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US20180303837A1 - Therapeutic regimen - Google Patents

Therapeutic regimen Download PDF

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Publication number
US20180303837A1
US20180303837A1 US15/961,394 US201815961394A US2018303837A1 US 20180303837 A1 US20180303837 A1 US 20180303837A1 US 201815961394 A US201815961394 A US 201815961394A US 2018303837 A1 US2018303837 A1 US 2018303837A1
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Prior art keywords
kaf156
malaria
lumefantrine
dose
days
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Jay Prakash JAIN
Franz Joel LEONG
Cornelis WINNIPS
Marie-Christine Wolf
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Novartis AG
Novartis Healthcare Pvt Ltd
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Novartis AG
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Assigned to NOVARTIS HEALTHCARE PRIVATE LIMITED reassignment NOVARTIS HEALTHCARE PRIVATE LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Jain, Jay Prakash
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS HEALTHCARE PRIVATE LIMITED
Assigned to NOVARTIS INSTITUTE FOR TROPICAL DISEASES PTE LTD reassignment NOVARTIS INSTITUTE FOR TROPICAL DISEASES PTE LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEONG, FRANZ JOEL
Assigned to NOVARTIS PHARMA AG reassignment NOVARTIS PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WINNIPS, CORNELIS, WOLF, MARIE-CHRISTINE
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS INSTITUTE FOR TROPICAL DISEASES PTE LTD
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS PHARMA AG
Publication of US20180303837A1 publication Critical patent/US20180303837A1/en
Priority to US16/669,275 priority Critical patent/US20200171037A1/en
Priority to US17/388,277 priority patent/US11738028B2/en
Priority to US18/219,507 priority patent/US20240180913A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • KAF156 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone
  • KAF156 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a
  • 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.
  • Malaria is one of the most important infectious diseases, which threatens about 3.2 billion people, almost half of the world's population.
  • malaria 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.
  • CQ chloroquine
  • PYR pyrimethamine
  • SFDX sulfadoxine
  • MEF mefloquine
  • ACTs artemisinin-based combination therapies
  • 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.
  • KAF156 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone
  • imidazolepiperazines This compound is structurally distinct from currently marketed antimalarial drugs and other experimental antimalarial compound classes currently in development.
  • the mechanism of action of KAF156 is still being characterized, but may be related to a previously uncharacterized gene ( Plasmodium falciparum cyclic amine resistance locus, Pfcarl).
  • KAF156 kills/inhibits the erythrocytic replication life cycle stages (blood stages) of the two main causative agents of human malaria, P. falciparum and P. vivax , both at low nanomolar EC50s (in vitro).
  • KAF156 has shown activity in liver stage models of Plasmodium infection, conferring causal prophylactic protection in animal infection models. Limited evidence of gametocyticidal activity may confer transmission blocking activity.
  • KAF156 has not demonstrated activity against liver hypnozoites and therefore has a low probability to be used for a radical cure for P. vivax .
  • KAF156 is equally potent against drug-sensitive and a broad panel of drug resistant malaria strains (Kuhen et al 2014 “KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission; Antimicrobial Agents and Chemotherapy; 2014; 58(9):5060-5067).
  • KAF156 By killing the malaria parasite at its early, asymptomatic liver stage, KAF156 has a potential to serve as a prophylactic treatment, preventing the disease to spread into the blood stream, and thus to pass into a mosquito which could otherwise infect another human.
  • KAF156 was previously tested in malaria in uncomplicated adult malaria patients, either in a 3 day dosing with a dose of 400 mg/day (patients affected by with P. vivax or P. falciparum ) or in a single dosing with a dose of 800 mg (patients affected by with P. falciparum ) (NCT01753323). The results are published in White et al. (New England Journal of Medicine, 375; 12, 2016). No serious adverse event was reported. The study shows that KAF156 has activity against vivax and falciparum malaria, including artemisinin-resistant parasites. One patient who had received the single 800-mg dose had repeated vomiting and was withdrawn from the study.
  • the invention addresses these needs by providing novel therapeutic regimen which employ novel new therapeutically effective amounts of 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; and new dosing regimens of KAF156, that are particularly adequate for short treatment duration and can be used in combination with another anti-malaria partner drug.
