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EP-4572767-B1 - COMBINATION OF NICLOSAMIDE AND SPIRONOLACTONE FOR USE IN THE TREATMENT OF FCOV INFECTION OR FELINE INFECTIOUS PERITONITIS

EP4572767B1EP 4572767 B1EP4572767 B1EP 4572767B1EP-4572767-B1

Inventors

  • PISAK, Mehmet Nevzat

Dates

Publication Date
20260506
Application Date
20220816

Claims (15)

  1. A combination of niclosamide and spironolactone for use in the treatment of FCoV infection or feline infectious peritonitis.
  2. A combination for use according to claim 1, wherein niclosamide and spironolactone are administered simultaneously, sequentially or separately.
  3. A combination for use according to any one of the preceding claims, wherein niclosamide and spironolactone are administered simultaneously.
  4. A combination for use according to any one of the preceding claims, wherein niclosamide and spironolactone are administered as immediate release formulation.
  5. A combination for use according to any one of the preceding claims, wherein niclosamide is administered to the subject within a range of 5 to 80 mg/kg per the weight of the subject.
  6. A combination for use according to claim 5, wherein niclosamide is administered to the subject within a range of 8 to 40 mg/kg per the weight of the subject.
  7. A combination for use according to any one of the preceding claims, wherein niclosamide is administered to the subject within a range of 10 to 300 mg per unit dose.
  8. A combination for use according to claim 7, wherein niclosamide is administered to the subject within a range of 20 to 200 mg per unit dose.
  9. A combination for use according to any one of the preceding claims, wherein spironolactone is administered to the subject within a range of 0.3 to 3 mg/kg per the weight of the subject.
  10. A combination for use according to claim 9, wherein spironolactone is administered to the subject within a range of 0.4 to 2 mg/kg per the weight of the subject.
  11. A combination for use according to claim 10, wherein spironolactone is administered to the subject within a range of 0.5 to 1.6 mg/kg per the weight of the subject.
  12. A combination for use according to any one of the preceding claims, wherein spironolactone is administered to the subject within a range of 0.1 to 25 mg/kg per unit dose.
  13. A combination for use according to claim 12, wherein spironolactone is administered to the subject within a range of 0.5 to 20 mg/kg per unit dose.
  14. A combination for use according to any one of the preceding claims, wherein niclosamide and spironolactone are administered 3 or 4 times in a day.
  15. A combination for use according to any one of the preceding claims, wherein niclosamide and spironolactone are administered in a fixed pharmaceutical composition.

Description

TECHNICAL FIELD The present invention provides a pharmaceutical composition comprising niclosamide and spironolactone for the treatment of FCoV infection or feline infectious peritonitis. BACKGROUND ART Animal epidemic diseases are the primary threat to the livestock and companion (pet) animals. Of the veterinary pathogens that cause these diseases, viruses are responsible for approximately half of the most important animal diseases. Animal viruses are divided into DNA and RNA viruses based on the genetic materials. The differences between DNA and RNA viruses include their lifetimes in target cells, how they attach to and enter host cells, and their biosynthesis, maturation, and release from cells. Compared with DNA viruses, RNA viruses have a higher mutation rate and cause more serious damage in the livestock industry. Lower mutation rates of DNA viruses were usually influenced by the viral genome and DNA repairing protein that benefit for proofread and correct replication errors. Oppositely, offspring of RNA viruses are usually produced 1 ± 2 mutations compared with their parent. RNA viruses are also divided into avian, fish, mammalian, and zoonotic viruses in domestic animal industries. There are more RNA viruses also being reported, apart from the classical swine fever virus (CSFV) and porcine reproductive and respiratory syndrome virus (PRRSV) which are the main RNA viruses that cause great losses in porcine industries. Because of their high mutation rates and the additional subgroups identified in recent years, both viruses are difficult to eliminate. Some RNA viruses not only infect animals but also humans, with the influenza virus the most typical RNA zoonotic virus. For example, H5N1 and H9N2 subgroups of the influenza virus are the main infectious pathogens affecting both humans and animals. Additionally, some RNA viruses primarily affecting humans, their transmission is directly related to contact with the virus containing body excretions of infected animals. For example, the main infection source of human Ebolavirus is close contact with pigs, dogs and non human primates. Similarly, Crimean-Congo haemorrhagic fever caused by Nairoviruses, may cause endemic outbreaks via transmission of the viruses from subclinically infected farm animals. Feline infectious peritonitis (FIP) is a common disease and a frequent reason for mortality; approximately 1 of every 200 new feline cases presented to American veterinary teaching hospitals represents a cat with FIP. It is also a major factor in kitten mortality. FIP is a fatal immune-mediated disease triggered by the specific genetic mutations that is giving monocyte invasion ability to the virus in feline coronavirus (FCoV) infected cats. FCoV belongs to the family Coronaviridae, a group of enveloped positive-stranded RNA viruses that are frequently found in cats. FCoV is distributed worldwide in household and stray cats. The virus is endemic especially in environments in which many cats are kept together in a small space (e.g., catteries, shelters, pet stores). There is virtually no multiple-cat household without endemic FCoV. Thus, once a cat in a household has contracted the disease, it is also important to provide prophylaxis for the healthy cats. There are two main forms of FIP: effusive (wet) and non-effusive (dry). While both types are fatal, the effusive form is more common (60-70% of all cases) and progresses more rapidly than the non-effusive form. In both forms of the disease, the mortality is 90-95% once the symptoms begin to manifest. There is a search for an effective antiviral treatment for cats with FIP. But unfortunately, most have not been very successful, although some studies have been performed with several antiviral therapies such as interferon and ribavirin. The only treatment with success so far has been the nucleoside analog GS-441524 which has 84-day treatment duration by injection and is only sold as a black-market product, since it is not currently approved by any medical authorities for human or veterinary diseases (Tasker et al, Viruses. 2021 Nov; 13(11):2228). Niclosamide is an anthelmintic drug that has been approved for human and animal use for over 50 years. It has been found to possess inhibitory effects against the SARS-CoV-2 virus (see Yoshikazu et al., Viruses, 2022, 14 (8), 1-13). In addition, spironolactone is an aldosterone antagonist that is used as a potassium sparing diuretic in dogs or cats that develop low potassium on other diuretic medications. It can be used as adjunctive treatment in congestive heart failure or as an adjunctive treatment for hypertension at a dose of 1-2 milligrams per kilogram orally every 12 hours for cats and at a dose of 0.5 to 4 milligrams per kilogram orally every 12-24 hours for dogs. However, there is still a need in the art for the treatment of RNA virus diseases, especially feline infectious peritonitis in animals such as cats and for a pharmaceutical compound or combination of comp