Karyopharm Therapeutics Inc. · NASDAQ:KPTI
Karyopharm Therapeutics — Technical Presentation (2015)
15 slides from Karyopharm Therapeutics's technical presentation, 2015
Slide 1: Nuclear Export Inhibitor KPT-8602 Is Highly Active Against Leukemic Blasts and Leukemia-Initiating Cells in PDX Models of AML
Nuclear Export Inhibitor KPT-8602 Is Highly Active Against Leukemic Blasts and Leukemia-Initiating Cells in Patient- Derived Xenograft Models of AML Julia Etchin, Alla Berezovskaya, Amy Saur Conway, Weihsu C. Chen, Erkan Baloglu, Yosef Landesman, William Senapedis, Joel Ellis, Dilara McCauley, Richa
Slide 2: Nuclear Exporter CRM1/XPO1
Nuclear Exporter CRM1/XPO1 • major protein nuclear export receptor • exports ~ 220 macromolecules that contain leucine-rich nuclear export signals (NES) • mediates export of RNA substrates (e.g. rRNAs, viral mRNAs, cellular mRNAs) • transports a variety of cancer proteins, including tumor suppressor
Slide 3: Overview of the XPO1-Mediated Pathway of Nuclear Export
Overview of the XPO1-Mediated Pathway of Nuclear Export Targeted XPO1 Inhibitor (KPT-SINE) Monecke et al, FASEB J Review, 2014
Slide 4: Novel XPO1 inhibitors: KPT-SINE
Novel XPO1 inhibitors: KPT-SINE • Developed based on the crystal structure XPO1 of CRM1/XPO1 (target Cys528 in the cargo-binding groove) • Orally bioavailable • Selinexor (KPT-330) is in clinical phase I/II trials in adults and children with AML – Preliminary results show that selinexor alone or in
Slide 5: Experimental scheme to determine the activity of KPT-8602 against primary bulk cells
Experimental scheme to determine the activity of KPT- 8602 against primary bulk cells Treatment Duration: Treatment Response: 4 weeks Patient Vehicle Control AML cells hCD45 - FITC hCD45+ in the BM SSC Leukemia Selinexor (KPT-330) hCD45 - FITC hCD45+ in the BM Progression M/Th or M/W/F SSC NSG mice
Slide 6: KPT-8602 is Highly Active against Bulk AML Cells in PDX Models of Patient AML
KPT-8602 is Highly Active against Bulk AML Cells in PDX Models of Patient AML Cytogenetically Normal MDS/AML Complex Karyotype AML AML (AML-CN) with FLT3-ITD (AML-CK) KPT-8602 greatly reduces the number of bulk AML cells in PDX models of high-risk AML; 2 mice demonstrated no detectable AML cells in
Slide 7: Experimental scheme: Response of LICs to KPT-8602 treatment
Experimental scheme: Response of LICs to KPT-8602 treatment After 4 weeks of Treatment Re-transplantation Assay 10^5 hCD45+ 10^4 hCD45+ 10^3 hCD45+ 10^2 hCD45+ cells cells cells cells Vehicle 10^5 hCD45+ 10^4 hCD45+ 10^3 hCD45+ 10^2 hCD45+ cells cells cells cells Selinexor 10^5 hCD45+ 10^4 hCD45+ 10
Slide 8: KPT-8602 is Highly Active against AML LICs in PDX models
KPT-8602 is Highly Active against AML LICs in PDX models KPT-8602 induced ~ 437 fold reduction in LIC frequency in the surviving AML cell population KPT-8602 induced ~ 150 fold reduction in LIC frequency KPT-8602 induced ~ 507 fold reduction in LIC frequency
Slide 9: Cytotoxic chemotherapy targets AML bulk cells, but leaves LIC that cause relapse
Cytotoxic chemotherapy targets AML bulk cells, but leaves LIC that cause relapse After Induction Diagnosis Chemotherapy Relapse LICs Leukemic progenitor cells
Slide 10: KPT-8602 targets AML bulk and Leukemia Initiating Cells (LICs) with high efficiency
KPT-8602 targets AML bulk and Leukemia Initiating Cells (LICs) with high efficiency Cure? After Induction KPT-8602 Diagnosis Chemotherapy Treatment LICs Leukemic progenitor cells
Slide 11: The effects of KPT-8602 on normal human leukocytes and hematopoietic stem and progenitor cells
The effects of KPT-8602 on normal human leukocytes and hematopoietic stem and progenitor cells 6.5X 3.1X KPT-8602, like KPT-330, shows minimal toxicity against normal HSPCs
Slide 12: The effects of KPT-8602 on normal HSCs
The effects of KPT-8602 on normal HSCs Normal Fold Reduction in human Secondary Transplant Normal HSC Frequency CD34+ Normal HSC frequency (compared to Frequency of Grafts Vehicle) Vehicle 1/7389 1 Selinexor 1/20496 2.77 KPT-8602 1/6264 0.85 KPT-8602, like KPT-330, shows minimal toxicity against nor
Slide 13: The effects of KPT-8602 on Survival of Complex Karyotype AML PDX Mice
The effects of KPT-8602 on Survival of Complex Karyotype AML PDX Mice On Treatment Off Treatment Months: 1 2 3 4 5 Vehicle KPT-330 KPT-8602 Moribund AML cells detected
Slide 14: The effects of KPT-8602 on Survival of MDS/AML PDX Mice
The effects of KPT-8602 on Survival of MDS/AML PDX Mice On Treatment Off Treatment Months: 1 2 3 4 5 6 7 Vehicle KPT-330 KPT-8602 Moribund AML cells detected No AML cells detected
Slide 15: Conclusions
Conclusions • KPT-8602 is highly active against bulk AML cells and LICs, but spares normal hematopoietic stem and progenitor cells • Both selinexor and KPT-8602 can completely eradicate leukemia cells in one of the two PDX models • KPT-8602 can be given daily to mice and has better tolerability comp
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