  • 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; and new dosing regimens of K
  • KAF156 or a pharmaceutically acceptable salt thereof, for use in preventing or treating malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein the compound is administered daily at a dose of about 200 mg to about 1000 mg for up to 5 days, e.g. 1 to 3 days, e.g. 1 or 2 days.
  • KAF156, or a pharmaceutically acceptable salt thereof, for use in preventing or treating malaria, or delaying the symptoms or ameliorating the conditions associated with malaria wherein the compound is administered daily at a dose of about 200 mg to about 350 mg for up to 5 days, e.g. 1 to 3 days, e.g. 1 or 2 days.
  • the invention provides methods of preventing or treating malaria, delaying the symptoms or ameliorating the conditions associated with malaria, comprising daily administering (e.g. once daily) to a subject in need thereof a therapeutically effective amount of an imidazolepiperazine, e.g. 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 optionally in combination with another anti-malaria drug, e.g. lumefantrine.
  • an imidazolepiperazine e.g. 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethan
  • KAF156 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone
  • methods of preventing or treating malaria, or delaying the symptoms or ameliorating the conditions associated with malaria comprising daily administering (e.g. once daily) to a subject in need thereof a dose of KAF156, or a pharmaceutically acceptable salt thereof, wherein the dose is of about 200 mg to about 350 mg and is administered for up to 5 days, e.g. 1 to 3 days, e.g. 1 or 2 days.
  • Disclosed herein are also improved formulations of lumefantrine, e.g. with enhanced bioavailability versus lumefantrine capsules, and the use of such formulations in combination with KAF156, e.g. with specific regimen of KAF156.
  • the invention provides an imidazolepiperazine, e.g. 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 preventing or treating malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein said imidazolepiperazine, e.g. KAF156, is administered daily (e.g. once daily) at a dose of about 200 mg to about 1000 mg, e.g. for up to 5 days, e.g.
  • KAF156 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-y
  • KAF156 or a pharmaceutically acceptable salt thereof, for use in preventing or treating malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein KAF156 is administered daily (e.g. once daily) at a dose of about 200 mg to about 350 mg, e.g. for up to 5 days, e.g. for 1 to 3 days.
  • KAF156 for use in preventing or treating malaria, to be administered daily (e.g. once daily), of about 200 mg to about 1000 mg, e.g. about 200 mg to about 350 mg (e.g. about 200 mg, about 350 mg, about 400 mg or about 800 mg) of KAF156.
  • compositions for use in preventing or treating malaria comprising KAF156, wherein KAF156 is to be administered daily (e.g. once daily) to a patient at a dose of about 200 mg to about 1000 mg, e.g. of about 200 mg to about 350 mg (e.g. about 200 mg, e.g. about 400 mg, e.g. about 800 mg), e.g. for up to 5 days, e.g. for 1 to 5 days, e.g. for 2 to 5 days, e.g. 1 to 3 days, e.g. 1 or 2 days.
  • KAF156 is to be administered daily (e.g. once daily) to a patient at a dose of about 200 mg to about 1000 mg, e.g. of about 200 mg to about 350 mg (e.g. about 200 mg, e.g. about 400 mg, e.g. about 800 mg), e.g. for up to 5 days, e.g. for 1 to 5 days, e.g. for 2 to 5 days, e
  • KAF156 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating malaria, characterized in that KAF156 or a pharmaceutically acceptable salt thereof is to be administered daily (e.g. once daily) to a patient at a dose of about 200 mg to about 1000 mg (e.g. about 200 mg, about 350 mg, about 400 mg or about 800 mg), e.g. for up to 5 days, e.g. for 1 to 5 days, e.g. for 2 to 5 days, e.g. 1 to 3 days, e.g. 1 or 2 days.
  • KAF156 or a pharmaceutically acceptable salt thereof is to be administered daily (e.g. once daily) to a patient at a dose of about 200 mg to about 1000 mg (e.g. about 200 mg, about 350 mg, about 400 mg or about 800 mg), e.g. for up to 5 days, e.g. for 1 to 5 days, e.g. for 2 to 5 days, e.g. 1 to 3 days, e.g.
