Lipid formulated compositions and methods for inhibiting expression of Eg5 and VEGF genes
View Patent ↗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.
1. 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, 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.
2. 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.
3. The method of claim 1 , wherein the AUC 0-last of f KSP siRNA is within about 80% to about 120% of a value selected, wherein said value is 30.9+/−21.1 μg*min/mL, 130.7+/−44.9 μg*min/mL, 201.3+/−38.6 μg*min/mL or 501.2+/−203.9 μg*min/mL.
4. The method claim 1 of, wherein the AUC 0-last of f VEGF siRNA is within about 80% to about 120% of a value selected, wherein said value is 36.3+/−20.8 μg*min/mL, 140.3+/−56.1 μg*min/mL, 207.7+/−36.3 μg*min/mL or 610.9+/−223.3 μg*min/mL.
5. The method of claim 1 , wherein the C max of KSP siRNA is within about 80% to about 120% of a value selected, wherein said value is 0.76+/−0.36 μg/mL, 2.3+/−0.54 μg/mL, 3.2+/−1.2 μg/mL and 9.8+/−4.1 μg/mL.
6. The method of claim 1 , wherein the C max of VEGF siRNA is within about 80% to about 120% of a value selected, wherein said value is 0.86+/−0.43 μg/mL, 2.5+/−0.56 μg/mL, 3.7+/−1.2 μg/mL and 9.7+/−2.7 μg/mL.
7. The method of claim 1 , wherein the composition has a dose-proportional maximum concentration (C max ) and area under curve (AUC) as measurable in the subject's plasma.
8. The method of claim 1 , wherein the dose-proportional AUC of KSP siRNA is 10 to 800 μg*min/mL as measurable in the subject's plasma.
9. The method of claim 1 , wherein the dose-proportional AUC of VEGF siRNA is 10 to 800 μg*min/mL as measurable in the subject's plasma.
10. The method of claim 1 , wherein the dose-proportional C max of KSP siRNA is 0.4 to 13 μg/mL as measurable in the subject's plasma.
11. The method of claim 1 , wherein the dose-proportional C max of VEGF siRNA is 0.4 to 13 μg/mL as measurable in the subject's plasma.
12. The method of claim 1 , wherein the AUC value of KSP siRNA is within an error of ±3 to 4-fold of a predicted KSP siRNA AUC value.
13. The method of claim 1 , wherein the AUC value of VEGF siRNA is within an error of ±3 to 4-fold of a predicted VEGF siRNA AUC value.
14. The method of claim 1 , wherein the rate of clearance for the composition (CL) is 103 mL/min as measurable in the subject's plasma.
15. The method of claim 1 , comprising administering to the human 0.1 mg/kg ALN-VSP02.
16. The method of claim 1 , comprising administering to the human 0.2 mg/kg ALN-VSP02.
17. The method of claim 1 , comprising administering to the human 0.4 mg/kg ALN-VSP02.
18. The method of claim 1 , comprising administering to the human 0.7 mg/kg ALN-VSP02.
19. The method of claim 1 , comprising administering to the human at least 0.4 mg/kg ALN-VSP02.
20. The method of claim 1 , comprising administering to the human at least 0.7 mg/kg ALN-VSP02.