diseases such as chronic obstructive pulmonary disease and heart failure as well as SCD.
  • FACIT-F Treatmental Assessment of Chronic Illness Therapy - Fatigue Scale
  • the questionnaire comprises 13 questions rated on a scale of zero to four points that measures a subject’s level of fatigue during usual daily activity over the course of one week. A score of less than 22 indicates “normal” levels of fatigue. A score of between 22 and 34 indicates mild-to-moderate fatigue. A score of 35 or more indicates severe fatigue.
  • FACIT-F has been shown to be a reliable and valid measure of fatigue in patients suffering from iron deficiency anemia (See, Acaster et al., Health and Quality of Life Outcomes (2015) 13:60).
  • a Patient Reported Outcomes Measurement Information System® (PROMIS) Fatigue assessment (e.g., PROMIS Fatigue 13a short form or “PROMIS Fatigue”).
  • PROMIS Fatigue is a universal person-centered assessment resource and evaluates ten different factors (pain impact, pain behavior, physical functioning, anxiety, depression, fatigue, satisfaction with discretionary social activities, satisfaction with social roles, sleep disturbance, and sleep related impairment).
  • PROMIS Fatigue scores have a mean of 50 and standard deviation (SD) of 10 in a referent population.
  • the referent population is usually the US General Population.
  • a score of 40 is one SD lower than the mean of the reference population.
  • a score of 60 is one SD higher than the mean of the reference population.
  • a score of 60 is one SD higher than the mean of the reference population.
  • a reduction in fatigue is characterized by at least at 5-point change in a subject’s fatigue score as compared to baseline.
  • a reduction in fatigue is characterized by at least at 8-point change in a subject’s fatigue score as compared to baseline.
  • a reduction in fatigue is characterized by at least at 10-point change in a subject’s fatigue score as compared to baseline.
  • a reduction in fatigue is characterized by a change of between 5- and 10-points in a subject’s fatigue score as compared to baseline.
  • fatigue in a subject is measured using one or more of the aforementioned tests.
  • the provided methods and uses comprise reducing at least one marker of erythropoiesis as compared to baseline in a subject with sickle cell disease.
  • at least one marker of erythropoiesis is selected from absolute reticulocyte count, percent reticulocyte (% reticulocyte) and erythropoietin.
  • the subject’s % reticulocyte is reduced about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s % reticulocyte is reduced about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s % reticulocyte is reduced about 30% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s erythropoietin is reduced about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s erythropoietin is reduced about 20% to about 65% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s erythropoietin is reduced about 40% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the markers of erythropoiesis described above are measured in the blood of the subject.
  • the provided methods and uses comprise reducing erythropoietin as compared to baseline in a subject with sickle cell disease.
  • the subject’s erythropoietin is reduced about 20% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s erythropoietin is reduced about 40% to about 50% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the provided methods and uses comprise increasing adenosine triphosphate (ATP) concentration as compared to baseline in a subject with sickle cell disease.
  • ATP adenosine triphosphate
  • the subject’s ATP concentration is increased by about 50% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s ATP concentration is increased by about 60% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s ATP concentration is increased by about 70% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s ATP concentration is increased by about 50% to about 90% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s ATP concentration is increased by about 60% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s ATP concentration is increased by about 70% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the provided methods and uses comprise decreasing 2,3 diphosphoglyceric acid (2,3 DPG) concentration as compared to baseline in a subject with sickle cell disease.
  • the subject’s 2,3 DPG concentration is reduced by about 40% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s 2,3 DPG concentration is reduced by about 60% or more as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s 2,3 DPG concentration is reduced by about 40% to about 80% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s 2,3 DPG concentration is reduced by about 50% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject’s 2,3 DPG concentration is reduced by about 60% to about 70% as compared to baseline following administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • treatment refers to reversing, alleviating, delaying the onset of, reducing the likelihood of developing, or inhibiting the progress of a condition (e.g., anemia and/or sickle cell disease) or one or more symptoms or complications of a condition or one or more complications of a condition described herein.
  • a condition e.g., anemia and/or sickle cell disease
  • treatment comprises administering Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same) to the subject.
  • following treatment or “following administration” are used interchangeably and mean the period after administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same).
  • such administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same) is continuous and uninterrupted, for example, once daily, every day for a period of time.
  • such administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising the same) is continuous, for example, once daily, every day for a period of time, and then such administration is discontinued for some period of time or permanently.
  • symptoms of sickle cell disease may include one or more of anemia, pain, swelling of hands and feet, infections, and vision problems.
  • complications of sickle cell disease may include one or more of stroke, acute chest syndrome, avascular necrosis, pulmonary hypertension, organ damage, splenic sequestration, hepatic sequestration, leg ulcers, gallstones, priapism, and deep vein thrombosis.
  • treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 may be administered after one or more signs or symptoms or complications of the sickle cell disease have developed or have been observed (i.e., therapeutic treatment) or after the subject has been diagnosed with sickle cell disease by a competent medical professional. Treatment may also be continued after symptoms or complications of sickle cell disease have improved, resolved, abated or stabilized. In some aspects, treatment includes delaying the onset of at least one symptom or complication of sickle cell disease for a period of time.
  • the terms “subject” and “patient” are used interchangeably and refer to a human that is 18 years of age or older. In some aspects, the terms “subject” and “patient” refer to a human that is 16 years of age or older. In some aspects, the terms “subject” and “patient” refer to a human that is 12 years of age or older.
  • the present methods and uses comprises administering a dose of about 1 mg to about 30 mg of Compound 1 (or a pharmaceutical composition comprising Compound 1 in the same amount) or administering a dose of an amount of a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in the same amount) that is equivalent to about 1 mg to about 30 mg of Compound 1.
  • a dose of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 is administered once or twice daily.
  • a dose of about 1 mg to about 30 mg of Compound 1 is administered once daily, or a dose of a solvate of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in the same amount) that is equivalent to about 1 mg to about 30 mg of Compound 1 is administered once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg to about 15 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg to about 15 mg of Compound 1, once daily.
  • a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 is administered at a dose that is equivalent to about 1 mg to about 15 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg to about 10 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg to about 10 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2.5 mg or about 5 mg or about 7.5 mg, once daily; or an amount of a pharmaceutically acceptable salt of Compound 1, or an amount of a solvate of Compound 1, or an amount of a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2.5 mg or about 5 mg or about 7.5 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg to about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1), is administered at a dose that is equivalent to about 1 mg to about 5 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2 mg to about 3 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2 mg to about 3 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 4 mg to about 6 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 4 mg to about 6 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 7 mg to about 8 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 7 mg to about 8 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 2.5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 2.5 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 5 mg of Compound 1, once daily.
  • Compound 1 (or a pharmaceutical composition comprising Compound 1) is administered at a dose of about 7.5 mg, once daily; or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered at a dose that is equivalent to about 7.5 mg of Compound 1, once daily.
  • the subject is administered at least one of hydroxyurea (HU), L- glutamine and crizanlizumab for the treatment of sickle cell disease in addition to Compound 1, or a solvate of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • HU hydroxyurea
  • L- glutamine and crizanlizumab for the treatment of sickle cell disease in addition to Compound 1, or a solvate of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject is administered folic acid in addition to Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject is administered folic acid in an amount that is equivalent to at least about 0.8 mg/day of folic acid in addition to Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • the subject is administered one or more of folic acid, hydroxyurea (HU), L-glutamine and crizanlizumab, in addition to Compound 1, or a solvate of Compound 1, or a pharmaceutically acceptable salt of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • folic acid hydroxyurea (HU)
  • HU hydroxyurea
  • crizanlizumab crizanlizumab
  • the subject of the described methods and uses has been previously treated with a pyruvate kinase (PK) activator other than Compound 1 and has discontinued treatment with said PK activator prior to administration of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1).
  • PK pyruvate kinase
  • the present methods and uses comprise administering Compound 1 (or a pharmaceutical composition comprising Compound 1).
  • Compound 1 refers to the non-solvated, non-salt, free base form of Compound 1.
  • the present methods and uses comprise administering a pharmaceutically acceptable salt or a solvate of a pharmaceutically acceptable salt of Compound 1.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically acceptable salt of Compound 1 or solvate of a pharmaceutically acceptable salt is a stoichiometric or non-stoichiometric salt.
  • a pharmaceutically acceptable salt of Compound 1 or solvate of a pharmaceutically acceptable salt is a stoichiometric salt. In some aspects, a pharmaceutically acceptable salt of Compound 1 or solvate of a pharmaceutically acceptable salt is a non-stoichiometric salt.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4 ⁇ salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 refers to Compound 1 or a pharmaceutically acceptable salt of Compound 1 comprising a stoichiometric or non-stoichiometric amount of solvent, or mixture of solvents, including organic or non-organic solvents (e.g., water).
  • the term “solvate” should be understood to refer to water (i.e., a hydrate) or an organic solvent.
  • a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a hydrate of Compound 1 or a hydrate of a pharmaceutically acceptable salt of Compound 1.
  • hydrate refers to solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprising a stoichiometric or non- stoichiometric amount of water.
  • a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a stoichiometric amount of solvent.
  • a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a non-stoichiometric amount of solvent.
  • a solvate of Compound 1 or a solvate of a pharmaceutically acceptable salt of Compound 1 comprises a stoichiometric or non-stoichiometric amount of water.
  • a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a non-stoichiometric or stoichiometric salt and a non-stoichiometric or stoichiometric amount of solvent.
