Compositions and methods for treating anemia
Inventors
Shalwitz, Robert • Hartman, Charlotte • Buch, Akshay • Shalwitz, Isaiah • Janusz, John • Gardner, Joseph
Assignees
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Publication Number
US-11857543-B2
Publication Date
2024-01-02
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 associated with or resulting from chemotherapy, or anemia associated with AIDS.
Core Innovation
The invention relates to treating anemia secondary to or associated with chronic kidney disease by orally administering an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutically acceptable salt thereof. The disclosure specifies daily dose levels including 150±130 mg, 300±130 mg, 450±130 mg, 600±130 mg, and 750±130 mg, and presents the oral dosing approach in a Phase 2b randomized double-blind placebo-controlled study context.
The treatment strategy includes monitoring hemoglobin and using hemoglobin measurements to guide dose administration. The approach includes suspending and resuming dosing based on hemoglobin thresholds and adjusting the daily dose in defined increments based on measured hemoglobin change, with the overall intent to increase hemoglobin and support sustained management of anemia associated with chronic kidney disease.
The disclosed material characterizes the therapeutic effect of the compound by reference to HIF prolyl hydroxylase inhibition and HIF-alpha stabilization, including effects on erythropoietin and iron mobilization. It also describes combination use with iron supplementation and, optionally, ESA rescue in ESA-refractory anemia settings.
The disclosure further provides chemical-structure context for the selected HIF stabilizer compound forms, including metabolite forms, pharmaceutically acceptable salts, solvates, hydrates, and tautomeric forms for Compound 13, and identifies compounds 10–13 in the treatment context.
Claims Coverage
The consolidated claim coverage centers on one independent oral treatment method for anemia secondary to or associated with chronic kidney disease using {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or a pharmaceutically acceptable salt thereof at defined daily doses. Dependent features refine the method with hemoglobin-based maintenance and dose adjustment, iron supplementation timing and ferritin targets, and a two-tablet daily dosing regimen.
Oral treatment of CKD-associated anemia with a specific HIF stabilizer compound at defined daily doses
A method for treating anemia secondary to or associated with chronic kidney disease comprising orally administering to a patient having said anemia an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutically acceptable salt thereof, where a daily dose comprises 150±130 mg, 300±130 mg, 450±130 mg, 600±130 mg, or 750±130 mg of the compound.
Hemoglobin maintenance or increase thresholds
The method includes maintaining or increasing a patient’s hemoglobin levels to specified ranges or relative to baseline.
Hemoglobin-measurement decision rule for adjusted daily dose increase
The method includes taking first and second hemoglobin measurements and, under specified thresholds for the second hemoglobin level and hemoglobin change, administering an adjusted daily dose of a compound greater than the initial daily dose.
Timed iron supplement administration in combination therapy
The method includes administering an iron supplement at least two hours after administering the compound.
Ferritin-targeted iron supplementation
The method further specifies administering an iron supplement at an amount that maintains ferritin at about 50 to about 300 ng/mL.
Two-tablet daily dosing with 150 mg tablets
The method wherein administering the daily dose as two tablets, each containing 150 mg of the compound.
Overall claim coverage is centered on oral administration of the specific HIF stabilizer compound or its pharmaceutically acceptable salt at particular daily dose levels for CKD-associated anemia, with dependent features that refine hemoglobin targets, dose adjustment rules based on hemoglobin measurements, and combination therapy timing and ferritin targets when iron supplement is used.
Stated Advantages
Increases hemoglobin, including hemoglobin increases relative to baseline, in the described CKD/anemia context.
Improves anemia treatment outcomes by maintaining or increasing hemoglobin levels within specified ranges or relative to baseline.
Enhanced iron mobilization associated with the described compounds.
Improves iron parameters by increasing total iron binding capacity (TIBC) without substantially increasing serum iron.
Avoids significant hepcidin decrease.
Preclinical/in vitro observations indicate HIF prolyl hydroxylase inhibition and increased EPO, supporting the hemoglobin-increasing effect.
Documented Applications
Treating anemia secondary to or associated with chronic kidney disease, including end stage renal disease and hemodialysis contexts.
Addressing ESA-refractory anemia, with optional ESA rescue described in combination contexts.
A Phase 2b randomized double-blind placebo-controlled clinical study in anemia secondary to CKD, using a daily dosing regimen described in the partial content.
Associated angiogenesis- and VEGF/GAPDH-related disorders, including wound healing and revascularization/vascularizing ischemic tissue, as described in the partial content.
Guided tissue regeneration (GTR), as referenced in the partial content.
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