Motesanib

AMG 706 (Motesanib)Description:IC50: Motesanib diphosphate (AMG-706) is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 2 nM/3 nM/6 nM, respectively [1].
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). Motesanib (AMG 706) is an orally administered small molecule belonging to angiokinase inhibitor class which acts as an antagonist of VEGF receptors, platelet-derived growth factor receptors, and stem cell factor receptors.
In vitro: Motesanib diphosphate has broad activity against the human VEGFR family, and displays >1000 selectivity against EGFR, Src, and p38 kinase. Motesanib Diphosphate significantly inhibits VEGF-induced cellular proliferation of HUVECs with an IC50 of 10 nM, while displaying little effect at bFGF-induced proliferation with an IC50 of >3,000 nM. Motesanib Diphosphate also potently inhibits PDGF-induced proliferation and SCF-induced c-kit phosphorylation with IC50 of 207 nM and 37 nM, respectively, but not effective against the EGF-induced EGFR phosphorylation and cell viability of A431 cells [1]. Althouth displaying little antiproliferative activity on cell growth of HUVECs alone, Motesanib diphosphate treatment significantly sensitizes the cells to fractionated radiation [2].
In vivo: Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects o AMG 706n body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706–treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies [1].
Clinical trial: Motesanib was originally investigated for effectiveness against advanced nonsquamous non-small-cell lung cancer (NSCLC), with Phase II trials indicating an effectiveness comparable to bevacizumab when they were both used in combination with paclitaxel/carboplatin. However a later and more detailed Phase III trial failed to show any benefit for the treatment of NSCLC. A second Phase III trial was started in 2012, which focused on patients from Asian backgrounds (performed on the bases of subgroup analysis) however this also failed to meet its primary endpoint. The drug has undergone a Phase II evaluation as first-line therapy for breast cancer however this study found no evidence to support further investigation. Phase II testing against persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas was also unsuccessful. There have also been 2 separate Phase II clinical trials for thyroid cancer which have both shown promising results (http://en.wikipedia.org/wiki/Motesanib).
Reference:
[1] Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006;66(17):8715-21.
[2] Kruser TJ1 Wheeler DL, Armstrong EA, Iida M, Kozak KR, van der Kogel AJ, Bussink J, Coxon A, Polverino A, Harari PM. Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors. Clin Cancer Res. 2010;16(14):3639-47.

A case report of motesanib-induced biliary sludge formation causing obstructive cholangitis with acute pancreatitis treated by endoscopic sphincterotomy.[Pubmed:27631212]

Medicine (Baltimore). 2016 Sep;95(37):e4645.

BACKGROUND: Gallbladder toxicity was reported in most Motesanib studies with varying frequency and at variable times after initiation of treatment. METHOD AND RESULTS: A 44-year-old man was admitted due to severe epigastric pain. The patient was diagnosed with non-small cell lung cancer 9 months ago and received 6 cycles of chemotherapy with Motesanib, paclitaxel, and carboplatin. Ultrasonography showed a large amount of sludge within gallbladder. Computed tomography scan demonstrated diffuse dilatation of biliary tree with distended gallbladder without evidence of stone and mild pancreatic swelling. Endoscopic retrograde cholangiopancreatography showed yellowish viscous mucoid plug impacting ampullary orifice and dilated bile duct with amorphous filling defect at distal half of common duct. Endoscopic sphincterotomy was performed to prevent biliary obstruction and recurrent pancreatitis after removal of mucoid material. CONCLUSION: To the best of our knowledge, this is the first report of obstructive cholangitis and acute pancreatitis associated with sludge formation during Motesanib therapy. Endoscopic sphincterotomy appears to be useful to treat and prevent biliary obstruction caused by Motesanib-induced biliary sludge.

Correction: challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience.[Pubmed:25811784]

PLoS One. 2015 Mar 26;10(3):e0121162.

[This corrects the article DOI: 10.1371/journal.pone.0108048.].

Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients.[Pubmed:27137719]

Clin Pharmacol Drug Dev. 2015 Nov;4(6):463-72.

Motesanib is a small molecule and potent multikinase inhibitor with antiangiogenic and antitumor activity. Population pharmacokinetic (POPPK) modeling of Motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients. The analysis included data collected from 451 patients from 8 clinical trials with oral doses of Motesanib ranging from 25 to 175 mg, either once daily or twice daily. The POPPK analyses were performed using nonlinear mixed-effect models with a sequential approach. Covariate effects of demographics and other baseline characteristics were assessed with stepwise covariate modeling. A 2-compartment model with food effect on absorption parameters fitted the PK data of Motesanib well. The effects albumin and sex on apparent clearance (CL/F) of Motesanib were statistically significant. The albumin effect was more important but remained below a 25% difference. A 1-compartment model fitted PK data of M4 well. Effects of race (Asian vs non-Asian) and dosing frequency were identified as statistically significant covariates on the CL/F of M4. The maximum effect of albumin would result in less than 25% change in Motesanib CL/F and as such would not warrant any dosing adjustment. However, faster elimination of M4 in Asian patients requires further investigation.

Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells.[Pubmed:27039732]

Asian Pac J Cancer Prev. 2016;17(3):1103-10.

In the present study, we investigated the effects of Motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that Motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that Motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of Motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

Motesanib is a potent ATP-competitive inhibitor of VEGFR1/2/3 with IC50s of 2 nM/3 nM/6 nM, respectively, and has similar activity against Kit, and is appr 10-fold more selective for VEGFR than PDGFR and Ret.

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