  • a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a non-stoichiometric salt and a non-stoichiometric amount of solvent.
  • a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a non-stoichiometric salt and a non-stoichiometric amount of water. In some aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a stoichiometric salt and a stoichiometric amount of solvent. In certain aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a stoichiometric salt and a stoichiometric amount of water.
  • a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a stoichiometric salt and a non-stoichiometric amount of solvent. In certain aspects, a solvate of a pharmaceutically acceptable salt of Compound 1 is comprised of a stoichiometric salt and a non-stoichiometric amount of water.
  • anhydrous refers to the solvate or non-solvate form of Compound 1 that is free (or substantially free) of water and may also be referred to as an “anhydrate”.
  • the present methods and uses comprise administering a sulfate salt of Compound 1 or a hydrate of a sulfate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a hemi sulfate salt of Compound 1 or a hydrate of a hemisulfate salt in the described amount, e.g., in an amount that is equivalent to the described amount of Compound 1. In some aspects, the present methods and uses comprise administering a hemisulfate hemihydrate salt of Compound 1 in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1).
  • the present methods and uses comprise administering a phosphate salt of Compound 1 or a hydrate of a phosphate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a DL-tartrate salt of Compound 1 or a hydrate of a DL-tartrate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a hydrochloride salt of Compound 1 or a hydrate of a hydrochloride salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1).
  • the present methods and uses comprise administering an oxalate salt of Compound 1 or a hydrate of a oxalate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a glycolate salt of Compound 1 or a hydrate of a glycolate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1). In some aspects, the present methods and uses comprise administering a tosylate salt of Compound 1 or a hydrate of a tosylate salt in the described amount (e.g., in an amount that is equivalent to the described amount of Compound 1).
  • the present methods and uses also comprise administering pharmaceutical compositions comprising each of the salts of Compound 1 as described herein.
  • the present methods and uses also comprise administering pharmaceutical compositions comprising the solvated salts of Compound 1 as described herein.
  • Polymorphic and/or crystalline forms of Compound 1, pharmaceutically acceptable salts of Compound 1, solvates of Compound 1, and solvates of pharmaceutically acceptable salts of Compound 1 are also included as part of the present methods and uses.
  • such forms include those described in US 63/466,552 and include crystalline Form A hemisulfate hemihydrate salt characterized by at least two, at least three, at least four, at least five, at least six, or seven x-ray powder diffraction peaks at 20 (2 theta) angles selected from 9.8° ( ⁇ 0.2°), 11.3° ( ⁇ 0.2°), 13.6° ( ⁇ 0.2°), 18.4° ( ⁇ 0.2°), 22.8 ° ( ⁇ 0.2°), 23.3 ° ( ⁇ 0.2°), and 28.6° ( ⁇ 0.2°); crystalline Form B phosphate salt characterized by at least two, at least three, at least four, at least five, at least six, or seven x-ray powder diffraction peaks at 20 angles selected from 10.2°( ⁇ 0.2°), 13.4°( ⁇ 0.2°), 13.6°( ⁇ 0.2°), 14.3°( ⁇ 0.2°), 16.8 °( ⁇ 0.2°), 20.3 °( ⁇ 0.2°), and 21.4
  • Amorphous (e.g., non-crystalline) forms of Compound 1, pharmaceutically acceptable salts of Compound 1, solvates of Compound 1, and solvates of pharmaceutically acceptable salts of Compound 1 are also included in the methods and uses described herein.
  • composition further comprises one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient refers to an inert substance, such as a carrier, adjuvant, additive, diluent or vehicle that does not adversely affect the pharmacological activity of the compound (including the crystalline or amorphous forms described herein) with which it is formulated.
  • the pharmaceutical formulations of the disclosure are comprised of crystalline Compound 1, or a crystalline pharmaceutically acceptable salt of Compound 1, or a crystalline solvate of Compound 1, or a crystalline solvate of a pharmaceutically acceptable salt of Compound 1.
  • the pharmaceutical formulations of the disclosure are comprised of amorphous Compound 1, or an amorphous pharmaceutically acceptable salt of Compound 1, or an amorphous solvate of Compound 1, or an amorphous solvate of a pharmaceutically acceptable salt of Compound 1.
  • a pharmaceutical composition of the disclosure comprises at least one of the following: Compound 1, a pharmaceutically acceptable salt of Compound 1, a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in a variety of solid state forms.
  • a pharmaceutical composition comprises at least one of the following: a crystalline form of Compound 1, a crystalline form of a pharmaceutically acceptable salt of Compound 1, a crystalline form of a solvate of Compound 1, or a crystalline form of a solvate of a pharmaceutically acceptable salt of Compound 1.
