阿斯利康的T790M牛逼新药AZD9291的1期临床结果出来了

老马 · 发表于 2013-12-2 00:44:04

本帖最后由老马于 2013-12-2 00:45 编辑

http://www.aacr.org/home/scienti ... r-therapeutics.aspx
http://webcast.aacr.org/

老马 · 发表于 2013-12-2 01:12:20

老马 · 发表于 2013-12-2 01:14:40

bstract Number:    B212
Presentation Title:    Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients
Presentation Time:    Monday, Oct 21, 2013, 12:30 PM - 3:00 PM
Location:    Exhibit Hall C-D
Author Block:    Peter Ballard1, Susan Ashton1, Darren Cross1, Richard Dimelow2, James Yates1. 1AstraZeneca, Macclesfield, Cheshire, United Kingdom; 2Wright-Dose, Altrincham, Cheshire, United Kingdom
Abstract Body:    Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need.
AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291.
A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations.

老马 · 发表于 2013-12-2 01:17:01

Abstract Number:    B94
Presentation Title:    Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor
Presentation Time:    Monday, Oct 21, 2013, 12:30 PM - 3:00 PM
Location:    Exhibit Hall C-D
Author Block:    M. Raymond V. Finlay1, Mark Anderton1, Susan Ashton1, Peter G. Ballard1, Rob H. Bradbury1, Sam Butterworth1, Nicola Colclough1, Darren A.E. Cross1, Heather L. McFarland2, Martine J. Mellor1, Richard A. Ward1, Mike J. Waring1. 1AstraZeneca, Oncology Innovative Medicines, Macclesfield, Cheshire, SK10 4TG, United Kingdom; 2AstraZeneca, Global Medicines Development, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Abstract Body:    Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 <0.025 μM) and activating mutations (PC9, cell phosphorylation IC50<0.025 μM) that also spares inhibition of the wild type form of the receptor (A431, cell phosphorylation IC50>0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.

老马 · 发表于 2013-12-2 01:29:15

本帖最后由老马于 2013-12-2 01:48 编辑

Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
http://pubs.acs.org/doi/pdf/10.1021/jm400822z

Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activa.rar (1.91 MB, 下载次数: 56)

Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activa.rar (206.23 KB, 下载次数: 51)

Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activa.rar (1.91 MB, 下载次数: 60)