XPO1 Inhibitor Represents New Treatment Paradigm in CLL, AML

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KPT-8602 allows a prolonged frequent dosing schedule in animal models of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia.
KPT-8602 allows a prolonged frequent dosing schedule in animal models of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia.

ORLANDO ­– KPT-8602, an exportin 1 (XPO1) inhibitor, allows a prolonged frequent dosing schedule, which leads to an excellent therapeutic benefit and less toxicity in animal models of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML).1

KPT-8602 is an oral selective inhibitor of nuclear export (SINE) compound that covalently modifies XPO1 that shows lower brain penetration, improved tolerability allowing for continuous dosing, and improved efficacy beyond any current XPO1 inhibitor.

”KPT-8602 inhibits XPO1 and restores subcellular localization of cargos,” said Zachary A. Hing, BS, of The Ohio State University Medical Scientist Training Program in Columbus, OH during a presentation at the 57th annual American Society of Hematology meeting.

In this study, researchers found that KTP-8602 induced a comparable level of cytotoxicity and inhibition of cell proliferation compared with KTP-330 in primary CLL tumors and in a representative panel of diffuse large B-cell cell lines. Results also showed that KPT-8602 inhibited proliferation and induced cell death in AML cell lines and primary AML blasts.

“KPT-8602 given twice per week provides a survival benefit in the Eμ-TCL1-transplant model of CLL,” Hing said, adding that “KPT-8602 daily improves survival in the Eμ-TCL1-transplant model.”

In animal models, KPT-8602 administered daily resulted in significantly improved survival compared with twice weekly dosing (P = .001). Mice that received daily KPT-8602 also had significantly smaller spleens and decreased levels of circulating leukemic cells compared with mice that received twice weekly KPT-8602 or KPT-330.

Researchers then evaluated KPT-8602 in combination with ibrutinib, which was found to further improve survival compared with KPT-330 plus ibrutinib (P = .008).

Furthermore, mice with AML given KPT-8602 5 times per week demonstrated better survival compared with those that received it twice weekly or KPT-330 twice weekly (P < .0001).

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The findings suggest that KPT-8602 represents a new treatment paradigm and warrants further evaluation in clinical trials of patients with hematologic malignancies, especially in combination with ibrutinib or other Bruton's tyrosine kinase inhibitors.

“KPT-8602 has similar in vitro potency to KPT-330, allows a prolonged and frequent dosing schedule, and shows inferior toxicity in 2 animal models of hematologic malignancies,” Hing concluded. “Our results support clinical development of the novel XPO1 inhibitor, KPT-8602, for CLL and AML patients.”

Reference

  1. Hing ZA, Fung HYJ, Ranganathan P, et al. Next generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematologic malignancies. Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL.

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