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Publication Number
US-12115153-B2
Publication Date
2024-10-15
Expiration Date
Abstract
Therapeutic methods and pharmaceutical compositions for treating cancer including a myeloproliferative neoplasm (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis in a human subject are described. In certain embodiments, the invention includes therapeutic methods of treating a MPN using a MDM2 inhibitor of Formula (I) or Formula (II).
Core Innovation
The invention relates to treating a myeloproliferative neoplasm (MPN) in a human subject by administering to a human subject in need thereof a therapeutically effective amount of an MDM2 inhibitor. The MDM2 inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, including APG-115 as an embodiment, and the disclosure further addresses pharmaceutical compositions containing MDM2 inhibitors, including formulations for oral administration and injection.
The disclosure also relates to MDM2 inhibitor compounds of Formula (I) and Formula (II), including solid-state forms such as amorphous and crystalline forms, including crystalline anhydrous forms. An anhydrous crystalline form is described as being characterized by powder X-ray diffraction peaks at about 2θ ≈ 11.6, 12.4, 18.6, 19.0, 21.6, and 23.6. The document further enumerates alternative MDM2 inhibitors by name, including RG7388/idasanutlin, triptolide, Nutlin-3a, HDM201, RG7112, and members of the Nutlin series.
The invention addresses myeloproliferative neoplasms including polycythemia vera (PV), myelofibrosis/PMF, essential thrombocythemia (ET), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), systemic mastocystosis (SM), and systemic mast cell disease (SMCD), among others. The disclosure also discusses disease subtype considerations, p53WT sensitivity, patient selection criteria including failure of ruxolitinib therapy and intolerance or resistance to hydroxyurea, and treatment schedules such as 21-day and 28-day cycles.
Claims Coverage
The claim coverage centers on treating MPNs with MDM2 inhibitors and includes 2 independent inventive features repeated across the inputs. The claims include a broader method of treating an MPN with a compound of Formula (I) or a pharmaceutically acceptable salt, and a specific refinement directed to chronic neutrophilic leukemia (CNL), with additional limitations for JAK2V617F mutation, prior ruxolitinib failure, and once-daily or twice-daily dosing at selected doses.
Treating an MPN with a Formula (I) MDM2 inhibitor
A method of treating a myeloproliferative neoplasm (MPN) comprising administering to a human subject in need thereof a therapeutically effective amount of an MDM2 inhibitor, wherein the MDM2 inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Treating a specific MPN subtype (CNL)
The method further characterizes the MPN as chronic neutrophilic leukemia (CNL).
Treating MPNs with a JAK2V617F mutation
The method is characterized by the presence of a JAK2V617F mutation in the MPN.
Patient selection based on failure of prior ruxolitinib therapy
The method is limited to a human subject who did not respond to prior ruxolitinib therapy.
Once-daily dosing using a defined selected dose list
Administer the compound of Formula (I) once daily at a selected dose from the listed milligram values.
Twice-daily dosing using a defined selected dose list
Administer the compound of Formula (I) twice daily at a selected dose from the listed milligram values.
Overall, the claim coverage centers on administering a therapeutically effective amount of an MDM2 inhibitor of Formula (I) or a pharmaceutically acceptable salt to treat an MPN, with dependent refinements specifying CNL, JAK2V617F mutation, prior ruxolitinib failure, and once-daily or twice-daily dosing at selected doses.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a myeloproliferative neoplasm (MPN) in a human, including polycythemia vera (PV), myelofibrosis/PMF, essential thrombocythemia (ET), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), systemic mastocystosis (SM), and systemic mast cell disease (SMCD).
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