  • the invention further provides therapeutic kits for preventing or treating malaria, comprising up to 5 daily doses of KAF156 or a pharmaceutically acceptable salt thereof, wherein the dose of KAF156 or a pharmaceutically acceptable salt thereof is of about 200 mg to about 1000 mg, e.g. of about 200 mg to about 350 mg, e.g. about 200 mg, e.g. about 350 mg, about 400 mg or e.g. about 800 mg.
  • the imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof is administered with another anti-malaria drug, e.g. lumefantrine, e.g. as a solid dispersion formulation or microemulsion, e.g. solid dispersion formulation of lumefantrine.
  • another anti-malaria drug e.g. lumefantrine, e.g. as a solid dispersion formulation or microemulsion, e.g. solid dispersion formulation of lumefantrine.
  • the invention provides pharmaceutical combinations comprising i) an imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof, and ii) another anti-malaria drug, e.g. lumefantrine; and such pharmaceutical combinations for use in preventing or treating malaria, or in delaying the symptoms or ameliorating the conditions associated with malaria.
  • pharmaceutical combinations comprising about 200 mg to 800 mg of KAF156 and about 400 mg to 1000 mg of lumefantrine.
  • pharmaceutical combinations comprising about 200 mg to 800 mg of KAF156 and about 400 mg to 1000 mg of lumefantrine, wherein lumefantrin is in form of a solid dispersion formulation or microemulsion, e.g. a solid dispersion formulation.
  • KAF156 and lumefantrine e.g. of KAF156 and solid dispersion formulation of lumefantrine.
  • the invention provides the use of KAF156 for the manufacture of a medicament for treating or preventing malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein the medicament is administered daily (e.g. once daily) during 1 to 5 days, e.g. 1 to 3 days, and comprises about 200 mg to about 1000 mg of KAF156.
  • KAF156 for the manufacture of a medicament for treating or preventing malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein the medicament is administered once and comprises about 200 mg, about 350 mg or about 400 mg of KAF156.
  • KAF156 for the manufacture of a medicament for treating or preventing malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein the medicament is administered daily (e.g. once daily) for three days and comprises about 200 mg, about 350 mg or about 400 mg of KAF156.
  • the invention provides the use of a combination of KAF156 and lumefantrine, e.g. a fixed dose combination, for the manufacture of a medicament for treating or preventing malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein the medicament is administered daily (e.g. once daily) and comprises about 200 mg of KAF156 and about 480 mg lumefantrine.
  • Lumefantrine may be in form of a solid dispersion formulation.
  • a combination of KAF156 and lumefantrine e.g. a fixed dose combination, for the manufacture of a medicament for treating or preventing malaria, or delaying the symptoms or ameliorating the conditions associated with malaria, wherein the medicament is administered daily (e.g. once daily) and comprises about 200 mg of KAF156 and about 960 mg lumefantrine.
  • Lumefantrine may be in form of a solid dispersion formulation.
  • a combination of KAF156 and lumefantrine e.g. a fixed dose combination
  • the medicament is administered daily (e.g. once daily) and comprises about 400 mg of KAF156 and about 480 mg lumefantrine.
  • Lumefantrine may be in form of a solid dispersion formulation.
  • a combination of KAF156 and lumefantrine e.g. a fixed dose combination
  • the medicament is administered daily (e.g. once daily) and comprises about 400 mg of KAF156 and about 960 mg lumefantrine.
  • Lumefantrine may be in form of a solid dispersion formulation.
  • FIG. 1 discloses the concentration time profiles of lumefantrine following single dose administration of 480 mg dose under fasting conditions as conventional tablet, SDF variant-1 and SDF variant-2 (human study).
  • FIGS. 2A and 2B describe Lumeantrine exposure in dog study.
  • FIGS. 3A and 3B describe KAF156 exposure in dog study.
  • KAF156 which is 2-amino-1-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone
  • composition “comprising” encompasses “including” as well as “consisting,” e.g. a composition “comprising” X may consist exclusively of X or may include something additional, e.g. X+Y.
  • treatment of malaria may be prophylactic (to prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • the term “prevent” or “prevention” refers to a partial or complete inhibition of development or progression of the disease.
