Combination therapies

• US 10,596,165 B2
• Filed: 02/12/2019
• Issued: 03/24/2020
• Est. Priority Date: 02/12/2018
• Status: Active Grant

• Current Assignee: resTORbio, Inc.
• Original Assignee: resTORbio, Inc.
• Inventors: Mannick, Joan, Schor, Chen, Teo, Grace
• Primary Examiner(s): Henley, III, Raymond J
• Application Number:
  US16/273,919
• Publication Number:
  US 20190247386A1
• Time in Patent Office: 406 Days
• Field of Search: 514 31, 5142315, 514293
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs

Abstract

The present invention provides methods and pharmaceutical compositions for the treatment or prevention of autophagy-related diseases, disorders, or conditions.

Claims

1. A method for the treatment of Parkinson'"'"'s disease or a disease, disorder, or condition associated with alpha-1 antitrypsin deficiency in a subject in need thereof, comprising administering to the subject an effective amount of a combination of an allosteric mTOR inhibitor and a catalytic mTOR inhibitor.

2. The method according to claim 1, wherein the allosteric mTOR inhibitor is selected from everolimus, sirolimus, temsirolimus, zotarolimus, umirolimus and deforolimus, and wherein the catalytic mTOR inhibitor is selected from RTB101, CCG168, Ku-0063794, WYE-354, and 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one.

3. The method according to claim 2, wherein the allosteric mTOR inhibitor is everolimus or sirolimus and the catalytic mTOR inhibitor is RTB101.

4. The method according to claim 3 for the treatment of Parkinson'"'"'s disease,

wherein:

the everolimus or sirolimus is administered at a dose of between about 0.01 and 10.0 mg/kg/week and the RTB101 is administered at a dose of between about 0.01 and 10.0 mg/kg/day;

the everolimus or sirolimus is administered at a dose of between about 0.01 and 20.0 mg/kg/week and the RTB101 is administered at a dose of between about 0.01 and 100.0 mg/kg/day;

the everolimus or sirolimus is administered at a dose of between about 0.01 and 30.0 mg/kg/week and the RTB101 is administered at a dose of between about 0.01 and 200.0 mg/kg/day;

the everolimus or sirolimus is administered at a dose of between about 0.01 and 40.0 mg/kg/week and the RTB101 is administered at a dose of between about 0.01 and 300.0 mg/kg/day;

or

the everolimus or sirolimus is administered at a dose of between about 0.01 and 50.0 mg/kg/week and the RTB101 is administered at a dose of between about 0.01 and 400.0 mg/kg/day.

5. The method according to claim 4, wherein the everolimus or sirolimus is administered at a dose of between about 5 and 40.0 mg/kg/week and the RTB101 is administered at a dose of between about 25 and 400.0 mg/kg/day.

6. The method according to claim 3 for the treatment of Parkinson'"'"'s disease, wherein, the everolimus or sirolimus is administered at a dose of between about 2 to about 6 mg/week and the RTB101 is administered at a dose of about 300 mg/week.

7. The method according to claim 4, wherein the Parkinson'"'"'s Disease is GBA-related Parkinson'"'"'s disease.

8. The method according to claim 3, wherein the allosteric mTOR inhibitor is everolimus.

9. The method according to claim 3, wherein the allosteric mTOR inhibitor is sirolimus.

10. The method according to claim 3 for the treatment of a disease, disorder, or condition associated with alpha-1 antitrypsin deficiency, wherein:

the everolimus or sirolimus is administered at a dose of between about 0.01 to 1 mg/kg/day and the RTB101 is administered at a dose of between 2.5 and 20 mg/kg/day.

11. The method according to claim 10, wherein the everolimus or sirolimus is administered at a dose of about 1.5 mg/kg/week and the RTB101 is administered at a dose of about 2.5 mg/kg/day.

12. The method according to claim 10, wherein the disease, disorder, or condition associated with alpha-1 antitrypsin deficiency is a disease of the liver.

13. The method according to claim 12, wherein the liver disease is selected from cirrhosis, hepatitis, hepatomegaly, jaundice, and liver failure.

14. The method according to claim 10, wherein the allosteric mTOR inhibitor is everolimus.

15. The method according to claim 10, wherein the allosteric mTOR inhibitor is sirolimus.

16. The method according to claim 1, wherein the allosteric mTOR inhibitor and the catalytic mTOR inhibitor are administered orally.