Compositions and methods for treating anemia
Inventors
Smith, Alexander • Chandorkar, Gurudatt Ajay • Ette, Ene Ikpong • Maroni, Bradley John • Hartman, Charlotte Suzanne • Farzaneh-Far, Ramin • Inrig, Jula Kern
Assignees
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Publication Number
US-11844756-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Provided herein are specific doses of, and dosing regimens for, using a HIF prolyl hydroxylase inhibitor in treating or preventing anemia, such as anemia secondary to or associated with chronic kidney disease, anemia secondary to or associated with non-dialysis dependent chronic kidney disease anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.
Core Innovation
The disclosure relates to HIF-alpha stabilizer and HIF-prolyl hydroxylase inhibitor approaches for treating anemia, including anemia secondary to non-dialysis dependent chronic kidney disease. The document describes Compound 1, and related chemical forms such as pharmaceutically acceptable salts, solvates/hydrates, and metabolites comprising phenolic glucuronide and acyl-glucuronide forms.
The document describes oral unit dosage form formulations comprising intra-granular components, extra-granular components, and film coating components. The formulation framework includes specified weight-percent ranges for Compound 1 and multiple excipients, tablet coating amount ranges, and defines the weight as the total weight of all intra-granular and extra-granular components.
The document further describes treatment of anemia in non-dialysis dependent chronic kidney disease by administering successive doses and by administering an initial daily dose with dose adjustments based on hemoglobin (Hgb) response. Patient eligibility parameters are described using clinical criteria including estimated glomerular filtration rate (eGFR), dialysis timing expectations, baseline hemoglobin, and laboratory thresholds for ferritin, transferrin saturation (TSAT), folate, and vitamin B12, together with an age requirement.
Claims Coverage
The independent claims cover four inventive aspects, spanning an oral tablet formulation for treating anemia, treating anemia secondary to non-dialysis dependent chronic kidney disease with specified patient eligibility criteria, and treating anemia in non-dialysis dependent chronic kidney disease using hemoglobin-response-based dose adjustment regimens. The claim set centers on a specific formulation architecture with intra-granular components, extra-granular components, and film coating components comprising defined weight ranges of Compound 1 and excipients.
Intra-granular, extra-granular, and film-coated tablet formulation for treating anemia
Administering to a patient a formulation comprising intra-granular components, extra-granular components, and film coating components, where the intra-granular components comprise about 60% to about 70% by weight of Compound 1, about 20% to about 30% by weight of microcrystalline cellulose, about 2.5% to about 3.5% by weight of sodium starch glycolate, and about 2.3% to about 3.3% by weight of a hydroxypropyl methylcellulose; the extra-granular components comprise about 2.5% to about 3.5% by weight of a sodium starch glycolate, about 0.2% to about 0.3% by weight of colloidal silicon dioxide, and about 0.55% to about 0.95% by weight of magnesium stearate; and the film coating component comprises about 1.0% to about 8% by weight of a tablet coating, wherein the weight is the total weight of all intra-granular and extra-granular components.
Successive dosing of a specified tablet formulation for non-dialysis dependent CKD-associated anemia with eligibility thresholds
A method of treating a anemia secondary to non-dialysis dependent chronic kidney disease by administering a sufficient number of successive doses of a formulation comprising intra-granular components, extra-granular components, and film coating components, wherein the intra-granular components comprise about 60% to about 70% by weight of Compound 1, about 20% to about 30% by weight of microcrystalline cellulose, about 2.5% to about 3.5% by weight of sodium starch glycolate, and about 2.3% to about 3.3% by weight of a hydroxypropyl methylcellulose; the extra-granular components comprise about 2.5% to about 3.5% by weight of a sodium starch glycolate, about 0.2% to about 0.3% by weight of colloidal silicon dioxide, and about 0.55% to about 0.95% by weight of magnesium stearate; the film coating component comprises about 1.0% to about 8% by weight of a tablet coating; and where the patient has at least 2, 3, 4, 5 or all of the listed eGFR and dialysis-status criteria and laboratory and age criteria.
Initial daily dose with hemoglobin-response-based adjustment rules for non-dialysis dependent CKD-associated anemia
A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease comprising administering to the patient an initial daily dose of Compound 1 as a formulation comprising intra-granular components, extra-granular components, and film coating components having the defined weight-percent ranges for Compound 1, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl methylcellulose, colloidal silicon dioxide, magnesium stearate, and tablet coating, where the dose adjustment rules are based on whether Hgb has not increased by more than 0.5 g/dL above baseline after 4 weeks; whether Hgb rises rapidly; whether Hgb falls below 10.0 g/dL; whether Hgb exceeds specified thresholds; and whether a dose adjustment is required to maintain Hgb at the desired level.
Initial daily dosing and hemoglobin-response-based escalation, reduction, and interruption for non-dialysis dependent CKD-associated anemia
A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease comprising administering to the patient an initial daily dose of Compound 1 as a formulation comprising intra-granular components, extra-granular components, and film coating components having the defined weight-percent ranges for Compound 1, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl methylcellulose, colloidal silicon dioxide, magnesium stearate, and tablet coating, where the dose adjustment rules include increasing the daily dose by 150 mg/day if Hgb has not increased by more than 0.5 g/dL above baseline after 4 weeks, reducing the daily dose by 150 mg/day if Hgb rises rapidly, increasing the daily dose by 150 mg/day if Hgb falls below 10.0 g/dL, reducing the daily dose by 150 mg/day when Hgb exceeds 12.0 g/dL, interrupting treatment when Hgb exceeds 13.0 g/dL until Hgb decreases to 12.5 g/dL or less, and thereafter resuming daily dosing with a daily dose reduced by 150 mg/day; and adjusting the daily dose by 150 mg/day if dose adjustment is required to maintain Hgb at the desired level.
Across the independent claims, the inventive subject matter is organized around an oral tablet formulation architecture with intra-granular, extra-granular, and film coating components defined by weight-percent ranges of Compound 1 and excipients, and treating anemia in non-dialysis dependent chronic kidney disease using successive dosing or initial dosing with dosing adjustments based on Hgb response, together with explicit patient eligibility criteria in one independent claim.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating anemia (including anemia secondary to non-dialysis dependent chronic kidney disease).
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