  • malaria refers to the diseases induced by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale or Plasmodium malaria, e.g. acute and cerebral malaria, e.g. uncomplicated P. falciparum malaria.
  • an effective amount” or “therapeutically effective amount” of an imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof refers to an amount of the imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof that will elicit a biological or medical response in a patient, for example, reduction or inhibition of a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the term “effective amount” or “therapeutically effective amount” is defined herein to refer to an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the condition treated.
  • pharmaceutically acceptable means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • the term “daily” refers to administering the drug, e.g. KAF156, lumefantrine, or the pharmaceutical combination comprising KAF156 and lumefantrine, in a daily manner, i.e. every day. It can correspond to a unique administration (once daily, also referred as QD) or several administrations a day, such as up to four times a day.
  • the drug e.g. KAF156, lumefantrine, or the pharmaceutical combination comprising KAF156 and lumefantrine
  • KAF156 is administered once a day administration.
  • lumefantrine is preferably administered once a day.
  • KAF156 in form of a free base
  • KAF156 is administered at a dose comprised between about 200 mg and about 800 mg, e.g. between about 200 mg and about 600 mg, e.g. between about 200 mg and about 500 mg, e.g. between about 250 mg and about 500 mg, e.g. between about 250 mg and about 450 mg, e.g. between about 200 mg and about 400 mg.
  • KAF156 in form of a free base
  • KAF156 is administered at a dose of about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg.
  • these doses are for daily administration, e.g. are daily doses. In other embodiments, these doses are for once daily administration.
  • new therapeutic regimens of KAF156 for use in preventing or treating malaria comprising administering (e.g. daily) a dose of KAF156 of about 200 mg to about 900 mg, e.g. about 200 mg to about 800 mg, e.g. about 200 mg to about 600 mg, e.g. about 200 mg to about 500 mg, e.g. about 250 mg to about 500 mg, e.g. about 250 mg to about 450 mg, e.g. about 200 mg to about 400 mg.
  • the therapeutic regimens of KAF156 for use in preventing or treating malaria comprise administering (e.g. daily) a dose of KAF156 of about 200 mg, 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 800 mg.
  • KAF156 or a pharmaceutically acceptable salt thereof is administered daily during up to 5 days, e.g. for 1 to 5 days, e.g. for 1 to 3 days, e.g. for 2 to 5 days, e.g. for 1 or 2 days, e.g. for one day.
  • a dose of KAF156 or a pharmaceutically acceptable salt thereof for unique administration e.g. unique daily administration.
  • kits for use in preventing or treating malaria comprising KAF156 or a pharmaceutically acceptable salt thereof, e.g. doses thereof to be administered daily. Additionally, such kits may comprise means for administering the imidazolepiperazine, e.g. KAF156 and instructions for use. These kits may contain one (or more) additional anti-malaria agent(s), e.g. lumefantrine.
  • kits comprising: a) a pharmaceutical composition comprising a therapeutically effective amount of an imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof; b) means for administering the imidazolepiperazine or a pharmaceutically acceptable salt thereof (KAF156) to a patient at risk of or having malaria; and c) instructions providing administering the imidazolepiperazine (e.g. KAF156) to the patient up to five days.
  • an imidazolepiperazine e.g. KAF156 or a pharmaceutically acceptable salt thereof
  • therapeutic kits comprising a) a pharmaceutical composition comprising a doses of an imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof, e.g. about 200 mg to about 1000 mg, e.g. about 200 mg, e.g. about 400 mg or e.g. about 800 mg; b) means for administering the imidazolepiperazine or a pharmaceutically acceptable salt thereof (KAF156) to a patient at risk of or having malaria; and c) instructions providing administering the imidazolepiperazine (e.g. KAF156) to the patient.
  • an imidazolepiperazine e.g. KAF156 or a pharmaceutically acceptable salt thereof
  • the therapeutic kit comprises doses of the imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof, e.g. KAF156, for daily administration during up to 5 days, e.g. 1 to 5 doses, e.g. 2 to 5 doses, e.g. 1 to 3 doses, e.g. 1 to 2 doses, e.g. one dose.
