WO2022049548A1

WO2022049548A1 - Kaf156 combinations and methods for the treatment of malaria

Info

Publication number: WO2022049548A1
Application number: PCT/IB2021/058077
Authority: WO
Inventors: Flavio Fabiani; Jay Prakash Jain; Allan Maclean; Cornelis Winnips; Marie-Christine Wolf
Original assignee: Novartis Ag
Priority date: 2020-09-04
Filing date: 2021-09-03
Publication date: 2022-03-10

Abstract

The present invention relates to dosing regimen of KAF156, as combination therapy with lumefantrine.

Description

KAF156 COMBINATIONS AND METHODS FOR THE TREATMENT OF MALARIA

FIELD OF THE INVENTION

The invention provides an imidazolepiperazine, such as 2-amino-l-(2-(4-fluorophenyl)-3-(4- fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone (KAF156), or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of malaria in combination with lumefantrine. 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, in combination with lumefantrine.

BACKGROUND OF THE INVENTION

[001] 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).

[002] 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. [003] 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.

[004] 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.

[005] 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.

[006] Some recent reports (Menard et al 2016; A worldwide map of Plasmodium falciparum KI 3-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 finding signifies that spread of resistance is inevitable, thus there is urgent need for new antimalarials with new mechanism of actions (Tun et al 2015;

Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the KI 3 molecular marker; Lancet Infect Dis; 15(4): 415-21). In addition, current falciparum malaria treatments require at least a 3-day dosing regimen which may contribute to therapeutic non-compliance in some patients. Indeed, patients often have resolution of clinical symptoms within 1 to 2 days and may neglect taking final doses. This may contribute to the development of drug resistance.

[007] 2-amino-l-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6- dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone (KAF156) is the first drug from a different and novel class of drugs called 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). In addition, 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. Also, 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).

[008] 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.

[009] 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 800mg (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. Five other patients vomited after receiving the single 800-mg dose, as compared with 1 patient with P. falciparum malaria in the multiple-dose cohort. Four patients who received the single 800-mg dose reported nausea, as compared with 1 patient with P. falciparum malaria in the multiple-dose cohort. Furthermore KAF156 was shown to be rapidly absorbed while having a longer half-life of about 50 hours. Antimalarial drugs that are eliminated rapidly (terminal elimination half-life inferior to 3 days) usually cannot cure falciparum malaria in a single dose. [0010] In view of the foregoing, there is a strong medical need for new therapies for malaria, which is a very common disease responsible of substantial morbidity and mortality. It is desirable to develop new treatment for that disease, including in areas where resistance to ACTs is emerging. Simplifying regimens by developing treatments that can be used in a once daily dose for less than 3 -day administration can improve treatment success and reduce probability of developing resistance via improved adherence and thus accelerate malaria eradication.

SUMMARY OF THE INVENTION

[0011] The invention addresses these needs by providing novel therapeutic regimen which employ novel new therapeutically effective amounts of an imidazolepiperazine, such as 2- amino-l-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,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 lumefantrine. Disclosed herein is 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 50mg to about lOOmg, to about 200mg to about 400mg for up to 2 days, e.g. 1 or 2 days. In particular is disclosed 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 with lumefantrine, daily at a dose of about 60mg to about 120mg to about 240 mg to about 480mg for up to 2 days, e.g. 1 or 2 days.

[0012] 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-l-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8- dimethyl-5,6-dihydroimidazo[l,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.

[0013] Disclosed herein are 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 2-amino-l-(2-(4- fhiorophenyl)-3-(4-fhiorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)- yl (ethanone (KAF156), or a pharmaceutically acceptable salt thereof, wherein the dose is of about 50mg to about lOOmg to about 200mg to about 400mg and is administered for up to 2 days, e.g. 1 or 2 days. For example are disclosed 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 50mg to about lOOmg to about 200mg to about 400mg and is administered for up to 2 days, e.g. 1 or 2 days.

[0014] 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.

[0015] In another aspect, the invention provides an imidazolepiperazine, e.g. 2-amino-l- (2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,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 50mg to about lOOmg to about 200mg to about 400mg, e.g. for up to 2 days, e.g. for 1 to 2 days. For example, there is provided 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 50mg to about lOOmg to about 200mg to about 400mg, e.g. for up to 5 days, e.g. for 1 to 2 days.

[0016] Disclosed herein are doses of KAF156 for use in preventing or treating malaria, to be administered daily (e.g. once daily), of about 50mg to about lOOmg to about 200mg to about 400mg of KAF156. [0017] Disclosed herein are pharmaceutical 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 50mg to about lOOmg to about 200mg to about 400mg, e.g. for up to 2 days, e.g. 1 or 2 days.

