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US-12622918-B2 - Formulations and dosages for administering a compound that inhibits MCL1 protein

US12622918B2US 12622918 B2US12622918 B2US 12622918B2US-12622918-B2

Abstract

The present disclosure is drawn to pharmaceutical formulations, aqueous solutions, and methods of treating cancer using the disclosed pharmaceutical formulations and aqueous solutions. The formulations and solutions comprise compounds of Formula I and may further comprise a cyclodextrin compound, such as hydroxypropyl-β-cyclodextrin and a buffer, such as glycine. The methods of treating cancer include the treatment of hematological malignances such as acute myelogenous leukemia, multiple myeloma, and non-Hodgkin's lymphoma.

Inventors

  • Ron C. KELLY
  • Michael T. Kennedy
  • Stevedat K. LA

Assignees

  • AMGEN INC.

Dates

Publication Date
20260512
Application Date
20200423
Priority Date
20191110

Claims (20)

  1. 1 . A pharmaceutical formulation for intravenous administration, the formulation comprising: a) a compound of Formula I or a salt thereof, wherein the compound of Formula I has the following structure: b) a cyclodextrin compound; c) a buffer; and d) water, wherein, the concentration of the compound of Formula I or the salt thereof in the formulation ranges from 15 mg/mL to 30 mg/mL and the pH of the formulation ranges from 8.7 to 9.9; wherein the buffer is glycine at a concentration ranging from 80 mM to 120 mM; and wherein the cyclodextrin compound is hydroxypropyl-β-cyclodextrin, and the amount of the cyclodextrin compound in the formulation ranges from 7.5 to 13 percent weight by weight.
  2. 2 . The pharmaceutical formulation of claim 1 , wherein the pH of the formulation is from 8.8 to 9.8.
  3. 3 . The pharmaceutical formulation of claim 2 , wherein the pH of the formulation ranges from 8.9 to 9.2.
  4. 4 . The pharmaceutical formulation of claim 1 , wherein the concentration of the compound of Formula I, or the salt thereof, in the formulation ranges from 20 to 30 mg/mL.
  5. 5 . The pharmaceutical formulation of claim 4 , wherein the concentration of the compound of Formula I, or the salt thereof, in the formulation ranges from 24 to 26 mg/mL.
  6. 6 . The pharmaceutical formulation of claim 1 , wherein the amount of the cyclodextrin compound in the formulation ranges from 9 to 11 percent weight by weight.
  7. 7 . The pharmaceutical formulation of claim 1 , wherein the formulation is buffered with glycine at a concentration ranging from 95 mM to 105 mM.
  8. 8 . The pharmaceutical formulation of claim 1 , wherein the volume of the formulation ranges from 5 mL to 25 mL.
  9. 9 . The pharmaceutical formulation of claim 8 , wherein the volume of the formulation ranges from 9 mL to 15 mL.
  10. 10 . The pharmaceutical formulation of claim 1 , wherein the formulation is an aqueous formulation comprising from 20 mg/mL to 30 mg/mL of the compound of Formula I and from 8 percent to 12 percent weight by weight hydroxypropyl-β-cyclodextrin and is buffered with 90 mM to 110 mM glycine to a pH of 8.8 to 9.2.
  11. 11 . The pharmaceutical formulation of claim 1 , wherein the formulation is an aqueous formulation comprising 25 mg/mL of the compound of Formula I and 10 percent weight by weight hydroxypropyl-β-cyclodextrin buffered with 100 mM glycine to a pH of 9.
  12. 12 . The pharmaceutical formulation of claim 10 , wherein the amount of the formulation ranges from 9 mL to 15 mL.
  13. 13 . The pharmaceutical formulation of claim 10 , wherein the formulation is contained within a vial.
  14. 14 . The pharmaceutical formulation of claim 13 , wherein the vial is a 20 mL borosilicate glass vial or a 20 mL aluminosilicate glass vial, wherein the vial is equipped with a stopper and an aluminum seal with a flip off cover.
  15. 15 . An aqueous solution of a therapeutic agent, the solution comprising: (a) a compound of Formula I or a salt thereof, wherein the compound of Formula I has the following structure: b) a cyclodextrin compound; c) a buffer; d) sodium chloride; and e) water, wherein, the amount of the compound of Formula I or the salt of the compound of Formula I in the solution ranges from 25 mg to 400 mg; wherein the buffer is glycine at a concentration ranging from 80 mM to 120 mM; and wherein the cyclodextrin compound is hydroxypropyl-β-cyclodextrin, and the amount of the cyclodextrin compound in the formulation ranges from 7.5 to 13 percent weight by weight.
  16. 16 . The aqueous solution of claim 15 , wherein the amount of the compound of Formula I or the salt of the compound of Formula I in the solution ranges from 200 mg to 360 mg.
  17. 17 . The aqueous solution of claim 15 , wherein the solution is contained in an IV bag.
  18. 18 . A method for making an aqueous solution suitable for intravenous infusion into a patient, the method comprising: combining the pharmaceutical formulation of claim 1 with a saline solution.
  19. 19 . The method of claim 18 , wherein the saline solution, prior to combining the pharmaceutical formulation with the saline solution, comprises sodium chloride in an amount ranging from 8 g/L to 10 g/L.
  20. 20 . An aqueous solution of a therapeutic agent, the solution comprising: a compound of Formula I or a salt thereof, wherein the compound of Formula I has the following structure: wherein, the compound of Formula I or the salt of the compound of Formula I is present in an amount ranging from 25 mg/m 2 to 960 mg/m 2 ; wherein the aqueous solution further comprises a cyclodextrin compound, a buffer, and sodium chloride; wherein the buffer is glycine at a concentration ranging from 80 mM to 120 mM; and wherein the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and the amount of the cyclodextrin compound in the formulation ranges from 7.5 to 13 percent weight by weight.

