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EP-4734994-A1 - INTERMITTENT DOSING METHODS FOR TREATING A CONDITION ASSOCIATED WITH INCREASED 15-PGDH

EP4734994A1EP 4734994 A1EP4734994 A1EP 4734994A1EP-4734994-A1

Abstract

Provided are intermittent dosing methods for treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject with a 15-PGDH inhibitor to reduce toxicity. Further, provided herein are methods of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject by administering a 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject falls below the EC50 of the 15-PGDH inhibitor, while maintaining therapeutic efficacy of the 15-PGDH inhibitor.

Inventors

  • CLARK, Annie M.
  • BAGNOL, DIDIER
  • WEBSTER, Micah
  • CASDIN, Alexander
  • FAHR, BRUCE

Assignees

  • Epirium Bio Inc.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject in an amount effective to inhibit 15- PGDH at a level sufficient to treat the condition, wherein the 15-PGDH inhibitor is administered to the subject at a dosing frequency that exhibits reduced toxicity to the subject as compared to a once every day dosing frequency of the 15-PGDH inhibitor at the same amount.
  2. 2. The method of claim 1, wherein the dosing frequency that exhibits reduced toxicity to the subject is less than once every day.
  3. 3. The method of claim 1, wherein the dosing frequency that exhibits reduced toxicity to the subject is once every 2 days, once every 3 days, once every 4 days, once every 5 days, one every 6 days, or once every 7 days.
  4. 4. The method of claim 1, wherein the dosing frequency that exhibits reduced toxicity to the subject is less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days.
  5. 5. The method of any one of claims 1-4, wherein the administering comprises administering the 15-PGDH inhibitor when a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor. .
  6. 6. A method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject at an amount effective to increase a plasma concentration of the 15-PGDH inhibitor in the subject to a level above the ECso of the 15-PGDH inhibitor, wherein the subject has received at least one dose of the 15-PGDH inhibitor prior to the administering, and wherein the administering comprises administering the 15-PGDH inhibitor to the subject when the subject has a plasma concentration of the 15-PGDH inhibitor that is below the ECso of the 15-PGDH inhibitor.
  7. 7. The method of claim 6, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours prior to the administering.
  8. 8. The method of claim 6 or 7, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 48 hours prior to the administering.
  9. 9. The method of any one of claims 6-8, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 72 hours prior to the administering.
  10. 10. The method of any one of claims 6-9, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours and less than 72 hours prior to the administering.
  11. 11. The method of any one of claims 5-10, wherein the administering comprises administering the 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold, or greater than 1000-fold lower than the ECso of the 15-PGDH inhibitor.
  12. 12. The method of any one of claims 5-11, wherein the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor in the subject is above the EC50 of the 15-PGDH inhibitor.
  13. 13. The method of any one of claims 5-12, wherein the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject by once a day administration.
  14. 14. The method of any one of claims 1-13, wherein the reduced toxicity is selected from the group consisting of: reduced neurological disorders, reduced muscle degeneration, reduced gastrointestinal and/or metabolic distress, reduced inflammation, or any combination thereof.
  15. 15. The method of any one of claims 1-14, wherein the reduced toxicity is measured by: safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism, and excretion (ADME) studies, reproductive and developmental toxicity, an evaluation of carcinogenic potential, or any combination thereof.
  16. 16. The method of any one of claims 1-15, wherein the administering comprises administering the 15-PGDH inhibitor to the subject by oral administration.
  17. 17. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a small molecule.
  18. 18. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is selected from -OCH 2 - -C(O)NH- -NHC(O)-, -C(O)NMe- -NMeC(O)-, - SCH 2 -, -S(O)CH 2 - -SO 2 CH 2 -; each Y is independently selected from N and CR 11 ; each R 1 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1 0 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R 2 is H and R 3 is -CF 3 ; or R 2 and R 3 are taken together to form oxo or thio; each R 4 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1 0 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl; each R 5 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1 0 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl; R 6 and R 7 are independently selected at each occurrence from H, C 1-6 alkyl, C 1- 6 heteroalkyl, C 1-6 haloalkyl, and C 3 - 10 cycloalkyl; each R 8 is independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 10 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 9 is independently selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 . 1 0 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; each R 10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C 3 . 1 0 cycloalkyl; each R 11 is independently selected from halo, -NR 6 R 7 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , - C(O)NR 6 R 7 , -SOR 9 , -SO 2 R 9 , -SO 2 NR 6 R 7 , -NR 10 C(O)R 8 , -NR 10 C(O)NR 6 R 7 , -NR 10 SO 2 R 8 , -NR 10 SO 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3 - 1 0 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  19. 19. The method of claim 18, wherein the compound is a compound of Formula la: or a pharmaceutically acceptable salt thereof.
  20. 20. The method of claim 18, wherein the compound is a compound of Formula lb: or a pharmaceutically acceptable salt thereof.