[0018] Disclosed herein are uses of 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 50mg to about lOOmg, to about 200mg to about 400mg e.g. for up to 2 days, e.g. 1 or 2 days.

[0019] The invention further provides therapeutic kits for preventing or treating malaria, comprising daily doses of KAF156 or a pharmaceutically acceptable salt thereof, wherein the dose of KAF156 or a pharmaceutically acceptable salt thereof is of about 50mg to about lOOmg to about 200mg to about 400mg.

[0020] In some of the above mentioned methods, therapeutic regimens, kits, uses, and pharmaceutical compositions, 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. [0021] Furthermore 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. In particular there is provided pharmaceutical combinations comprising about 50mg to lOOmg to 200mg to 400mg of KAF156 and about 60mg to 120mg to 240mg to 480 mg of lumefantrine. For example, there are provided pharmaceutical combinations comprising about 50mg to lOOmg to 200mg to 400mg of KAF156 and about 60 to 120mg to 240mg to 480mg of lumefantrine, wherein lumefantrin is in form of a solid dispersion formulation or microemulsion, e.g. a solid dispersion formulation.

[0022] In particular there are provided fixed combinations of KAF156 and lumefantrine, e.g. of KAF156 and solid dispersion formulation of lumefantrine. [0023] Various (enumerated) embodiments of the disclosure are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0024] Furthermore 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 2 days, and comprises about 50mg to about lOOmg to about 200mg to about 400mg of KAF156.

[0025] For example, there is provided 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 once and comprises about 50mg, or about lOOmg, or about 200mg, or about 400mg of KAF156.

[0026] For example, there is provided 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) for three days and comprises about 50mg, about lOOmg about 200mg, about 400mg of KAF156.

[0027] Furthermore 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 50mg about lOOmg about 200mg about 400mg of KAF156 and about 60mg about 120mg about 240mg about 480mg lumefantrine. Lumefantrine may be in form of a solid dispersion formulation.

[0028] In one embodiment, there is provided 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 50mg, or about lOOmg, or about 200mg, or about 400mg of KAF156 and about 60mg or about 120mg, or about 240mg, or about 480mg of lumefantrine. Lumefantrine may be in form of a solid dispersion formulation. [0029] In another embodiment, there is provided 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 50mg, or aboutlOOmg, or about 200mg, or about 400mg of KAF156 and about 60mg, or aboutl20mg, or about 240mg, or about 480mg of lumefantrine. Lumefantrine may be in form of a solid dispersion formulation.

[0030] In yet another embodiment, there is provided 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 50mg or about lOOmg, or about 200mg, or about 400mg of KAF156 and about 60mg, or about 120mg, or about 240mg, or about 480mg lumefantrine. Lumefantrine may be in form of a solid dispersion formulation.

DETAILED DESCRIPTION OF THE INVENTION

[0031] KAF156 (which is 2-amino-l-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8- dimethyl-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone), is an imidazolepiperazine of formula (i)

[0032] It is described in WO2011/006143 (example 412). [0033] Various aspects of the disclosure are described in further detail in the following subsections. All patents, published patent applications, publications, references and other material referred to herein are incorporated by reference herein in their entirety.

[0034] The term “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.

[0035] According to the invention, 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. Within the meaning of the present invention, 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.

[0036] As used herein 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.

[0037] The term “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.

[0038] The term “about” or “approximately” shall have the meaning of within 10%, more preferably within 5%, of a given value or range.

[0039] The term “pharmaceutically acceptable” means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).

[0040] 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.

[0041] Preferably KAF156 is administered once a day administration. Similarly lumefantrine is preferably administered once a day.

[0042] According to the invention, KAF156 (in form of a free base) is administered at a dose comprised between about 500mg and about 50mg. In specific embodiments, these doses are for daily administration, e.g. are daily doses. In other embodiments, these doses are for once daily administration.

[0043] In some embodiments, there are provided new therapeutic regimens of KAF156 for use in preventing or treating malaria, comprising administering (e.g. daily) a dose of KAF156 of up to about 400mg.

[0044] For example, the therapeutic regimens of KAF156 for use in preventing or treating malaria, comprise administering (e.g. daily) a dose of KAF156 of about 50mg or about lOOmg or about 200mg or about 400mg.

[0045] According to the invention, KAF156 or a pharmaceutically acceptable salt thereof, is administered daily during up to 2 days, e.g. for 1 or 2 days, e.g. for one day. In specific embodiments, there is provided a dose of KAF156 or a pharmaceutically acceptable salt thereof for unique administration, e.g. unique daily administration.