Description

FIELD OF THE INVENTION The present invention relates to novel formulations including compounds of Formula I and/or salts thereof and to methods of treating cancer including hematological malignancies such as acute myelogenous leukemia, multiple myeloma, and Non-Hodgkin's lymphoma in patients with such malignancies. The invention also relates to dosage amounts and schedules for treating such diseases. BACKGROUND OF THE INVENTION Programmed cell death or apoptosis is regulated by a complex network of protein-protein interactions between the pro- and anti-apoptotic subgroups that form the B-cell lymphoma/leukemia 2 (BCL2) protein family (Czabotar et al, Nat'l Rev Mol Cell Biol. 15:49-63 (2014); Strasser et al, EMBO J. 30:2667-3683 (2011); Kozopas et al, Proc Nat'l Acad Sci USA 90:3516-3520 (1993)). Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic member of this family and promotes cell survival. In contrast, pro-apoptotic family members such as the mitochondrial-pore forming factors BCL2 homologous antagonist/killer (BAK), BCL2-associated X (BAX), or the BCL2 homology 3 (BH3)-only protein family members, such as BCL2-interacting mediator of cell death (BIM) and p53-upregulated modulator of apoptosis (PUMA), are critical effectors for the induction of apoptosis. Upon the induction of apoptotic stimuli, pro-apoptotic BH3-only proteins bind MCL1 and other pro-survival BCL2 family members, disrupting interactions between MCL1 and the pro-apoptotic effector proteins, BAK and BAX. This disruption leads to activation and oligomerization of BAK and BAX; mitochondrial other outer membrane permeabilization (MOMP); the release of cytochrome C; caspase activation; and cell death (Czabotar et al (2014); Strasser et al, (2011)). Myeloid cell leukemia 1 is expressed in a range of human and mouse tissues. In the mouse, for example, conditional gene-knockout studies have shown that MCL1 is important for the survival of a number of cell types including lymphocytes, hematopoietic stem cells, neutrophils, and cardiomyocytes (Thomas et al, Genes Dev 27:1365-1377 (2014); Wang et al, Genes Dev 27:1351-1364 (2013); Strasser et al, (2011)). Over-expression of MCL1 has also been implicated in the development of a number of solid and hematopoietic cancers (Ashkenazi et al. Nature Rev 15:273-284 (2017); Merino et al, Sci Transl Med 9:1-10 (2017); Kotschy et al, Nature 538:477-482 (2016); Glaser et al, Genes Dev. 26:120-125 (2012)). The compound of Formula I and salts of the compound of Formula I are compounds that inhibit MC11 protein. The structure of the compound of Formula I is shown below: Compounds of Formula I and salts thereof and methods for synthesizing the compound are described in WO 2016/033486 and U.S. Pat. No. 9,562,061. These references are incorporated by reference herein in their entireties as if specifically set forth. A need for suitable formulations, doses, and dosing schedules that include compounds that inhibit MCL1 protein such as the compound of Formula I and/or salts of the compound of Formula I exists. Also needed are formulations and amounts of such formulations useful for treating cancer and particularly hematological malignancies such as acute myelogenous leukemia (AML), multiple myeloma (MM), and non-Hodgkin's lymphoma (NHL) among others. SUMMARY OF THE INVENTION In one aspect, the invention provides a pharmaceutical formulation, the formulation comprising: a) a compound of Formula I or a salt thereof, wherein the compound of Formula I has the following structure: b) a cyclodextrin compound;c) a buffer; andd) water, wherein, the concentration of the compound of Formula I or the salt thereof in the formulation ranges from 15 mg/mL to 30 mg/mL and the pH of the formulation ranges from 8.7 to 9.9. In another aspect, the invention provides an aqueous solution of a therapeutic agent, the solution comprising: (a) a compound of Formula I or a salt thereof, wherein the compound of Formula I has the following structure: b) a cyclodextrin compound;c) a buffer;d) sodium chloride; ande) water, wherein, the amount of the compound of Formula I or the salt of the compound of Formula I in the solution ranges from 25 mg to 400 mg. In yet another aspect, the invention provides a method for making an aqueous solution suitable for intravenous infusion into a patient, the method comprising: combining the pharmaceutical formulation of any one of embodiments 1-36 with a saline solution. In yet another aspect, the invention provides a method of treating a cancer patient, the method comprising: administering to the patient an aqueous solution comprising the compound of Formula I or a salt of the compound of Formula I, wherein the compound of Formula I has the following structure: and further wherein, the compound of Formula I or the salt of the compound of Formula I is present in an amount ranging from 25 mg/m2 to 960 mg/m2. In still another aspect, the invention provides an aqueous solution of a therapeutic agent, the solution