  • Such doses can be of about 200 mg to about 1000 mg, e.g. about 200 mg, e.g. about 300 mg, e.g. about 305 mg, e.g. about 400 mg or e.g. about 800 mg of KAF156 (as free base).
  • therapeutic kits comprising one to five doses of KAF156, or a pharmaceutically acceptable salt thereof, for daily administration, wherein said doses are of about 200 mg to about 1000 mg, e.g. about 200 mg, e.g. about 300 mg, about 350 mg, e.g. about about 400 mg or e.g. about 800 mg of KAF156 (as free base).
  • the imidazolepiperazine e.g. KAF156 or a pharmaceutically acceptable salt thereof is administered with another anti-malaria drug, e.g. lumefantrine.
  • the treatment e.g. KAF156 or a combination of KAF156 with another anti-malaria agent, should provide adequate parasiticidal serum levels over a period of at least 6-7 days (3 parasite life-cycles approximately) in order to achieve curing the patient.
  • compositions comprising i) an imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof, e.g. KAF156, and ii) another anti-malaria agent, e.g. lumefantrine.
  • KAF156 as a free base
  • KAF156 is to be administered daily at a dose of about 200 mg to about 1000 mg, e.g. about 200 mg to about 900 mg, e.g. about 200 mg to about 800 mg, e.g. about 200 mg to about 600 mg, e.g. about 200 mg to about 500 mg, e.g. about 200 mg to about 350 mg, e.g. about 200 mg to about 300 mg, e.g. about 250 mg to about 500 mg, e.g. about 250 mg to about 450 mg, e.g. about 250 mg to about 350 mg, e.g. about 200 mg to about 400 mg, e.g. about 300 mg to about 400 mg.
  • compositions comprising i) daily doses of KAF156, and ii) another anti-malaria agent, for preventing or treating malaria, wherein the dose of KAF156 (as free base) is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 800 mg.
  • the second anti-malaria agent is selected from the group consisting of proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine and pyronaridine.
  • the second anti-malaria agent is lumefantrine.
  • Lumefantrine may be in the form of as a solid dispersion formulation.
  • lumefantrine is to be administered daily at a dose of about 400 mg to 1000 mg, e.g. about 400 mg to about 500 mg, e.g. about 900 mg to about 1000 mg.
  • lumefantrine is to be administered daily at a dose of about 480 mg or about 960 mg.
  • imidazolepiperazine e.g. KAF156 or a pharmaceutically acceptable salt thereof, e.g. KAF156
  • the second anti-malaria agent e.g. lumefantrine
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of i) an imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof, e.g. KAF156, and ii) the second anti-malaria agent, e.g. lumefantrine, to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • an imidazolepiperazine e.g. KAF156 or a pharmaceutically acceptable salt thereof, e.g. KAF156
  • the second anti-malaria agent e.g. lumefantrine
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, i.e. the imidazolepiperazine and the second anti-malaria agent, e.g. KAF156 and lumefantrine, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, i.e. the imidazolepiperazine and the second anti-malaria agent, e.g. KAF156 and lumefantrine, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • imidazolepiperazine e.g. KAF156 or a pharmaceutically acceptable salt thereof will be administered via any of the usual and acceptable modes known in the art.
  • the imidazolepiperazine, e.g. KAF156 can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising the imidazolepiperazine, e.g. KAF156, optionally in combination with a second anti-malaria agent, e.g.
  • lumefantrine in association with at least one pharmaceutically acceptable carrier or diluent
  • oral compositions can be tablets or gelatin capsules comprising the imidazolepiperazine, e.g. KAF156, together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g.
  • Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations may also be used.
  • Suitable formulations for topical application, e.g. to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • lumefantrine can be prepared as a solid dispersion.
  • solid dispersion refers to dispersion of an active molecule in an inert carrier in the solid state prepared by solvent, melting or solvent-melting methods.
  • compositions can be prepared using different processes e.g. solvent evaporation, spray drying, melt extrusion, fluid bed granulation technology, solvent evaporation, use of polymers, melt cooling.
  • solvent evaporation e.g. solvent evaporation, spray drying, melt extrusion, fluid bed granulation technology, solvent evaporation, use of polymers, melt cooling.
