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EP-4734999-A1 - METHOD OF TREATING DEPRESSION USING SELTOREXANT

EP4734999A1EP 4734999 A1EP4734999 A1EP 4734999A1EP-4734999-A1

Abstract

A method of treating an orexin-2 mediated disorder in a human subject in need thereof is provided. The method comprises administering seltorexant or a pharmaceutically acceptable salt or hydrate thereof at a therapeutically effective daily dose to the subject, when the subject does not have a hepatic impairment. The method also comprises administering seltorexant or the pharmaceutically acceptable salt or hydrate thereof at a reduced dose less than the daily dose to the subject, when the subject has moderate hepatic impairment.

Inventors

  • DEVINENI, Damayanthi
  • LI, LINGJUE

Assignees

  • Janssen Pharmaceutica NV

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. What is claimed is: 1. A method of treating an orexin-2 mediated disorder in a human subject in need thereof, the subject having moderate hepatic impairment, the method comprising: administering seltorexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose that is less than a therapeutically effective daily dose adapted for treatment of a human subject having normal hepatic function.
  2. 2. A method of treating an orexin-2 mediated disorder in a human subject in need thereof, the method comprising: if the subject has moderate hepatic impairment, administering seltorexant or a pharmaceutically acceptable salt or hydrate thereof at a reduced dose that is less than a therapeutically effective daily dose adapted for treatment of a human subject having normal hepatic function; if the subject has severe hepatic impairment, not administering seltorexant or a pharmaceutically acceptable salt or hydrate thereof to the subject; and if the subject does not have moderate to severe hepatic impairment, administering seltorexant or a pharmaceutically acceptable salt or hydrate thereof at the daily dose to the subject.
  3. 3. The method of claim 1 or 2, wherein the subject having the moderate hepatic impairment has a Child-Pugh score from 7 to 9.
  4. 4. The method of any one of claims 1-3, wherein seltorexant is administered as a free base.
  5. 5. The method of any one of claims 1-3, wherein a hydrochloride salt of seltorexant is administered.
  6. 6. The method of any one of claims 1-5, wherein the orexin-2 mediated disorder is depression or insomnia.
  7. 7. The method of claim 6, wherein the orexin-2 mediated disorder is depression.
  8. 8. The method of claim 7, wherein the depression is major depressive disorder.
  9. 9. The method of claim 7, wherein the depression is bipolar depression.
  10. 10. The method of any one of claims 7-9, wherein the subject has concurrent insomnia symptoms.
  11. 11. The method of claim 10, wherein the subject has an ISI score of greater than or equal to 15.
  12. 12. The method of claim 6, wherein the orexin-2 mediated disorder is insomnia.
  13. 13. The method of any one of claims 1-12, wherein seltorexant is orally administered.
  14. 14. The method of claim 13, wherein the daily dose is about 20 mg/day to about 60 mg/day.
  15. 15. The method of claim 14, wherein the reduced dose is about 5 mg/day to about 20 mg/day.
  16. 16. The method of claim 15, wherein the reduced dose is about 20 mg/day.
  17. 17. The method of claim 15, wherein the reduced dose is about 15 mg/day.
  18. 18. The method of claim 15, wherein the reduced dose is about 10 mg/day.
  19. 19. The method of claim 15, wherein the reduced dose is about 5 mg/day.
  20. 20. The method of claim 14, wherein the daily dose is selected to provide an unbound average plasma concentration of seltorexant between about 0.75 ng/mL and about 1.5 ng/mL when administered the human subject having normal hepatic function.

