Lipid formulated compositions and methods for inhibiting expression of Eg5 and VEGF genes

1. A method of treating endometrial cancer in a subject in need thereof, comprising administering to the subject at least about 0.7 mg/kg (based on the total weight of siRNA in mg per kg of body weight) of a composition comprising:

(i) DLinDMA;

(ii) DPPC;

(iii) PEG2000-C-DMA;

(iv) cholesterol,

(v) an siRNA targeting Eg5/KSP; and

(vi) an siRNA targeting VEGF.

2. The method of claim 1 , wherein the subject has previously failed to respond to cancer treatment.

3. The method of claim 1 , wherein the siRNA targeting Eg5/KSP is AD12115.

4. The method of claim 1 , wherein the siRNA targeting VEGF is AD3133.

5. The method of claim 1 , wherein about 1.0 mg/kg of the composition is administered.

6. The method of claim 1 , wherein at least about 1.0 mg/kg of the composition is administered.

7. The method of claim 1 , wherein the subject has advanced cancer with liver involvement.

8. The method of claim 1 , wherein the composition is administered by intravenous (IV) infusion once every two weeks.

9. The method of claim 8 , wherein the duration of each IV infusion ranges from about 15 minutes to about 3 hours.

10. The method of claim 1 , wherein the composition is administered to the subject once every 2 weeks for at least four weeks.

11. The method of claim 1 , wherein the molar ratio of DLinDMA:DPPC:cholesterol:PEG2000-C-DMA is about 57.1:7.1:34.4:1.4.

12. The method of claim 1 , wherein the molar ratio of siRNA targeting Eg5/KSP to siRNA targeting VEGF is about 1 to 1.

13. The method of claim 1 , further comprising administering a corticosteroid to the subject.

14. The method of claim 1 , wherein the composition is ALN-VSP02 and provides a mean KSP siRNA AUC 0-last from about 10 to about 1100 μg*min/mL, a mean KSP siRNA C max from about 0.4 to about 10.0 μg/mL, a mean VEGF siRNA AUC 0-last from about 10 to about 1200 μg*min/mL and a mean VEGF siRNA C max from about 0.4 to about 18 μg/mL.

15. The method of claim 1 , wherein following administration of a first dose of 1 mg/kg of the composition, the AUC 0-last of KSP siRNA is within about 80% to about 125% of 15393.10±6002.12 ng*hr/mL, and/or following administration of a second dose of 1 mg/kg of the composition, the AUC 0-last of KSP siRNA is within about 80% to about 125% of 9984.02±2517.30 ng*hr/mL.

16. The method of claim 1 , wherein following administration of a first dose of 1 mg/kg of the composition, the C max of KSP siRNA is within about 80% to about 125% of 15314.98±5347.86 ng/mL, and/or following administration of a second dose of 1 mg/kg of the composition, the C max of KSP siRNA is within about 80% to about 125% of 12440.80±9615.15 ng/mL.

17. The method of claim 1 , wherein following administration of a first dose of 1 mg/kg of the composition, the AUC 0-last of VEGF siRNA is within about 80% to about 125% of 16404.33±7280.14 ng*hr/mL, and/or following administration of a second dose of 1 mg/kg of the composition, the AUC 0-last of VEGF siRNA is within about 80% to about 125% of 9563.98±2173.22 ng*hr/mL.

18. The method of claim 1 , wherein following administration of a first dose of 1 mg/kg of the composition, the C max of VEGF siRNA is within about 80% to about 125% of 15843.73±7014.77 ng/mL, and/or following administration of a second dose of 1 mg/kg of the composition, the C max of VEGF siRNA is within about 80% to about 125% of 12681.94±8811.54 ng/mL.

19. A method of treating a subject in need of treatment, comprising administering to the subject a 1.0 mg/kg dosage of a composition comprising

(i) DLinDMA;

(ii) DPPC;

(iii) PEG2000-C-DMA;

(iv) cholesterol,

(v) an siRNA targeting Eg5/KSP; and

(vi) an siRNA targeting VEGF;

via intravenous (IV) infusion once every 2 weeks, wherein

the composition has a dose-proportional maximum concentration (C max ) and area under curve (AUC) as measurable in the subject's plasma;

the AUC 0-last of KSP siRNA is within about 80% to about 125% of 15393.10±6002.12 or 9984.02±2517.30 ng*hr/mL;

the C max of KSP siRNA is within about 80% to about 125% of 15314.98±5347.86 or 12440.80±9615.15 ng/mL;

the AUC 0-last of VEGF siRNA is within about 80% to about 125% of 16404.33±7280.14 or 9563.98±2173.22 ng*hr/mL; and

the C max of VEGF siRNA is within about 80% to about 125% of 15843.73±7014.77 or 12681.94±8811.54 ng/mL.

20. A method of treating a subject in need of treatment, comprising administering to the subject a 1.25 mg/kg dosage of a composition comprising

(vii) DLinDMA;

(viii) DPPC;

(ix) PEG2000-C-DMA;

(x) cholesterol,

(xi) an siRNA targeting Eg5/KSP; and

(xii) an siRNA targeting VEGF;

via intravenous (IV) infusion once every 2 weeks, wherein

the composition has a dose-proportional maximum concentration (C max ) and area under curve (AUC) as measurable in the subject's plasma;

the AUC 0-last of KSP siRNA is within about 80% to about 125% of (i) 33929.01±18334.75 ng*hr/mL or (ii) 28833.57 ng*hr/mL;

the C max of KSP siRNA is within about 80% to about 125% of (i) 21937.49±7642.00 ng/mL or (ii) 17897.05 ng/mL;

the AUC 0-last of VEGF siRNA is within about 80% to about 125% of (i) 33442.95±18558.98 ng*hr/mL or (ii) 31072.98 ng*hr/mL; and

the C max of VEGF siRNA is within about 80% to about 125% of (i) 21578.94±6798.07 ng/mL or (ii) 18230.74 ng/mL.

21. The method of claim 19 , wherein the subject has cancer.

22. The method of claim 19 , wherein the subject has advanced cancer with liver involvement.

23. The method of claim 19 , wherein the subject has endometrial cancer.

24. The method of claim 19 , wherein the duration of each IV infusion is 15 minutes.

25. The method of claim 19 , wherein the duration of each IV infusion 15 minutes to 3 hours.

26. The method of claim 19 , wherein the composition is administered to the subject once every 2 weeks for at least four weeks.

27. The method of claim 19 , wherein the composition is administered to the subject once every two weeks for at least 8 weeks.

28. The method of claim 19 , further comprising administering a corticosteroid to the subject.