  • the techniques that can be used are known to the one skilled in the art, and are described e.g. in Gahoi et al (Int. J Pharm Sci. Rev. Res. 8 (2), 170-175. 2011), Balaji et al (International Journal of Pharmacy and Pharmaceutical Sciences, Vol 6 Issue 2, 2014), Fule et al (Int. J. drug del. 4, 2012, 95-106).
  • the solid dispersion can further be mixed with other excipients and can be formulated into capsule or tablet dosage forms. Excipients that can be used can be e.g.
  • poloxamer 188 e.g. in higher amount than the drug, e.g. four times more than the drug amount of drug
  • PVP Polyvinylpyrollidone
  • the solid dispersion of lumefantrine comprises excipients selected from the group consisting of Solupus, Eudragit EPO, PVP K30 and mixture thereof, e.g. selected from the group consisting of Eudragit EPO, PVP K30 and mixture thereof.
  • solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug.
  • hydrophilic carriers such as e.g. polyvinylpyrrolidone (Povidone, PVP), polyethylene glycols (PEG 6000), Surfactants like Tween-80, Poloxamer, and Sodium Lauryl Sulphate (SLS).
  • lumefantrine can be prepared as a microemulsion, e.g. as described in Patel (DARU J. Pharm. Sci, 21 (27), 2013).
  • lumefantrine can be in amorphous state.
  • pharmaceutical combination comprising about 200 mg of KAF156 (as free base), and about 400 mg to 500 mg of lumefantine (as free base), e.g. about 480 mg lumefantrine (as free base), for daily administration.
  • pharmaceutical combination comprising about 300 mg or 350 mg of KAF156 (as free base), and about 400 mg to 500 mg of lumefantine (as free base), e.g. about 480 mg lumefantrine (as free base), for daily administration.
  • pharmaceutical combination comprising about 400 mg of KAF156 (as free base) and about 400 mg to 500 mg of lumefantine (as free base), e.g. about 480 mg lumefantrine (as free base), for daily administration.
  • pharmaceutical combination comprising about 800 mg of KAF156 (as free base) and about 400 mg to 500 mg of lumefantine (as free base), e.g. about 480 mg lumefantrine (as free base), for daily administration.
  • pharmaceutical combination comprising about 200 mg of KAF156 (as free base) and about 900 mg to 1000 mg of lumefantine (as free base), e.g. about 960 mg lumefantrine (as free base), for daily administration.
  • pharmaceutical combination comprising about 300 mg or 350 mg of KAF156 (as free base) and about 900 mg to 1000 mg of lumefantine (as free base), e.g. about 960 mg lumefantrine (as free base), for daily administration.
  • pharmaceutical combination comprising about 400 mg of KAF156 (as free base) and about 900 mg to 1000 mg of lumefantine (as free base), e.g. about 960 mg lumefantrine (as free base), for daily administration.
  • the pharmaceutical combinations comprising KAF156 and lumefantine are fixed dose combinations.
  • lumefantrine can be formulated as a solid dispersion formulation.
  • compositions of Examples 1 and 2 have shown significantly higher dissolution at pH 1 and pH2 in presence and in absence of a surfactant.
  • Bioavailability of the solid dispersion capsule formulation was assessed in male beagle dogs along with the conventional tablet (composition/process similar to Coartem®) and microemulsion.
  • Lumefantrine-SD capsule has an improved absorption profile and less food effect, leading to exposure which allows for a once-daily regimen.
  • subjects had no food or liquid (except water) for at least 10 hours prior to administration of study drug and continued to fast for at least 4 hours post dose.
  • subjects were provided a high fat breakfast (total of 916 calories with 178, 241, and 497 calories from protein, carbohydrate, and fat, respectively). The meal was served and consumed within 30 minutes and study drug was administered within 5 minutes after completion of the meal. All doses were administered with 180-240 mL water.
  • the study population comprised healthy male subjects of at least 50 kg in weight (BMI within 18.0-30.0 kg/m2). A total of 49 male subjects (18-44 years) were randomized into Part 1 of the study and of these, 16 subjects continued into Part 2 of the study.
