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US-12616700-B2 - Therapeutic regimen

US12616700B2US 12616700 B2US12616700 B2US 12616700B2US-12616700-B2

Abstract

The present invention relates to dosing regimen of a new antimalarial drug, as monotherapy or combination therapy.

Inventors

  • Jay Prakash JAIN
  • Franz Joel LEONG
  • Cornelis WINNIPS
  • Marie-Christine Wolf

Assignees

  • NOVARTIS AG

Dates

Publication Date
20260505
Application Date
20230707
Priority Date
20170424

Claims (6)

  1. 1 . A method of preventing or treating malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, in a subject in need thereof, comprising administering to said subject about 100 mg of 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H)-yl) ethanone, or a pharmaceutically acceptable salt thereof, in combination with a second anti-malaria drug; wherein the second anti-malaria drug is lumefantrine; and wherein the lumefantrine is administered daily at a dose of about 15 mg/kg.
  2. 2 . The method of claim 1 , wherein the lumefantrine is formulated as a solid dispersion.
  3. 3 . The method of claim 1 , wherein said 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H)-yl) ethanone, or a pharmaceutically acceptable salt thereof, is administered daily during 1 to 5 days.
  4. 4 . The method of claim 1 , wherein said 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H)-yl) ethanone, or a pharmaceutically acceptable salt thereof, is administered daily during 1 to 3 days.
  5. 5 . The method of claim 1 , wherein said 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H)-yl) ethanone, or a pharmaceutically acceptable salt thereof, and the lumefantrine are used in a non-fixed dose combination.
  6. 6 . The method of claim 1 , wherein said 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H)-yl) ethanone, or a pharmaceutically acceptable salt thereof, and the lumefantrine are used in a fixed dose combination.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation application of U.S. application Ser. No. 17/388,277, filed Jul. 29, 2021, which is a Continuation U.S. application Ser. No. 16/669,275, filed Oct. 30, 2019, which is a Continuation of U.S. application Ser. No. 15/961,394, filed Apr. 24, 2018, and claims the benefit of priority to Indian Patent Application No. 201711014459, filed Apr. 24, 2017. The entire teachings of the aforementioned applications are incorporated herein by reference. FIELD OF THE INVENTION The invention provides an imidazolepiperazine, such as 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone (KAF156), or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of malaria, optionally in combination with another anti-malaria drug. The invention relates to methods of preventing, treating, delaying the symptoms or ameliorating the conditions associated with malaria, comprising administering to a subject in need thereof said imidazolepiperazine or a pharmaceutically acceptable salt thereof, optionally in combination with another anti-malaria drug. Specifically, the invention provides new dosing regimen of 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone, or a pharmaceutically acceptable salt thereof, and combinations comprising said compound, and another anti-malaria drug. BACKGROUND OF THE INVENTION Malaria is one of the most important infectious diseases, which threatens about 3.2 billion people, almost half of the world's population. Despite increasing international efforts for malaria control, in 2015, there were 214 million cases worldwide of malaria and 438 000 deaths according to the latest estimates of the World Health Organization. Sub-Saharan Africa carries a disproportionately high share of the global malaria burden. In 2015, the region was home to 88% of malaria cases and 90% of malaria deaths. Also, in areas with high transmission of malaria, children under 5 are particularly susceptible to infection, illness and death; more than two thirds (70%) of all malaria deaths occur in this age group (306 000 estimates deaths in 2015). Malaria is an infectious disease caused by four protozoan parasites: Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria. These four parasites are typically transmitted by the bite of an infected female Anopheles mosquito. Malaria is a problem in many parts of the world and over the last few decades the malaria burden has steadily increased. An estimated 1-3 million people die every year from malaria—mostly children under the age of 5. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs, with the exception of the artemisinin derivatives. Malaria is characterized by fever, headache, muscle ache, back pain, joint pains, nausea, sometimes vomiting and coughs; in severe case it leads to coma and finally it causes death. Standard antimalarial drugs such as chloroquine (CQ), pyrimethamine (PYR), sulfadoxine (SFDX) and mefloquine (MEF) have become largely ineffective in many malaria endemic regions. The only exceptions are the artemisinin-based combination therapies (ACTs) such as Novartis' Coartem®/Riamet® and Eurartesim®, current standard-of-care for P. falciparum malaria. Coartem® is a fixed combination of artemether, an artemisinin derivative, and lumefantrine. Dosing is weight-based and the standard dose is composed of 80 mg artemether and 480 mg lumefantrine twice daily for three days. As stated in the prescribing information Coartem must be administered with high fat food, since food is known to increase the bioavailability of lumefantrine by up to 16-fold and of artemether by up to 3-fold. The administration of Coartem with food is also important to achieve sufficient exposure of lumefantrine up to day 7, which is required for high cure rate. In acute malaria illness and in malaria endemic countries, non-adherence to this treatment requirement could lead to treatment failure. Some recent reports (Menard et al 2016; A worldwide map of Plasmodium falciparum K13-Propeller polymorphisms; N. Engl. J. Med; 374(25):2453-64) suggest that decades of continuous use of artemisinin and bisquinoline derivatives as monotherapies may have fostered the emergence of drug resistance in Plasmodium species in Southeast Asia. Reduced in vitro susceptibility of P. falciparum to artemisinin in this region has been documented. Recent studies showed that artemisinin resistance extends over more of southeast Asia than had previously been known, and is now present close to the border with India (Menard et al 2016). If widespread artemisinin drug resistance was to occur, malaria pharmacotherapy would be severely impaired. This find