JPWO2021175857A5

JPWO2021175857A5 -

Info

Publication number: JPWO2021175857A5
Application number: JP2022552946A
Authority: JP
Publication date: 2024-03-12

Claims

A pharmaceutical composition for the treatment of inflammation , comprising plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof .

2. The pharmaceutical composition of claim 1, wherein the inflammation is associated with activation of Toll-like receptors.

A pharmaceutical composition according to claim 1 for the treatment of pneumonia .

A pharmaceutical composition according to claim 1 for the treatment of acute respiratory distress (ARDS).

A pharmaceutical composition according to claim 1 for the treatment of immunopathology.

A pharmaceutical composition according to claim 1 for the treatment of hypercytokinemia.

A pharmaceutical composition according to claim 1 for the treatment of sepsis.

A pharmaceutical composition according to claim 1 for the treatment of graft-versus-host disease.

A pharmaceutical composition according to claim 1 for the treatment of pathogen-induced inflammation.

10. The pharmaceutical composition according to claim 9 , wherein the pathogen is a virus.

10. The pharmaceutical composition according to claim 9, wherein the pathogen is a bacterium.

Pharmaceutical composition according to claim 1 , for the combined treatment of inflammation associated with activation of Toll-like receptors or pathogen-induced inflammation and viral infection.

A pharmaceutical composition according to claim 1 for use as an anti-inflammatory and antiviral agent.

13. The pharmaceutical composition according to claim 2 or 12, wherein the Toll-like receptor is activated by a virus.

8. A pharmaceutical composition according to any one of claims 3 to 7, wherein said pneumonia, acute respiratory distress (ARDS), immunopathology, hypercytokinemia or sepsis is induced by a virus.

The virus is a single-stranded RNA virus , Flaviviridae, Picornaviridae, Togaviridae, Caliciviridae, Retroviridae, Coronaviridae, Orthomyxoviridae, Phleboviridae , Arenaviridae , dsDNA virus. , herpesviridae, yellow fever virus (YFV), hepatitis C virus, West Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), swine fever virus, Zika Virus (ZIKV), CoV, SARS-CoV-2, foot-and-mouth disease virus, enterovirus A71, coxsackie virus, rhinovirus, hepatitis A, chikungunya virus, Sindbis virus, Semliki Forest virus, eastern equine encephalitis virus, western equine encephalitis virus, Venezuelan equine encephalitis virus, Rubella virus, Lagovirus, Norovirus, Nebovirus, Recovirus, Sapovirus, Barovirus, Vesivirus, Norwalk virus, HIV, Influenza, Sandfly fever virus or Rift Valley fever virus, Pichinde virus, 16. A pharmaceutical composition according to any one of claims 10 and 12 to 15, selected from herpes simplex virus type 1, herpes simplex virus type 2, or a respiratory virus .

17. Pharmaceutical composition according to claim 16 for the treatment of COVID-19 , wherein the virus is a CoV virus and is SARS-CoV-2 .

18. A pharmaceutical composition according to claim 17 for the treatment of pneumonia or ARDS caused by COVID-19.

19. According to any one of claims 16 to 18, the CoV infection is a mild infection; and/or the CoV infection is a moderate infection; and/or the CoV infection is a severe infection. Pharmaceutical composition .

said CoV infection is an acute CoV infection, preferably said CoV infection is an acute COVID-19 infection; and/or said CoV infection is an ongoing symptomatic CoV infection, preferably said CoV infection is an ongoing symptomatic COVID-19 infection and/or said CoV infection is a post-CoV syndrome, persistent CoV or long-term CoV; preferably said CoV infection is a post-COVID-19 syndrome, persistent CoV; 19. A pharmaceutical composition according to any one of claims 16 to 18 , which is COVID-19 or long-term COVID.

The post-CoV syndrome, persistent CoV, or long-term CoV includes the cardiovascular system, respiratory system, gastrointestinal system, nervous system, musculoskeletal system, metabolic system, renal system, skin system, otorhinolaryngology, blood system, and autonomic nervous system. 21. The pharmaceutical composition according to claim 20 , wherein one or more symptoms arising from the system include: psychiatric problems, generalized pain, fatigue and/or persistent fever.

for the treatment of patients with signs and symptoms of CoV infection (preferably COVID-19) for up to 4 weeks; and/or for the treatment of patients with signs and symptoms of CoV infection (preferably COVID-19) for 4 weeks to 12 weeks; and/or for the treatment of patients with signs and symptoms of CoV infection, preferably COVID-19, for more than 12 weeks . Composition .

A pharmaceutical composition according to any one of claims 16 to 18 for the prevention, mitigation or treatment of persistent COVID, long COVID or post-COVID syndrome, preferably by said prevention, mitigation or treatment. , the likelihood of the patient suffering from symptoms of persistent COVID, long COVID or post-COVID syndrome is minimized; more preferably, said treatment minimizes the symptoms of CoV infection. .

21. According to any one of claims 16 to 20 , the treatment reduces the infectivity of a CoV patient; including when the patient is asymptomatic or has few symptoms but has a high viral load. Pharmaceutical composition .