  • PK samples were obtained and evaluated in all subjects at all dose levels. Blood samples for PK analysis of lumefantrine were collected at pre-dose and 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 216, and 264 hours post-dose.
  • Lumefantrine concentration was determined by a validated Liquid chromatography-Mass spectrometry (LC-MS/MS) method with a Lower Limit of Quantification (LLOQ) of 50 ng/mL.
  • LC-MS/MS Liquid chromatography-Mass spectrometry
  • LLOQ Lower Limit of Quantification
  • the bioanalytical method consisted of protein precipitation followed by solid phase extraction of human plasma samples and analysis of diluted samples by LC-MS/MS in Multiple Reaction Monitoring (MRM) positive mode using Electrospray Ionization (ESI) as the ionization technique.
  • MRM Multiple Reaction Monitoring
  • ESI Electrospray Ionization
  • the lower and upper limits of quantification for linear range were 50.0 ng/mL and 20000 ng/mL respectively using 10 ⁇ L of human plasma.
  • Lumefantrine in human plasma is stable for 44 hours at room temperature; 9 months at ⁇ 70° C.; 3 freeze/thaw cycles at ⁇ 70° C.
  • the extract is stable for 100 hours in an autosampler at 8° C.
  • the stability data could cover the period from sampling to analysis of all study samples.
  • calibration concentrations 50, 100, 200, 500, 2000, 5000, 16000 and 20000 ng/mL bias was within the range of ⁇ 15.0% at all concentrations except for LLOQ (50 ng/mL) for which it was within the range of ⁇ 20.0%.
  • LLOQ 50 ng/mL
  • quality control samples 150 ng/mL, 2500 ng/mL and 15000 ng/mL bias was within the range of ⁇ 15.0% for at least 2 ⁇ 3 of the individual values.
  • Concentrations below the LLOQ were considered as “zero” for pharmacokinetic analysis.
  • the following pharmacokinetic parameters were determined from the plasma concentration-time data by non-compartmental analysis in Phoenix WinNonlin (Version 6.4): C max , T max , AUC 0-72h , AUC last , AUC inf , T 1/2 , Vz/F and CL/F.
  • the linear trapezoidal rule was used for AUC calculation.
  • Sample size Part 1: 36 subjects (12 per cohort) had complete data from each cohort for which would allow adequate detection of at least a 1.5-fold change. For the observed ratios from 1.5 to 5.0-fold change the predicted 90% confidence intervals for the primary pharmacokinetic parameter ratio (AUC inf , AUC last . and C max based on log transformation) are: 1.5 (1.08, 2.09), 2.0 (1.44, 2.78), 3.0 (2.15, 4.18), 4.0 (2.87, 5.57), 5.0 (3.59, 6.96) using the historic data on variability. In Part 2, no formal statistical calculations were considered in calculating the sample size.
  • the log transformed primary pharmacokinetic parameters C max , AUC last and AUC inf were analyzed separately by using a linear effects model with treatment as fixed effects.
  • the estimated mean and 90% confidence intervals of treatment difference were back transformed to obtain the geometric mean ratio and 90% confidence intervals of the ratio and those were reported to represent the relative bioavailability of SD formulation(s) variant-1 vs. conventional tablet and SDF variant-2 vs. conventional tablet.
  • lumefantrine was absorbed with median T max of 6 hours with some initial lag time.
  • n* number of subjects with non-missing values Reference: Cohort 1: 480 mg conventional tablets (Fasting) Test-1: Cohort 2: 480 mg SD variant-1 capsules (Fasting) Test-2: Cohort 3: 480 mg SD variant-2 capsules (Fasting)
  • the rate and extent of absorption of lumefantrine from both the SD formulations was enhanced significantly relative to conventional formulation.
  • the C max for SD formulation variant-1 was 47.9 ⁇ g/mL.
  • the C max for SD formulation variant-1 and SD formulation variant-2 was about 19-fold and about 13-fold higher respectively, compared to conventional formulation under fasting conditions.
  • the bioavailability (through AUC last ) of lumefantrine from SD formulation variant-1 and variant-2 increased up to about 48-fold and about 24-fold, respectively, relative to conventional formulation.
  • both variants demonstrated positive food effect and less than proportional increase in exposure between 480 mg and 960 mg doses.