  • a pharmaceutical composition comprises at least one of the following: an amorphous form of Compound 1, an amorphous form of a pharmaceutically acceptable salt of Compound 1, an amorphous form of a solvate of Compound 1, or an amorphous form of a solvate of a pharmaceutically acceptable salt of Compound 1.
  • a pharmaceutical composition comprises a mixture of one or more of the following: a crystalline or amorphous form of Compound 1, a crystalline or amorphous form of a pharmaceutically acceptable salt of Compound 1, a crystalline or amorphous form of a solvate of Compound 1, or a crystalline or amorphous form of a solvate of a pharmaceutically acceptable salt of Compound 1.
  • compositions described herein can be prepared by any method known in the art of pharmacology.
  • preparatory methods include the steps of bringing Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 into association with at least one excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, filling and/or shaping (by any number of methods) the mixture into a dosage form and/or packaging the product into a desired single- or multi-dose unit.
  • compositions comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or as liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 into association with an excipient, such as, for example, a carrier, which constitutes one or more necessary ingredients.
  • an excipient such as, for example, a carrier, which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing one or more of the crystalline or amorphous forms of the disclosure with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients (excipients).
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more excipients such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 can be combined in an intimate admixture with one or more pharmaceutical excipients according to conventional pharmaceutical compounding techniques.
  • the excipients can take a wide variety of forms depending on the form of preparation desired for oral administration.
  • compositions for an oral dosage form any of the usual pharmaceutical media can be employed as excipients, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, antioxidants, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, antioxidants, and disintegrating agents can be used in the case of oral solid preparations.
  • suitable oral dosage forms include, but are not limited to, powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Carriers such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, silicified microcrystalline cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cationexchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked polyvinylpyrrolidone
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (c.g, carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),
  • Exemplary binding agents include, but are not limited to, starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, silicified microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, wax
  • suitable fillers for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), silicified microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle.
  • Too little of a disintegrant may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used in the dosage forms comprising Compound 1 as described herein or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1 or a pharmaceutically acceptable salt of a solvate of Compound 1.
  • the amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Exemplary preservatives include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.
  • antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl.
  • Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, is
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Exemplary natural oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sas
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • the active ingredient therein may be combined with various scenting/perfuming, sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Film coatings may be used, such as, for example, Opadry® II Blue film coat [polyvinyl alcohol, titatnium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E132] and the like.
  • Surfactants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene stearoyl
  • hydrophilic-non-ionic surfactants may include, but are not limited to, PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 gly
  • Suitable lipophilic surfactants include, but are not limited to, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the disclosure and to minimize precipitation of the compound of the disclosure.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol (PEG), polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; polyethylene glycol 660 12-hydroxy stearate, amides and other nitrogen-containing compounds such
  • solubilizers may also be used. Examples include, but are not limited to, mixtures of one or more of the following: triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of less than about 10%, less than about 25%, less than about 50%, about 100%, or up to less than about 200% by weight, based on the combined weight of the drug, and other excipients.
  • solubilizer may also be used, such as less than about 5%, less than about 2%, less than about 1% or even less.
  • the solubilizer may be present in an amount of less than about 1% to about 100%, more typically less than about 5% to less than about 25% by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, but are not limited to, filmcoatings, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • the excipient is selected from one or more of mannitol, sorbitol, inositol, silicified microcrystalline cellulose (SMCC), Croscarmellose Sodium, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), pregelatinized starch (starch 1500), microcrystalline starch, Sodium Stearyl Fumarate, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, polyvinyl alcohol, titatnium dioxide, macrogol/polyethylene glycol, sorbitan fatty acid esters, talc, FD&C blue #2/indigo carmine aluminum lake/E132.
  • SMCC silicified microcrystalline cellulose
  • Croscarmellose Sodium cross-linked poly
  • the excipient is selected from one or more of silicified microcrystalline cellulose (SMCC), Croscarmellose Sodium, Sodium Stearyl Fumarate, polyvinyl alcohol, titatnium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E132.
  • SMCC silicified microcrystalline cellulose
  • Croscarmellose Sodium Croscarmellose Sodium
  • Sodium Stearyl Fumarate polyvinyl alcohol
  • titatnium dioxide polyvinyl alcohol
  • talc titatnium dioxide
  • FD&C blue #2/indigo carmine aluminum lake/E132 FD&C blue #2/indigo carmine aluminum lake/E132.
  • the excipient is selected from one or more of silicified microcrystalline cellulose (SMCC), croscarmellose Sodium, Sodium Stearyl Fumarate, and Opadry® II Blue film coat.
  • SMCC silicified microcrystalline cellulose
  • croscarmellose Sodium croscarmellose Sodium
  • Sodium Stearyl Fumarate Sodium Stearyl Fumarate
  • the excipient is selected from one or more of mannitol, pregelatinized starch (starch 1500), hydrogenated vegetable oil, and Opadry® II Blue film coat.
