Treatments with nirogacestat

Patent metadata

Field	Value
Publication number	US-12138246-B2
Application number	US-202418624670-A
Country	US
Kind code	B2
Filing date	Apr 2, 2024
Priority date	May 20, 2022
Publication date	Nov 12, 2024
Grant date	Nov 12, 2024

Abstract

The present disclosure relates to improved methods of treatment with nirogacestat.

First claim

What is claimed:

1. A method for treating therapeutic treatment of desmoid tumor in a patient in need thereof comprising orally administering to the patient 150 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt thereof twice daily without concomitant administration of a moderate or strong CYP3A inhibitor or a moderate or strong CYP3A inducer, wherein the method further comprises one or more of:
(a) upon the patient having Grade 3 or 4 diarrhea persisting for at least 3 days despite medical therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the diarrhea is resolved to no higher than a Grade 1 diarrhea or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily;
(b) upon the patient having Grade 3 or 4 hypophosphatemia persisting for at least 3 days despite replacement therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the hypophosphatemia is resolved to no higher than a Grade 1 hypophosphatemia or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily;
(c) upon the patient having Grade 3 or 4 hypokalemia despite replacement therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the hypokalemia is resolved to no higher than a Grade 1 hypokalemia or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily;
(d) upon the patient having an alanine transaminase (ALT) or aspartate aminotransferase (AST) of 3 to 5 times upper limit of normal (ULN), withholding the nirogacestat or pharmaceutically acceptable salt thereof until the ALT, AST, or both are resolved to less than 3 times ULN or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily; and
(e) upon the patient having an ALT or AST of greater than 5 times ULN, permanently discontinuing treatment with the nirogacestat or pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the moderate or strong CYP3A inhibitor is selected from grapefruit products, Seville oranges, and starfruit.

3. The method of claim 1 , wherein the method comprises avoiding concomitant administration of nirogacestat or a pharmaceutically acceptable salt thereof with starfruit, Seville oranges, grapefruit, and juice from any of these fruits.

4. The method of claim 1 , wherein the strong CYP3A inhibitor is itraconazole, ketoconazole, or clarithromycin.

5. The method of claim 1 , wherein the moderate CYP3A inhibitor is erythromycin or fluconazole.

6. The method of claim 1 , wherein the strong CYP3A inducer is rifampin.

7. The method of claim 1 , wherein the moderate CYP3A inducer is efavirenz.

8. The method of claim 1 , wherein the method comprises avoiding concomitant administration of nirogacestat or a pharmaceutically acceptable salt thereof with a gastric acid reducing agent.

9. The method of claim 1 , wherein the method comprises avoiding concomitant administration of nirogacestat or a pharmaceutically acceptable salt thereof with proton pump inhibitors and H2-receptor antagonists.

10. The method of claim 1 , wherein the method comprises avoiding concomitant administration of nirogacestat or a pharmaceutically acceptable salt thereof with a CYP3A substrate, a CYP2C19 substrate, or both.

11. The method of claim 1 , further comprising:
(f) for another severe adverse reaction, life-threatening adverse reaction, or persistent intolerable Grade 2 adverse event, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the adverse reaction is resolved to no higher than a Grade 1 adverse reaction or baseline and then, after considering the potential benefit and likelihood of recurrence of the adverse reaction, (A) restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily and (B) upon recurrence of the severe or life-threatening adverse reaction at the 100 mg (free base equivalent dose) twice daily dose, permanently discontinuing treatment with the nirogacestat or pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the method comprises (a) upon the patient having Grade 3 or 4 diarrhea persisting for at least 3 days despite medical therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the diarrhea is resolved to no higher than a Grade 1 diarrhea or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

13. The method of claim 1 , wherein the method comprises (b) upon the patient having Grade 3 or 4 hypophosphatemia persisting for at least 3 days despite replacement therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the hypophosphatemia is resolved to no higher than a Grade 1 hypophosphatemia or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

14. The method of claim 1 , wherein the method comprises (c) upon the patient having Grade 3 or 4 hypokalemia despite replacement therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the hypokalemia is resolved to no higher than a Grade 1 hypokalemia or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

15. The method of claim 1 , wherein the method comprises (d) upon the patient having an ALT or AST of 3 to 5 times ULN, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the ALT, AST, or both are resolved to less than 3 times ULN or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

16. The method of claim 1 , wherein the method comprises (e) upon the patient having an ALT or AST of greater than 5 times ULN, permanently discontinuing treatment with the nirogacestat or pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the method comprises:
(a) upon the patient having Grade 3 or 4 diarrhea persisting for at least 3 days despite medical therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the diarrhea is resolved to no higher than a Grade 1 diarrhea or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily;
(b) upon the patient having Grade 3 or 4 hypophosphatemia persisting for at least 3 days despite replacement therapy, withholding the nirogacestat or pharmaceutically acceptable salt thereof until the hypophosphatemia is resolved to no higher than a Grade 1 hypophosphatemia or baseline and then restarting oral administration of the nirogacestat or pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily;
(c) upon the patient having Grade 3 or 4

Assignees

• Springworks Therapeutics Inc

Inventors

• Lim Allison
• Cheng Shinta
• Shearer Todd Webster
• Williams Rex
• Patterson Kristin

Classifications

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/536

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title