25. A pharmaceutical composition according to any one of claims 1 to 24 , wherein the plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered in combination with a corticosteroid, preferably dexamethasone.

26. The pharmaceutical composition of claim 25 , wherein the plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof and the corticosteroid are administered simultaneously, separately, or sequentially.

The said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, preferably Any of claims 1 to 26 , administered according to a daily dosage regimen for 2 to 5 days, 3 to 5 days, or 3, 4 or 5 days; most preferably for 3 or 5 days; most preferably for 3 days. The pharmaceutical composition according to item 1.

The said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is 5 mg or less per day, 4.5 mg or less per day, 4 mg or less per day, 3.5 mg or less per day, 3 mg or less per day, 2.5 mg or less per day, or 2 mg/day or less; 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5 mg/day preferably 1 mg/day, 1.5 mg/day, 2 mg/day or 2.5 mg/day; more preferably 1.5 to 2.5 mg/day; most preferably 1.5 mg/day, 20 mg/day or 2.5 mg/day 28. A pharmaceutical composition according to any one of claims 1 to 27 , administered in doses.

The plitidepsin or its pharmaceutically acceptable salt or stereoisomer is 1 to 50 mg, 1 to 40 mg, 1 to 30 mg, 1 to 20 mg, 1 to 15 mg, 3 to 15 mg, 3 to 12 mg, 4 to 12 mg, 4 ~10mg, or 4.5-10mg; 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg or 10mg; preferably 4.5mg, 5mg, 6mg, 7.5 29. Pharmaceutical composition according to any one of claims 1 to 28 , administered at a total dose of mg, 8 mg, 9 mg or 10 mg; more preferably 4.5 to 7.5 mg/day.

said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered by injection ; optionally,
the infusion is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, or a 3 hour infusion; preferably a 1.5 hour infusion;
30. A pharmaceutical composition according to any one of claims 1 to 29 .

1.5 mg plitidepsin was administered as a 1.5 hour infusion once daily for 3 consecutive days; or 2 mg plitidepsin was administered as a 1.5 hour infusion once daily for 3 consecutive days; 2.5 mg plitidepsin was administered as a 1.5 hour infusion once daily for 3 consecutive days; administered as an infusion once daily for 3 consecutive days; or 1 mg plitidepsin administered as a 1.5 hour infusion once daily for 5 consecutive days; or 2 mg plitidepsin administered as a 1.5 hour infusion once daily for 5 consecutive days; 31. A pharmaceutical composition according to any one of claims 1 to 30 , which is administered for 5 days.

said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered using a loading dose and a maintenance dose ; optionally,
The medication regimen is
2.5 mg loading dose on day 1, 2 mg/day maintenance dose on subsequent days;
2.5 mg loading dose on day 1 and 1.5 mg/day maintenance dose on subsequent days;
2.5 mg loading dose on day 1, 1 mg/day maintenance dose on subsequent days;
loading dose of 2.5 mg on day 1 and maintenance dose of 0.5 mg/day on subsequent days;
2 mg loading dose on day 1 and 1.5 mg/day maintenance dose on subsequent days;
2 mg loading dose on day 1, 1 mg/day maintenance dose on subsequent days;
2 mg loading dose on day 1 and maintenance dose of 0.5 mg/day on subsequent days;
Loading dose of 1.5 mg on day 1 and maintenance dose of 1 mg/day on subsequent days;
1.5 mg loading dose on day 1 and maintenance dose of 0.5 mg/day on subsequent days; or
loading dose of 1 mg on day 1 and maintenance dose of 0.5 mg/day on subsequent days ;
32. A pharmaceutical composition according to any one of claims 1 to 31 .

The plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered in combination with a corticosteroid , and the corticosteroid is administered in combination with the administration of the plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof. administered on the same day ; optionally,
Said corticosteroid may also be administered on one or more subsequent days; preferably said corticosteroid is administered in combination with said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for 1 to 3 days. and the corticosteroid is further administered on one or more of days 4 to 10; optionally,
the corticosteroid is administered intravenously on the day of administering the plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, but is administered orally or by IV on a subsequent day;
33. A pharmaceutical composition according to any one of claims 1 to 32 .

said corticosteroid is dexamethasone, preferably dexamethasone is administered IV at a dose of 6.6 mg/day on the day that said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered; optionally ,
said dexamethasone is administered orally or IV at a dose of 6 mg/day on one or more of subsequent days, preferably days 4, 5, 6, 7, 8, 9, and 10. ,
34. A pharmaceutical composition according to claim 33 .

said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered intravenously (IV) at 1.5 mg/day in combination with dexamethasone 6.6 mg/day IV on days 1 to 3; followed by dexamethasone 6 mg/ day orally (PO)/IV from day 4 until up to day 10 (as determined by the physician depending on the patient's clinical status and evolution); or
said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered intravenously (IV) at 2.0 mg/day in combination with dexamethasone 6.6 mg/day IV on days 1 to 3; followed by dexamethasone 6 mg/ day orally (PO)/IV from day 4 until up to day 10 (as determined by the physician depending on the patient's clinical status and evolution); or
said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered intravenously (IV) at 2.5 mg/day in combination with dexamethasone 6.6 mg/day IV on days 1 to 3; Any of claims 1 to 34 , wherein dexamethasone 6 mg/day is subsequently administered orally (PO)/IV from day 4 up to day 10 (according to the physician's judgment according to the patient's clinical condition and evolution). The pharmaceutical composition according to item 1.