  • the excipient is selected from one or more of sorbitol, cross- sodium carboxymethyl starch (sodium starch glycolate), zinc stearate, and Opadry® II Blue film coat.
  • the excipient is selected from one or more of silicified microcrystalline cellulose (SMCC), Croscarmellose Sodium, Sodium Stearyl Fumarate, polyvinyl alcohol, titatnium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E132, olyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tri stearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span SMCC), Croscarmellose Sodium,
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered in or administered as an oral dosage form.
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered as a tablet.
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound l(or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) is administered as a capsule.
  • the terms “as”, “in” and “as part of’ when referring to the administration of the active pharmaceutical ingredient (i.e., Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) are used interchangeably and mean that the active pharmaceutical ingredient is contained in an oral dosage form, including, for example, a tablet, capsule, granules/minitablets, lozenge, syrup and the like.
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered as part of a spray-dried dispersion.
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is administered as part of a pharmaceutical composition comprising a spray-dried dispersion comprising at least one polymer selected from copovidone, hypromellose acetate succinate based amorphous solid, medium grade (HPMCAS-MG), and polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA).
  • a spray-dried dispersion comprising at least one polymer selected from copovidone, hypromellose acetate succinate based amorphous solid, medium grade (HPMCAS-MG), and polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA).
  • the tablet composition comprises about 2% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 98% w/w ( ⁇ 2%) comprising one or more excipients.
  • the tablet composition comprises about 5% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 95% w/w ( ⁇ 2%) of one or more excipients.
  • the tablet composition comprises about 7% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 93% w/w ( ⁇ 2%) of one or more excipients.
  • the tablet composition comprises about 10% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 90% w/w ( ⁇ 2%) of one or more excipients.
  • the tablet composition comprises about 12% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 88% w/w ( ⁇ 2%) of one or more excipients.
  • the tablet composition comprises about 15% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 85% w/w ( ⁇ 2%) of one or more excipients.
  • the tablet composition comprises about 18% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 82% w/w ( ⁇ 2%) of one or more excipients.
  • the tablet composition comprises about 20% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 80% w/w ( ⁇ 2%) of one or more excipients.
  • the tablet composition comprises about 25% w/w ( ⁇ 1%) of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and about 75% w/w ( ⁇ 2%) of one or more excipients.
  • a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable excipient that has been processed to generate particles of a consistent size (“milled powder”).
  • processing the milled powder comprises milling a composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and a pharmaceutically acceptable excipient for an amount of time suitable to bring about a desired particle size.
  • the particle size of the milled powder is less than about 200 pm.
  • the particle size of the milled powder is less than about 100 pm. In some aspects, the particle size of the milled powder is less than about 75 pm. In some aspects, the particle size of the milled powder is less than about 50 pm. In some aspects, the particle size of the milled powder is less than about 45 pm. In some aspects, the particle size of the milled powder is less than about 40 pm. In some aspects, the particle size of the milled powder is less than about 35 pm. In some aspects, the particle size of the milled powder is less than about 30 pm. In some aspects, the particle size of the milled powder is less than about 25 pm. In some aspects, the particle size of the milled powder is less than about 20 pm.
  • the particle size of the milled powder is less than about 15 pm. In some aspects, the particle size of the milled powder is less than about 10 pm. In some aspects, the particle size of the milled powder is less than about 5 pm. In some aspects, the particle size of the milled powder is less than about 1 pm. In some aspects, the particle size of the milled powder is less than about 500 nm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 200 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 100 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 75 pm.
  • the particle size of the milled powder ranges from about 500 nm to about 50 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 45 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 40 pm. In some aspects, the particle size of the milled powder ranges from about 500 nm to about 35 pm. In some aspects, the particle size of the milled powder ranges from about 1 pm to about 45 pm. In some aspects, the particle size of the milled powder ranges from about 1 pm to about 40 pm. In some aspects, the particle size of the milled powder ranges from about 1 pm to about 35 pm.
  • the particle size of the milled powder is about 45 pm. In some aspects, the particle size of the milled powder is about 40 pm. In some aspects, the particle size of the milled powder is about 35 pm. In some aspects, the particle size of the milled powder is about 30 pm. In some aspects, the particle size of the milled powder is about 25 pm. In some aspects, the particle size of the milled powder is about 5 pm. In some aspects, the particle size of the milled powder is about 4 pm. In some aspects, the particle size of the milled powder is about 3 pm. In some aspects, the particle size of the milled powder is about 2 pm. In some aspects, the particle size of the milled powder is about 1 pm. The term “about,” as used herein with respect to particle size, means +/- 5 pm.