Description

METHOD OF TREATING DEPRESSION USING SELTOREXANT CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of the priority of U.S. Provisional Patent Application No.63/524,198, filed June 29, 2023, the disclosure of which is incorporated by reference herein. FIELD OF INVENTION [0002] The present invention relates to methods for treating and/or preventing depression comprising administering to a subject in need thereof a therapeutically effective amount of an orexin-2 receptor antagonist, specifically, seltorexant. BACKGROUND OF INVENTION [0003] Orexins (also known as hypocretins) are neuropeptides expressed by neurons in the perifornical area, the dorsomedial hypothalamus and the lateral hypothalamus (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A.95, 322-327; Sakaurai et al, 1998, Cell 92, 573-585). Orexinergic neurons project to many areas of the brain including other hypothalamic nuclei, the midline paraventricular thalamus, brain stem nuclei, the ventral tegmental area and nucleus accumbens shell. (Peyron et al., 1998, J. Neurosci. 18, 9996-10016) Orexin neuropeptides, classified as either orexin-A or orexin-B, bind to the seven transmembrane G-protein coupled receptors orexin-1 (OX1R) and orexin-2 (OX2R) (de Lecea et al., 1998; Proc. Natl. Acad. Sci. U.S.A. 95, 322-327; Sakaurai et al, 1998, Cell 92, 573-585). While orexin-A is non-selective for OX1R and OX2R, orexin-B shows higher affinity for OX2R (Sakaurai et al, 1998, Cell 92, 573- 585). Orexin receptor antagonists are classified as single orexin receptor (SORAs) or dual receptor antagonists (DORAs). [0004] Hypothalamic orexinergic neurons expressing discharge during active wake, are virtually silent during non-rapid eye movement sleep and show transient discharges during rapid eye movement sleep (Lee, 2005, J. Neuroscience 25(8): 6716 - 6720; Takahashi, 2008, Neuroscience, 153: 860 - 870). This activity pattern supports the notion that the orexins are endogenous, potent, arousal (wakefulness)-promoting peptides. Studies using single unit recordings also show that OX-containing neurons are preferentially activated during rewarding appetitive behaviors (Hassani et al., 2016. J Neuroscience 36(5): 1747-1757). BRIEF SUMMARY OF THE INVENTION [0005] In one aspect of the present application a method of treating an orexin-2 mediated disorder in a human subject in need thereof is provided. In some examples, the orexin- 2 mediated disorder may include, but is not limited to, depression and insomnia. The depression may include, but is not limited to, major depressive disorder, bipolar depression or concurrent depression and insomnia symptoms having an ISI score of greater than or equal to 15. The method comprises administering seltorexant or a pharmaceutically acceptable salt or hydrate thereof (e.g. as a free base or a hydrochloride salt) at a therapeutically effective daily dose to the subject, when the subject does not have a hepatic impairment. The method also comprises administering seltorexant or the pharmaceutically acceptable salt or hydrate thereof at a reduced dose less than the daily dose to the subject, when the subject has moderate hepatic impairment (e.g., a Child-Pugh score from 7 to 9). In some examples, the method may further comprise administering seltorexant or a pharmaceutically acceptable salt or hydrate thereof at the daily dose to the subject, when the subject has mild hepatic impairment (e.g., a Child-Pugh score from 5 to 6). In additional examples, the method may also further comprise not administering seltorexant or a pharmaceutically acceptable salt or hydrate to the subject, when the subject has severe hepatic impairment (e.g., a Child-Pugh score at or above 10). [0006] For treatment of depression (e.g. major depressive disorder, bipolar depression or concurrent depression and insomnia symptoms having an ISI score of greater than or equal to 15) administration of seltorexant or the pharmaceutically acceptable salt or hydrate thereof at the daily dose provides a first unbound average plasma concentration of seltorexant within an effective therapeutic range, when the subject does not have a hepatic impairment, and at the reduced dose provides a second unbound average plasma concentration of seltorexant within the effective therapeutic range, when the subject has moderate hepatic impairment. Additionally, administration of seltorexant or the pharmaceutically acceptable salt or hydrate thereof at the daily dose may provide a third unbound average plasma concentration of seltorexant within the effective therapeutic range, when the subject has mild hepatic impairment. In some examples, the administration of seltorexant or the pharmaceutically acceptable salt or hydrate thereof at the reduced dose is more therapeutically effective than the daily dose in the subject, when the subject has the moderate hepatic impairment. [0007] In some examples, the subject may have an inadequate response to an antidepressa