Lipid Formulated Compositions and Methods for Inhibiting Expression of Eg5 and VEGF Genes

Abstract

This invention relates to compositions containing double-stranded ribonucleic acid (dsRNA) in a SNALP formulation, methods of using the compositions to inhibit the expression of the Eg5/KSP and VEGF, and methods of using the compositions to treat pathological processes mediated by Eg5/KSP and VEGF expression, such as cancer.

We claim: 
     
         1 . A method of treating a subject in need of treatment, comprising administering to the subject a dosage of a composition comprising ALN-VSP02 via intravenous (IV) infusion once every 2 weeks. 
     
     
         2 . The method of  claim 1 , wherein the subject has cancer or advanced cancer with liver involvement. 
     
     
         3 . The method of  claim 1 , wherein the dosage of ALN-VSP02 is selected from the group consisting of at least 0.1, 0.2, 0.3, 0.4, 0.7, 1.0, 1.25, 1.5, 1.7, 2.0, 3.0, and at least 6.0 mg/kg. 
     
     
         4 . The method of  claim 1 , wherein the dosage is at least 0.4 mg/kg or at least 0.7 mg/kg. 
     
     
         5 . The method of  claim 1 , wherein duration of each IV infusion is 15 minutes to 3 hours. 
     
     
         6 . The method of  claim 1 , wherein the composition is administered to the subject once every 2 weeks for at least four weeks or for at least 8 weeks. 
     
     
         7 . The method of  claim 1 , further comprising preadministration with at least one compound selected from the group consisting of dexamethasone, H1 and H2 blockers, and acetaminophen. 
     
     
         8 . A method of treating a human having advanced cancer with liver involvement, comprising administering to the human 0.1, 0.2, 0.4, or 0.7 mg/kg ALN-VSP02 via 15 minute intravenous (IV) infusion once every 2 weeks for eight weeks. 
     
     
         9 . The method of  claim 8 , further comprising preadministration with at least one compound selected from the group consisting of dexamethasone, H1 and H2 blockers, and acetaminophen. 
     
     
         10 . The method of  claim 8 , wherein the ALN-VSP02 provides a mean KSP siRNA AUC 0-last  from 10 to 800 μg*min/mL, a mean KSP siRNA C max  from 0.4 to 13 μg/mL, a mean VEGF siRNA AUC 0-last  from 10 to 800 μg*min/mL and a mean VEGF siRNA C max  from 0.4 to 13 μg/mL. 
     
     
         11 . The method of  claim 8 , wherein the composition has a dose-proportional maximum concentration (Cmax) and area under curve (AUC) as measurable in the subject's plasma. 
     
     
         12 . The method of  claim 8 , wherein the dosage is about 0.1 to about 0.7 mg/kg. 
     
     
         13 . The method of  claim 8 , wherein the dose-proportional AUC of KSP siRNA is 10 to 800 μg*min/mL as measurable in the subject's plasma and/or the dose-proportional AUC of VEGF siRNA is 10 to 800 μg*min/mL as measurable in the subject's plasma and/or the dose-proportional Cmax of KSP siRNA is 0.4 to 13 μg/mL as measurable in the subject's plasma and/or the dose-proportional Cmax of VEGF siRNA is 0.4 to 13 μg/mL as measurable in the subject's plasma. 
     
     
         14 . The method of  claim 8 , wherein the AUC value of KSP siRNA is within an error of ±3 to 4-fold of a predicted KSP siRNA AUC value. 
     
     
         15 . The method of  claim 8 , wherein the AUC value of VEGF siRNA is within an error of ±3 to 4-fold of a predicted VEGF siRNA AUC value. 
     
     
         16 . The method of  claim 8 , wherein the rate of clearance for the composition (CL) is 103 mL/min as measurable in the subject's plasma.