Compositions comprising PKM2 modulators and methods of treatment using the same
Inventors
Warner, Steven L. • Bearss, David J. • Foulks, Jason Marc
Assignees
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Publication Number
US-11712433-B2
Publication Date
2023-08-01
Expiration Date
Abstract
A compound of Structure (I): or a pharmaceutically acceptable salt thereof, alone or in combination with a second therapeutic agent, as well as methods of treating a PKM2-mediated disease or disorder using the same are provided herein.
Core Innovation
The invention provides a method of treating a cancer by administering an effective amount of a compound of Structure (I) or a pharmaceutically acceptable salt thereof in combination with a PD-1 inhibitor, where the PD-1 inhibitor is nivolumab. The cancer is resistant to checkpoint inhibitor therapy in the absence of the compound of Structure (I).
The invention further provides a method of treating a cancer by administering an effective amount of a compound of Structure (I) or a pharmaceutically acceptable salt thereof together with a PD-1 inhibitor and a CTLA-4 inhibitor. In this combination, the PD-1 inhibitor is nivolumab and the CTLA-4 inhibitor is ipilimumab, and the cancer is resistant to checkpoint inhibitor therapy in the absence of the compound of Structure (I).
The disclosed treatment context includes intermediate- or poor-risk stage IV renal cell carcinoma, first-line stage III or IV unresectable advanced melanoma, metastatic colorectal cancer having MSI-H or dMMR after progression following fluoropyrimidine, oxaliplatin, and irinotecan, and advanced renal cell carcinoma that has failed antiangiogenic therapy. The method is positioned to address checkpoint inhibitor resistance by adding the compound of Structure (I) to PD-1 and, in another embodiment, to PD-1 plus CTLA-4 immunotherapy.
Claims Coverage
Two independent claims are identified. Across the independent claims, the core inventive coverage centers on combining a compound of Structure (I) with specific checkpoint inhibitors for cancers resistant to checkpoint inhibitor therapy without the compound of Structure (I).
Compound of Structure (I) with nivolumab for checkpoint-resistant cancer
Administering to a subject in need thereof an effective amount of a compound of Structure (I) or a pharmaceutically acceptable salt thereof in combination with a PD-1 inhibitor where the PD-1 inhibitor is nivolumab, and treating a cancer that is resistant to checkpoint inhibitor therapy in the absence of the compound of Structure (I).
Compound of Structure (I) with nivolumab plus ipilimumab for checkpoint-resistant cancer
Administering to a subject in need thereof an effective amount of a compound of Structure (I) or a pharmaceutically acceptable salt thereof in combination with a PD-1 inhibitor and a CTLA-4 inhibitor, where the PD-1 inhibitor is nivolumab and the CTLA-4 inhibitor is ipilimumab, and treating a cancer that is resistant to checkpoint inhibitor therapy in the absence of the compound of Structure (I).
The independent claims cover two immunotherapy combinations: Structure (I) plus nivolumab for checkpoint inhibitor-resistant cancers, and Structure (I) plus nivolumab and ipilimumab for the same resistance criterion absent Structure (I).
Stated Advantages
Structure (I) addition to anti-CTLA-4 further supports near-maximal efficacy in the MC38 model.
PD-1/CTLA-4 combination therapy with or without Structure (I) produces profound tumor regression and tumor-free survivors, including a 10/10 tumor-free survivor outcome in a Structure (I) 100 mg/kg triple-therapy condition.
The document reports synergy in a CT26 model for Structure (I) plus anti-PD-1.
Adverse events/weight loss are described as largely negligible in the reported preclinical data.
Documented Applications
Preclinical evaluation of a compound of Structure (I) in MC38 syngeneic murine colon carcinoma in C57BL/6 mice, including monotherapy and combination studies with anti-PD-1 and/or anti-CTLA-4, with tumor growth outcomes and survival outcomes.
Preclinical evaluation of synergy in a CT26 colon carcinoma model for Structure (I) plus anti-PD-1.
Tumor immune microenvironment evaluation workflow using flow cytometry panels assessing T cell subsets and macrophage/MDSC markers, and reporting checkpoint marker changes and trends toward altered immune suppressive/regulatory populations.
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