Description

INTERMITTENT DOSING METHODS FOR TREATING A CONDITION ASSOCIATED WITH INCREASED 15-PGDH CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 63/510,874, filed on June 28, 2023, and U.S. Provisional Application No. 63/588,989, filed on October 9, 2023, each of which is incorporated herein by reference in its entirety. BACKGROUND [0002] Prostaglandins are a group of physiologically active lipid compounds with diverse biological effects. Treatment of conditions, diseases, or disorders may require activation of prostaglandins, or inhibition of inactivation of prostaglandins. Hydroxyprostaglandin dehydrogenases, such as 15 -hydroxyprostaglandin dehydrogenase (15-PGDH) are involved in the inactivation of prostaglandins. As such, conditions, diseases, or disorders associated with prostaglandins can be prevented, treated and/or managed using inhibitors of hydroxyprostaglandin dehydrogenase, such as inhibitors of 15-PGDH. [0003] However, therapeutic agents such as inhibitors can have drug toxicity, which can lead to adverse effects on a subject. In order for these therapeutic agents to be approved for clinical application, they are tested for toxicity. Several therapeutic agents entering clinical trials can fail because they are unsafe or ineffective due to toxicity. INCORPORATION BY REFERENCE [0004] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material. SUMMARY [0005] There is an unmet need for methods and dosing regimens for reducing toxicity (e.g., neurotoxicity) associated with 15-PGDH inhibitor treatment. This disclosure meets this unmet need. [0006] In one aspect, provided herein is a method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject in an amount effective to inhibit 15-PGDH at a level sufficient to treat the condition, wherein the 15-PGDH inhibitor is administered to the subject at a dosing frequency that exhibits reduced toxicity to the subject as compared to a once every day dosing frequency of the 15-PGDH inhibitor at the same amount. [0007] In some instances, the dosing frequency that exhibits reduced toxicity to the subject is less than once every day. In some instances, the dosing frequency that exhibits reduced toxicity to the subject is once every 2 days, once every 3 days, once every 4 days, once every 5 days, one every 6 days, or once every 7 days. In some instances, the dosing frequency that exhibits reduced toxicity to the subject is less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days. In some instances, the administering comprises administering the 15-PGDH inhibitor when a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor. [0008] In another aspect, the present disclosure provides a method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject at an amount effective to increase a plasma concentration of the 15-PGDH inhibitor in the subject to a level above the ECso of the 15-PGDH inhibitor, where the subject has received at least one dose of the 15-PGDH inhibitor prior to the administering, and where the administering comprises administering the 15-PGDH inhibitor to the subject when the subject has a plasma concentration of the 15-PGDH inhibitor that is below the EC50 of the 15-PGDH inhibitor. [0009] In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 48 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15- PGDH inhibitor greater than 72 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15 -PGDH inhibitor greater than 24 hours and less than 72 hours prior to the administering. [0010] In some embodiments, the administering comprises administering the 15-PDGH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2- fold, at least 5-fold, at least 10-f