[0046] Provided herein are therapeutic 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.

[0047] Accordingly, disclosed herein are therapeutic 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 two days.

[0048] In other embodiments are provided 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 50mg to about lOOmg to about 200mg to about 400mg; 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.

[0049] In some embodiments 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 2 days, e.g. 1 to 2 doses, e.g. one dose. Such doses can be of about 50mg to about lOOmg to about 200mg to about 400mg, of KAF156 (as free base).

[0050] For example, there are provided therapeutic kits comprising one to five doses of KAF156, or a pharmaceutically acceptable salt thereof, for daily administration, wherein said doses are of about 50mg to about lOOmg, to about 200mg to about 400mg of KAF156 (as free base).

[0051] In some of the above mentioned methods, therapeutic regimens, kits, uses, and pharmaceutical compositions, the imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof is administered with another anti-malaria drug, e.g. lumefantrine.

[0052] According to the invention, 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.

[0053] Accordingly there are provided pharmaceutical combinations 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.

[0054] In some embodiments, there are provided pharmaceutical combinations comprising KAF156, and ii) another anti-malaria agent, for use in preventing or treating malaria, wherein KAF156 (as a free base) is to be administered daily at a dose of about 50mg to about lOOmg, to about 200mg, to about 400mg.

[0055] For example there are provided pharmaceutical combinations 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 50mg or about lOOmg or about 200mg or about 400mg. [0056] In some embodiments, 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.

[0057] In particular, the second anti-malaria agent is lumefantrine.

[0058] Lumefantrine may be in the form of as a solid dispersion formulation.

[0059] According to the invention, lumefantrine is to be administered daily at a dose of about 60 to 480mg, e.g. about 60mg to about 120mg, e.g. about 120mg to about 240mg, e.g. about 240mg to about 480mg. For example, lumefantrine is to be administered daily at a dose of about 60mg or about 120mg or about 240 mg or about 480mg.

[0060] According to the invention, imidazolepiperazine, e.g. KAF156 or a pharmaceutically acceptable salt thereof, e.g. KAF156, can be administered prior to, simultaneously with, or after the second anti-malaria agent, e.g. lumefantrine.

[0061] The terms “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. [0062] The term “pharmaceutical combination” as used herein 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. The term “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. The term “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. [0063] In general, the 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.

[0064] 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 can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, 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. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The 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. 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. For example, 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.

[0065] According to the invention, lumefantrine can be prepared as a solid dispersion. The term 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.

[0066] Said 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. 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); poloxamer 407, PEG800, solutol, gelucire, Polyvinylpyrollidone (PVP) (e.g. PVP K30) or basic butylated methacrylate copolymer (e.g. Eudragit EPO).

Preferably, 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.

[0067] The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. Herein is described the preparation of solid dispersions using hydrophilic carriers, such as e.g. polyvinylpyrrolidone (Povidone, PVP), polyethylene glycols (PEG 6000), Surfactants like Tween-80, Poloxamer, and Sodium Lauryl Sulphate (SLS).

[0068] According to the invention, lumefantrine can be prepared as a microemulsion, e.g. as described in Patel (DARU J. Pharm. Sci, 21 (27), 2013).

[0069] According to the invention, lumefantrine can be in amorphous state.

[0070] According to the invention, there are provided pharmaceutical combination comprising about 50mg or lOOmg of KAF156 (as free base), and about 60mg to 240mg of lumefantine (as free base), e.g. about 120mg lumefantrine (as free base), for daily administration. [0071] According to the invention, the pharmaceutical combinations comprising KAF156 and lumefantine (e.g. as described hereinabove) are fixed dose combinations. In such a fixed dose combination, lumefantrine can be formulated as a solid dispersion formulation.

[0072] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to the persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

EXAMPLES

Example 1 : lumefantrine solid dispersion capsule composition

Ingredient mg/unit % w/w

Lumefantrine drug substance 75.000 18.75

Polyvinylpyrollidone K30 120.000 26.25

Eudragit EPO 105.000 26.25

Croscarmellose sodium 64.000 16.00

Microcrystalline cellulose 30.000 7.50

Poloxamer l88 15.000 3.75

Colloidal Silicon dioxide 4.000 1.00

Magnesium stearate 2.000 0.50

Total capsule fill 400.000 100.00

Example 2: lumefantrine solid dispersion (SD) capsule composition

The compositions of Examples 1 and 2 have shown significantly higher dissolution at pH 1 and pH2 in presence and in absence of a surfactant.