  • the SD formulations achieved considerable increase in bioavailability without the need to be administered with food rich in fat.
  • each animal received a single 6- ⁇ g/kg intramuscular injection of pentagastrin approximately 60 minutes prior to test article administration. Washout between each treatment was approximately 7-8 days.
  • Oral 150 a 40 2/1 3 Lumefantrine-SDF sachet and KAF156 tablet (FCT) Oral 15 b and 100 c 5 bd and 1 cf 3/1 3 Lumefantrine-SDF capsule Oral 150 e 2 eg 4/1 3 Lumefantrine-SDF sachet Oral 15 b 5 bd 5/1 3 KAF156 tablet (FCT) Oral 100 c 1 cf a Lumefantrine suspension dose is 600 mg (containing 25% drug load) in 40 mL/animal or 150 mg/animal Lumefantrine.
  • Lumefantrine-SD sachet suspension dose is 3.37 g (containing 17.78% drug load) in 199 mL vehicle (or 16.9 mg/mL) and will be dosed at 3 mg/mL (LUM566), 15 mg/kg, and 5 mL/kg.
  • the dose of KAF156 will be 100 mg (1 ⁇ 100 mg).
  • d Units are mL/kg.
  • e The dose of Lumefantrine will be 150 mg (2 ⁇ 75 mg capsules).
  • f Units are tablets/animal.
  • g Units are capsules/animal.
  • Ratio (Phase 2:Phase 5) KAF156 Dog 1 Dog 2 Dog 3* Mean SD Cmax 2.6 2.5 3.3 2.8 0.4 AUClast 2.7 2.9 5.2 3.6 1.4 AUCinf 2.6 2.8 5.3 3.6 1.5 *dog 3 had emesis after dosing in Phase 5, i.e. possible dose lose
  • One population PK model for KAF156 and one population PK model for LUM-SDF variant 1 were implemented in Monolix 4.4.0 as part of Monolix Suite 2016R1 (Lixoft, Paris, France) using the SAEM algorithm. Simulations were performed using simulx function of mlxR 3.1.0 package in R-3.2.3. The final models were used to perform simulations for different dosing regimens. Individual PK profiles for KAF156 and LUM-SDF variant-1 up to 500 hours under different combination regimens were simulated using the final models.
  • Cohort 1 KAF156 400 mg and LUM-SDF 960 mg once daily (QD) for 1 day
  • the infection will be measured through PCR-corrected adequate clinical and parasitological response (ACPR). PCR-Uncorrected ACPR at Days 15, 29 and 43 (i.e. 14, 28 and 42 days postdose), and PCR-corrected ACPR at Days 15 and 43 (i.e. 14 and 42 days post-dose) will be performed. Incidence rate of recrudescence and reinfection at Days 15, 29 and 43 will be measured, as well as Parasite and Fever Clearance Times (PCT and FCT). Proportion of patients with parasitaemia at 12, 24, and 48 hours after treatment will be estimated.
  • ACPR PCR-corrected adequate clinical and parasitological response
  • PCT and FCT Parasite and Fever Clearance Times
  • Eligible patients will be enrolled into one out of the up to four dosing cohorts i.e. up to three investigational drug dosing arms and a control arm. Dosing will be adjusted based on children's body weight similar to the adjustment of Coartem®.
  • Part A male and female patients ⁇ 12 years and with a body weight ⁇ 35.0 kg
  • Part B after determining the effective/tolerated doses and regimens in adolescent and adult patients, male and female patients ⁇ 2 and ⁇ 12 years and with a body weight ⁇ 10.0 kg will be included
  • liver disease e.g. chronic hepatitis, cirrhosis, compensated or decompensated, history of hepatitis B or C, hepatitis B or A vaccination in last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis
  • Severe vomiting defined as more than 3 times in the 24 hours prior to inclusion in the study or severe diarrhea defined as more than 3 watery stools per day
  • Women of child bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for the duration of the study.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Anemia Hemoglobin level ⁇ 8 g/dL

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TW201842911A (zh) 2018-12-16
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WO2018198021A1 (en) 2018-11-01
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US11738028B2 (en) 2023-08-29
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