  • At least 90% of a representative sample of the milled powder has a particle size of less than about 100 pm, about 90 pm, about 80 pm, about 70 pm, about 60 pm, about 50 pm, about 40 pm, about 30 pm, about 20 pm, or about 10 pm. In some aspects, at least about 90% of a representative sample of the milled powder has a particle size of less than about 60 pm.
  • the pharmaceutical composition comprises amorphous Compound 1.
  • the pharmaceutical composition comprises amorphous Compound 1 and at least one excipient.
  • the pharmaceutical composition comprises a solid dispersion.
  • the pharmaceutical composition comprises amorphous Compound 1, or an amorphous pharmaceutically acceptable salt of Compound 1, or an amorphous solvate of Compound 1, or an amorphous solvate of a pharmaceutically acceptable salt of Compound 1 in a solid dispersion.
  • the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and one or more polymer(s).
  • the solid dispersion is a spray dried dispersion.
  • the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, one or more polymer(s), and one or more surfactant(s).
  • the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 and at least one polymer. In some aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, at least one polymer, and at least one surfactant.
  • the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises the non-salt (free form) of Compound 1. In other aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises a pharmaceutically acceptable salt of Compound 1. In certain aspects the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises a non-stoichiometric pharmaceutically acceptable salt of Compound 1. In certain other aspects the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises a stoichiometric pharmaceutically acceptable salt of Compound 1. In other aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises the monohydrate free form of Compound 1. In other aspects, the solid dispersion or pharmaceutical composition comprising the solid dispersion comprises non-hydrated (anhydrous) free form of Compound 1.
  • the solid dispersion comprises at least one polymer that is a water-soluble polymer. In other aspects, the solid dispersion comprises at least one polymer that is a cellulosic polymer. In further aspects, the solid dispersion comprises at least one polymer that is a cellulose ether, cellulose ester, cellulose co-carboxyester, cellulose phthalate, cellulose succinate, or mixtures thereof.
  • the solid dispersion comprises at least one polymer that is methylcellulose (MC); ethylcellulose (EC); hydroxyethylcellulose (HEC); hydroxypropyl methyl cellulose (HPMC) such as HPMC 606 or HPMC E5; hydroxypropyl cellulose (HPC); carboxymethyl ethyl cellulose (CMEC); hydroxypropyl methyl cellulose acetosuccinate (HPMCAS) such as HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, HPMCAS/SLS, HPMCAS AS-MF, HPMCAS-HF; hydroxypropyl methyl cellulose phthalate (HPMCP); cellulose acetate phthalate (CAP); cellulose acetate groups having at least a half of cellulose acetate in hydrolyzed form; polyvinylpyrrolidone such as PVP K-12, PVPVA, PVP K30, PVP K 29/32, or PVPVA 64; polyoxyethylenepolyoxypropylene cop
  • the solid dispersion comprises one or more polymers selected from hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, and polyvinylpyrrolidone (PVP), and mixtures thereof.
  • HPMC hydroxypropyl methyl cellulose
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • HPMCP hydroxypropyl methyl cellulose phthalate
  • HPC hydroxypropyl cellulose
  • ethylcellulose cellulose acetate phthalate
  • PVP polyvinylpyrrolidone
  • one or more polymers in the solid dispersion is a cellulose- based polymer such as HPMC, HPMCAS, HPC, and ethylcellulose.
  • at least one polymer in the solid dispersion is
  • At least one polymer in the solid dispersion is HPMC. In yet further aspects, at least one polymer in the solid dispersion is PVP. In still further aspects, at least one polymer in the solid dispersion is ethylcellulose. In additional aspects, at least one polymer in the solid dispersion is copovidone.
  • the polymer is (or the one or more polymers are) present in the solid dispersion in an amount of about 10% w/w to about 90% w/w (e.g., about 20% w/w to about 80% w/w; about 30% w/w to about 70% w/w; about 40% w/w to about 60% w/w; or about 15% w/w to about 35% w/w).
  • the polymer is (or the one or more polymers are) present in the solid dispersion in an amount of about 10% w/w to about 80% w/w, about 30% w/w to about 75% w/w, about 40% w/w to about 65% w/w, about 45% w/w to about 55% w/w, about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w, about 50% w/w, about 51% w/w, about 52% w/w, about 53% w/w, or about 54% w/w.
  • the polymer is (or the one or more polymers are) present in the solid dispersion in an amount of about 48% w/w, about 48.5% w/w, about 49% w/w, about 49.5% w/w, about 50% w/w, about 50.5% w/w, about 51% w/w, about 51.5% w/w, about 52% w/w, or about 52.5% w/w.
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is present in the solid dispersion in an amount of about 10% w/w to about 90% w/w (equivalent to the amount of non-solvated free form Compound 1) (e.g., about 20% w/w to about 80% w/w; about 30% w/w to about 70% w/w; about 40% w/w to about 60% w/w; or about 15% w/w to about 35% w/w).
  • Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, is present in the solid dispersion in an amount of about 10% w/w to about 90% w/w, or about 20% w/w to about 80% w/w, or about 30% w/w to about 70% w/w.
  • the solid dispersion further comprises a surfactant.
  • the surfactant is selected from sodium lauryl sulfate (SLS), vitamin E or a derivative thereof (e.g., vitamin E TPGS), docusate sodium, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), pol oxamers (such as Pol oxamer 335 and Pol oxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, pluronic copolymers (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof.
  • SLS sodium lauryl sulfate
  • vitamin E or a derivative thereof e.g., vitamin E TPGS
  • docusate sodium sodium dodecyl sulfate
  • polysorbates such as Tween 20 and Tween 80
  • pol oxamers such as Pol o
  • the surfactant is SLS. In other embodiments, the surfactant is vitamin E or a derivative thereof (e.g., vitamin E TPGS). [00183] In some aspects, the surfactant is present in the solid dispersion in an amount of about 0.1% w/w to about 10% w/w, about 0.5% w/w to about 2% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 4% w/w, or about 1% w/w to about 5% w/w.
  • the surfactant is present in the solid dispersion in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, or about 1% w/w.
  • the surfactant is present in the solid dispersion in an amount of about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w.
  • the disclosure relates to processes for preparing a solid dispersion using one or more of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, as described herein.
  • the process comprises spray-drying a mixture comprising one or more of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, a polymer, and an appropriate solvent or solvent mixture.
  • the solid dispersion prepared according to the processes described herein comprises one or more of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 in substantially amorphous form.
  • the process comprises combining one or more of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 as described herein with a polymer and a solvent to form a mixture that is an emulsion, solution, or suspension; and spray-drying the mixture to produce the solid dispersion.
  • the at least one polymer utilized is described above.
  • the solvent is methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or a mixture thereof. In other aspects, the solvent is methylene chloride and methanol.
  • one or more of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 as described herein may be used as one of the starting materials in a process to prepare a solid dispersion.
  • one or more of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 used as one of the starting materials in the process to prepare a solid dispersion may be crystalline prior to dissolution in the solvent or mixture of solvents used to form the solid dispersion and is one of the crystalline forms of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 described herein.
  • the solid dispersion is prepared by spray drying a solution that was made according to the aforementioned process using one or more of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1.
  • Spray drying involves atomization of a liquid solution containing, e.g., a solid and a solvent or solvent mixture, and removal of the solvent or solvent mixture. Atomization may be done, for example, through a two-fluid or pressure or electrosonic nozzle or on a rotating disk. Removal of the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 °C). Techniques and methods for spray-drying may be found in Perry's Chemical Engineering Handbook, 6th Ed., R. H. Perry, D. W. Green & J. O. Maloney, eds., McGraw-Hill Book Co. (1984); and Marshall "Atomization and Spray- Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954).
  • a range of values is intended to serve as a shorthand method of referring individually to each separate value falling within the range as well as the highest and lowest values that define the range and that each value is incorporated into the specification as if it were individually recited herein, unless expressly stated to the contrary.
  • a range of values from X to Y includes both X and Y and all the values in between X and Y.
  • Table 3 shows data from separate clinical studies of SCD using mitapivat (a PK activator), etavopivat (a PK activator), Oxbryta® and GBT601 (both hemoglobin S (HbS) polymerization inhibitors).
  • the data in Table 3 are not from head-to-head studies (either with each other or with Compound 1) but rather were compiled from publicly available sources.
  • Oxbryta® and GBT601 have different mechanisms of action as compared to Compound 1 (as well as mitapivat and etavopivat).
  • Subjects (patients) afflicted with Sickle Cell Disease will have their baseline vasoocclusive crisis (VOC) events and/or sickle cell pain crisis events from the previous 12 months i.e., annualized rate of VOCs or SCPCs measured or reported by the subject prior to administration (e.g., prior to starting treatment).
  • VOC vasoocclusive crisis
  • SCPC sickle cell pain crisis events
  • the subjects will be administered an oral dose of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1, once daily.
  • VOC and/or SCPC events refer to acute episodes of pain with no cause other than a vaso-occlusive event that require a medical facility visit (including a hospital, an emergency room, or clinic) and treatment with oral or parenteral opioids, or parenteral NSAIDs.
  • VOCs and/or SCPCs Acute chest syndrome, hepatic sequestration, splenic sequestration, and/or priapism requiring a visit to a medical facility for treatment are also considered VOCs and/or SCPCs. This example can be extended for several months to at least one year or more.
  • One or more of the following assessment tools can be used to measure changes to various aspects of a subject’s quality of life (QoL) including, but not limited to fatigue, pain and other measurements of physical function.