36. The medicament according to any one of claims 33 to 35 , wherein the corticosteroid is administered 20 to 30 minutes before commencing treatment with the plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof. Composition .

Before said patient begins treatment with said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof , preferably 20 to 30 minutes, the following drugs:
Ondansetron 8mg IV (or equivalent);
diphenhydramine hydrochloride 25 mg IV (or equivalent); and ranitidine 50 mg IV (or equivalent)
37. A pharmaceutical composition according to any one of claims 1 to 36 , wherein the pharmaceutical composition receives:

38. The pharmaceutical composition of any one of claims 1-37 , wherein on days 4 and 5, the patient receives ondansetron (or equivalent) 4 mg PO twice daily.

said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered as a single dose (on day 1) ; optionally,
Said single dose is 1-10mg, 4-10mg, 4.5-10mg; 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg or 10mg; More preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; more preferably 5-9 mg, 6.5-8.5 mg, 7-8 mg or most preferably 7.5 mg.
31. A pharmaceutical composition according to any one of claims 1 to 30 .

said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered as a 1.5 hour infusion ; and/or
the corticosteroid is administered according to the regimen defined in any one of claims 33 to 36; and/or
20 to 30 minutes before administration of said plitidepsin or its pharmaceutically acceptable salt or stereoisomer, the following prophylactic agents:
Ondansetron 8 mg IV (or equivalent), especially by slow infusion over 15 minutes;
Diphenhydramine hydrochloride 25mg IV (or equivalent);
Ranitidine 50mg IV (or equivalent)
is administered; and/or
After administration of said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, ondansetron 4 mg is given orally every 12 hours for 3 days ;
40. A pharmaceutical composition according to claim 39 .

If the dexamethasone is dexamethasone phosphate and is administered on the day that said plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof is administered, it is administered at a dose of 8 mg (equivalent to a dose of 6.6 mg base); 41. A pharmaceutical composition according to any one of claims 1 to 40 , which when administered subsequently is administered at a dose of 7.2 mg (equivalent to a dose of 6.6 mg base).

plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof for treating inflammation; for treating inflammation associated with activation of Toll-like receptors; for treating pneumonia, acute respiratory distress (ARDS), and To treat immunopathology, in particular disorders selected from hypercytokinemia (cytokine storm syndrome), sepsis and graft-versus-host disease; to treat pathogen-induced inflammation; activation of Toll-like receptors or for the combined treatment of pathogen-induced inflammation and viral infection; or for use as an anti-inflammatory and antiviral agent; together with instructions for use;

Pharmaceutical composition according to claim 1, for reducing the expression and/or secretion of one or more proinflammatory cytokines in a subject or in a sample obtained from a subject or in a cell culture. A pharmaceutical composition comprising plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof .

2. A pharmaceutical composition according to claim 1, for increasing macrophage activation and/or recruitment in a subject, or in a sample obtained from a subject, or in a cell culture, comprising plitidepsin or its pharmaceutical composition. A pharmaceutical composition comprising a pharmaceutically acceptable salt or stereoisomer .

A pharmaceutical composition for the treatment of inflammation comprising a corticosteroid , wherein the corticosteroid is administered in combination with plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof .

42. A pharmaceutical composition for the treatment of inflammation , comprising plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, and a corticosteroid , the use being as defined in any one of claims 1 to 41 . A pharmaceutical composition .

including corticosteroids, to treat inflammation , or to treat inflammation associated with activation of Toll-like receptors, or to treat inflammation associated with activation of Toll-like receptors, or to treat inflammation in pneumonia, acute respiratory distress (ARDS), and immunopathology, especially high for treating disorders selected from cytokineemia (cytokine storm syndrome), sepsis and graft-versus-host disease, or for treating pathogen-induced inflammation, or related to activation of Toll-like receptors Use of a pharmaceutical composition for the combined treatment of inflammation or pathogen-induced inflammation and viral infection, or for use as an anti-inflammatory and antiviral agent, said treatment comprising plitidepsin or its pharmaceutically acceptable A pharmaceutical composition comprising the administration of a salt or stereoisomer of

plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, and a corticosteroid, for the treatment of inflammation , or for the treatment of inflammation associated with activation of Toll-like receptors, or for treating disorders selected from pneumonia, acute respiratory distress (ARDS), and immunopathology, in particular hypercytokinemia (cytokine storm syndrome), sepsis and graft-versus-host disease, or pathogen-induced inflammation. Pharmaceutical compositions for the treatment or for the combined treatment of inflammation associated with activation of Toll-like receptors or pathogen-induced inflammation and viral infections, or for use as anti-inflammatory and antiviral agents .

49. A pharmaceutical package comprising plitidepsin or a pharmaceutically acceptable salt or stereoisomer thereof, and a corticosteroid, together with instructions for use , as defined in any one of claims 1 to 48 .