Example 3 : lumefantrine microemulsion composition

As can be seen in the table below, the presence of butylated hydroxytoluene as a stabilizer at a level of 0.5% has resulted in significant improvement in the stability of the microemulsions which is evident by the decreased levels of Lumefantrine step-4 impurity. Stability data at 4 week time point for microemulsion

Example 3 : open-label, randomized, in adolescents and children with confirmed and uncomplicated P. falciparum malaria.

This study will explore, in part, the effect of food on lumefantrine and KAF156 PK in a Run-in Cohort of male and female patients 12 to < 18 years old with malaria caused by P. falciparum, before younger patients are assessed. Then, efficacy, safety and tolerability of the combination of KAF156 and LUM-SDF will be evaluated in younger male and female patients with and without food, first in Cohort 1 of patients 2 to < 12 years old and then in Cohort 2 of patients 6 months to < 2 years old. Randomization is stratified by country for the first 24 patients in the Run-in cohort, by body weight for the first 24 patients in Cohort 1 (aged 6 to < 12 years) and by age group (6 to < 12 years and 2 to < 6 years) and country in the remaining patients in Cohort 1, and by country in Cohort 2 to achieve the equal treatment allocation within weight band/age group/country.

[0073] At screening, eligible patients will be randomized into one of the three cohorts and two arms, to be administered KAF156 and LUM-SDF (Solid Dispersion Formulation) dose combinations:

[0074] Arm 1: KAF156 provided as 50 mg or 100 mg tablets based on body weight, and LUM-SDF provided as 60 mg, 120 mg or 240 mg or 480 mg powder in sachet, QD (once daily) for 2 days in fasted condition [0075] Arm 2: KAF156 provided as 50 mg or 100 mg tablets based on body weight, and LUM-SDF provided as 60 mg, 120 mg or 240 mg or 480 mg powder in sachet, QD (once daily) for 2 days fed condition

[0076] Primary outcome will be measured through as a percentage of Participants with Polymerase Chain Reaction (PCR)-corrected and uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 (Cohorts 1 and 2). A patient is considered as PCR- corrected ACPR at Day 29 if the patient does not meet any of the criteria of Early Treatment Failure (ETF) (up to Day 4), Late Clinical Failure (LCF) (Day 5 to Day 29) or Late Parasitological Failure (LPF) (Day 8 to Day 29), and is absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days (Day 8 or later) is due to reinfection based on PCR genotyping. A presence of parasitaemia after 7 days of treatment initiation is considered as a reinfection only if the parasitaemia is clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later match with the parasite strain at baseline based on PCR genotyping. Treatment failures after 7 days due to reinfection based on PCR genotyping are not considered as failure for PCR-corrected analyses but will be considered as failure for PCR uncorrected analyses

Inclusion criteria

[0077] Patients eligible for inclusion in this study must fulfill all of the following criteria:

1. In Run-in Cohort: Male and female patients 12 to < 18 years of age, with a body weight > 35.0 kg

In Cohort 1 : Male and female patients 2 to < 12 years of age, with a body weight > 10.0 kg

In Cohort 2: Male and female patients 6 months to < 2 years of age, with a body weight > 5.0 kg

2. Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films

3. P. falciparum parasitemia of > 1,000 and < 150,000 parasites/pL at the time of pre-screening

4. Axillary temperature > 37.5 °C or oral/tympanic/rectal temperature > 38.0 °C; or history of fever during the previous 24 hours (at least documented verbally) 5. Written informed consent has been obtained from parent / legal guardian before any assessment is performed. If the parent/legal guardian is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines

6. The patient and his/her parent/legal guardian is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.

Exclusion criteria

[0078] Patients fulfilling any of the following criteria are not eligible for inclusion in this study.

[0079] Medical history and clinical status:

1. Mixed Plasmodium infections as per light microscopy results

2. Signs and symptoms of severe malaria according to WHO 2015

3. Significant, non-plasmodial co-infections including tuberculosis

4. Patients with concurrent febrile illnesses (e.g., typhoid fever, known or suspected COVID19)

5. Known relevant 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

6. Major congenital defects

7. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency

8. Immunosuppressive therapy (steroids, immune modulators or immune suppressors) within 3 months prior to recruitment. (For corticosteroids, this will mean prednisone, or equivalent, > 0.5 mg/kg/day. Inhaled and topical steroids are allowed)

9. Repeated 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 in the 24 hours prior to inclusion in the study) 10. Active duodenal ulcer, ulcerative colitis, Crohn’s disease, chronic (i.e., > 2 weeks) use of non-steroidal anti-inflammatory drugs (NSAIDs)

11. Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia

12. Anemia (hemoglobin level <7 g/dL)

13. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., HIV patients on ART therapy or TB patients on treatment), or which may jeopardize the patient in case of participation in the study. The investigator should make this determination in consideration of the patient’s medical history and/or clinical or laboratory evidence of any of the following:

• AST/ALT > 3 x the upper limit of normal range (ULN), regardless of the level of total bilirubin

• AST/ALT > 1.5 and < 2 x ULN and total bilirubin is > ULN

• Total bilirubin > 2 x ULN regardless of the level of AST/ALT

14. Resting QT interval corrected by Fridericia’s formula (QTcF) > 450 ms at screening

15. Creatinine > 2 x ULN in the absence of dehydration. In case of dehydration, creatinine should be < 2 x ULN after oral/par enteral rehydration

16. Any severe disease condition which might prohibit participation in this study

17. Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment

18. Known active or uncontrolled thyroid disease

19. Inability to swallow oral medication (in tablet and/or liquid form)

20. Patients with prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five (5) plasma half-lives (or within 4 weeks of screening if half-life is unknown)

21. Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer

22. Patients taking medications prohibited by the protocol

23. Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance within 3 months of dosing 24. History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease

25. Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study

26. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes

Claims

1. 2-amino-l -(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6- dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone, or a pharmaceutically acceptable salt thereof, administered daily at a dose of up to about 400 mg.

2. The compound according to claim 1 , wherein the compound is administered daily at a dose of about 50 to about 200 mg.

3. The compound according to claim 1 or 2, administered in combination with a synergistically effective amount of lumefantrine, or a pharmaceutically acceptable salt thereof.

4. The combination according to claim 3, wherein the combination is administered separately or sequentially.

5. The compound according to claims 1 to 3 or the combination of claim 4, administered orally.

6. The combination according to claims 3 to 5 wherein the lumefantrine and 2-amino-l-(2- (4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,2- a]pyrazin-7(8H)-yl)ethanone, or a pharmaceutically acceptable salt thereof are administered in a weight ratio of 1.2 : 1.

7. The combination according to claim 6, wherein the lumefantrine is administered up to three times a day for a total daily dose of up to about 480 mg.

8. The combination according to claim 6, wherein the lumefantrine is administered up to 3 times a day for a total daily dose of about 60 mg to about 240 mg.

9. The compound according to claims 1 to 3 or the combination of claims 4 to 8, wherein the compound is administered daily for up to 2 days.

10. The compound according to claims 1 to 3 or the combination of claims 4 to 8, wherein the compound is administered in a dose of about 50mg to about 200mg.

11. The combination according to claim 4 to 8, wherein compound, or a pharmaceutically acceptable salt thereof is administered in a dose of about 60mg to about 240mg.

12. The combination according to claim 11, wherein the lumefantrine, or a pharmaceutically acceptable salt thereof is in a microemulsion, microemulsion preconcentrate or solid dispersion.

22 The combination according to claim 12 wherein the lumefantrine is in a solid dispersion formulation comprising a hydrophilic matrix phase, a surfactant, and optionally a stabilizer. The combination according to claim 13, wherein the stabilizer is butylated hydroxytoluene. 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 up to about 400 mg of 2-amino-l-(2-(4-fluorophenyl)-3-(4- fhiorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone, or a pharmaceutically acceptable salt thereof, in combination with up to about 480 mg lumefantrine, or a pharmaceutically acceptable salt thereof, delivered daily, during 1 to 2 days. The method according to claim 15, wherein said 2-amino-l-(2-(4-fluorophenyl)-3-(4- fhiorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone is administered at a dose of about 50mg. The method according to claim 16, wherein said lumefantrine is administered daily at a dose of about 60mg to about 480mg. The method according to claim 17, wherein the lumefantrine is administered daily at a dose of about 60mg to 240 mg. A kit comprising lumefantrine and 2-amino-l-(2-(4-fluorophenyl)-3-(4- fhiorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone, or a pharmaceutically acceptable salt thereof in separate unit dosage forms, wherein said unit dosage forms are suitable for administering lumefantrine and 2-amino-l-(2-(4- fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[l,2-a]pyrazin- 7(8H)-yl)ethanone, or a pharmaceutically acceptable salt thereof in synergistically effective amounts. A method of using lumefantrine in the manufacture of a pharmaceutical kit of claim 19. A method of using 2-amino-l-(2-(4-fhiorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl- 5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)ethanone, or a pharmaceutically acceptable salt thereof in the manufacture of a kit of claim 19.