  • QoL quality of life
  • Subjects (patients) afflicted with sickle cell disease will have their baseline QoL assessment measured or reported using one or more of the following assessment tools prior to administration (e.g., prior to starting treatment).
  • One or more of the following assessment tools may be used to assess a subject’s quality of life as compared to baseline: Patient-Reported Outcomes Measurements Information System (PROMIS) Pain Intensity, Adult Sickle Cell Quality of Life Measurements Information System (ASCQ-Me-) Pain Impact, Patient-Reported Outcomes Measurements Information System (PROMIS) Physical Function, Patient Global Impressions of Severity and Change (PGIS and PGIC), European Quality of Life (EuroQoL) Group 5-level EQ-5D, Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F), Adult Sickle Cell Quality of Life Measurement (ASCQ-Me-), Patient-Reported Outcome Measurement Information System® (PROMIS) and the Six Minute Walking Test (6MWT).
  • PROMIS Patient-Reported Outcomes Measurements Information System Pain Intensity, Adult Sickle Cell Quality of Life Measurements Information System
  • ASCQ-Me- Pain Impact
  • PROMIS Patient-Reported Outcomes Measurements Information System
  • the subjects will be administered an oral dose of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1), once daily.
  • PROMIS pain intensity la is a single-item instrument measuring self-reported average level of pain intensity over the last 7 days using an 11 -point numeric rating scale from 0 (no pain) to 10 (worst imaginable pain).
  • PROMIS pain intensity la questionnaires will be provided to subjects before (to establish a baseline), during, and after treatment. The trend in scores over time will determine the level of favorable outcome (e.g., the improvement in a subject’s PROMIS pain intensity la) for each subject.
  • the PROMIS pain intensity la - can be used throughout a subject’s treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) as necessary.
  • the ASQC-Me- Pain Impact evaluates interference of pain on subject’s lives via 5 items, each using a 5 -point verbal rating scale. Scores are expressed as T-scores, representing a standardized score with a mean of 50 and a standard deviation of 10; higher scores represent healthier status.
  • ASQC-Me- Pain Impact questionnaires will be provided to subjects before (to establish a baseline), during, and after treatment. The trend in scores over time will determine the level of favorable outcome (e.g., the improvement in a subject’s ASQC-Me- Pain Impact) for each subject.
  • the ASQC-Me- Pain Impact can be used throughout a subject’s treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) as necessary.
  • Subjects (patients) afflicted with Sickle Cell Disease will have their baseline function, fatigue, and pain measured or reported prior to administration.
  • the subjects will be administered an oral dose of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) once daily.
  • the function, fatigue, and pain of the patient will be measured and reassessed to determine whether there is any improvement during treatment. This example can be extended for several months to at least one year or more.
  • PROMIS Physical Function 8-Item short form derived from the PROMIS Physical Function item bank, contains 8 questions assessing limitations associated with daily physical activities that are relevant for specific patient populations. Scores are expressed as T-scores, representing a standardized score with a mean of 50 and a standard deviation of 10. Higher scores represent better physical functioning.
  • PROMIS Physical Function questionnaires will be provided to subjects before, during, and after treatment. The trend in scores over time will determine the level of favorable outcome (e.g., the improvement in a subject’s PROMIS Physical Function) for each subject.
  • the PROMIS Physical Function can be used throughout a subject’s treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) as necessary.
  • PGIS and PGIC questions are patient-reported prospective and retrospective ratings, respectively, of disease-related concepts or overall status.
  • the PGIS is a validated, single-item, measure used to assess the quality of life impact or severity of a specific health condition.
  • the PGIC is a validated, single-item measure used to assess the change over time in a particular concept or overall status.
  • the PGIS questions will be administered to assess severity of the following 3 concepts as perceived by the subject over the recall periods note below on a 4-point scale, for example, ranging from “none” to “severe”.
  • PGIS and PGIC can be used throughout a subject’s treatment with Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1 (or a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a solvate of Compound 1, or a solvate of a pharmaceutically acceptable salt of Compound 1) as necessary.

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Abstract

L'invention concerne des méthodes de traitement de la drépanocytose comprenant l'administration par voie orale d'un composé 1 : ou d'un sel pharmaceutiquement acceptable du composé 1, ou d'un solvate du composé 1, ou d'un solvate d'un sel pharmaceutiquement acceptable du composé 1, ou d'une composition pharmaceutique comprenant le composé 1, ou un sel pharmaceutiquement acceptable du composé 1, ou un solvate du composé 1, ou un solvate d'un sel pharmaceutiquement acceptable du composé 1, à des doses spécifiques.
PCT/US2025/021249 2024-03-27 2025-03-25 Utilisation d'un activateur de pk dans le traitement de la drépanocytose Pending WO2025207563A1 (fr)

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Citations (1)

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