WO2020225283A1

WO2020225283A1 - Nk1 inhibitors for the treatment of malaria

Info

Publication number: WO2020225283A1
Application number: PCT/EP2020/062521
Authority: WO
Inventors: Manuel Vicente SALINAS-MARTIN
Original assignee: Plus Vitech, S.L.
Priority date: 2019-05-08
Filing date: 2020-05-06
Publication date: 2020-11-12
Also published as: ZA202109826B

Abstract

The present invention relates to the treatment of malaria using a NK₁ inhibitor.

Description

NK1 INHIBITORS FOR THE TREATMENT OF MALARIA

FIELD OF THE INVENTION

The present invention relates to the treatment of malaria using a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof.

BACKGROUND TO THE INVENTION

Malaria is a mosquito-bome infectious diseases that affects human and animals. It is caused by single-celled microorganisms of the Plasmodium group. There are many species of Plasmodium, but the five species that regularly infect humans are P. vivax, P. falciparum, P. malariae, P. ovale, and P. knowlesi. P. falciparum is by far the most lethal in humans, and results in hundreds of thousands of deaths per year.

Malaria is treated with antimalarial medications. The most effective treatment for P. falciparum infection is the use of artemisinins in combination with other antimalarials (known as artemisinin-combination therapy, or ACT). Additional antimalarials used in ACT include amodiaquine, lumefantrine, mefloquine and sulfadoxine/pyrimethamine.

ACT is about 90% effective when treating uncomplicated malaria. However, ACT is significantly less effective in severe/complicated malaria, where mortality rates are high (10% to 50%).

Despite the availability of the above therapies, drug resistance represents a growing problem. Resistance is common against all classes of antimalarial drugs apart from artemisinins. Artemisinins are expensive, which limits their use in the developing world, and in addition resistance to artemisinins has now been detected. For these reasons, there remains an urgent need to develop more effective, well-tolerated and affordable treatments for malaria.

Aprepitant and its prodrug fosaprepitant are neurokinin 1 (NKi) inhibitors that have been approved for treating nausea and vomiting, for example acute or delayed

chemotherapy-induced nausea and vomiting, or post-operative nausea and vomiting.

Aprepitant has also been investigated for use in treating a variety of other diseases, including depression and cancer. However, the inventors are not aware of any reported uses of aprepitant, or other NKi inhibitors, in treating infectious disease such as malaria. SUMMARY OF THE INVENTION

It has now surprisingly been found that NKi inhibitors, such as aprepitant, are effective antimalarial drugs. In particular, as described in the examples below, a patient with chemotherapy-refractory cancer was given aprepitant as an off-label compassionate treatment of the cancer. The patient also presented with immunosuppression.

Shortly after treatment commenced, the patient was identified as also suffering from malaria. Standard antimalarial drugs triggered an adverse reaction in the patient, and had to be discontinued immediately. However, treatment of the patient’s cancer with aprepitant was continued and, surprisingly, also resulted in an effective and non-toxic treatment of the patient’s malaria.

Further in vivo an in vitro testing described in the examples below confirm that NKi inhibitors are effective against Plasmodium, and thus can act as effective antimalarial drugs.

Accordingly, the present invention provides a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or pharmaceutically acceptable salt thereof, for use in treating malaria in patient in need thereof.

The present invention further provides:

a method of treating malaria in a patient in need thereof, which method comprises administering to said patient a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or pharmaceutically acceptable salt thereof; and

use of a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of malaria in patient in need thereof.

DETAILED DESCRIPTION

The present invention is concerned with the treatment of malaria using a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or pharmaceutically acceptable salt thereof.

NKi inhibitors

NKi inhibitors are a well-known class of drug, and any suitable NKi inhibitor can be used in the present invention.

Typically, the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant, lanepitant, LY-686017, L-733,060, L- 732,138, L -703,606, WIN 62,577, CP-122721, TAK-637, R673, CP-100263, WIN 51708, CP-96345, L-760 735, CP-122721, L-758 298, L-741 671, L-742 694, CP-99994 or T- 2328, or a pharmaceutically acceptable salt of any thereof.

Preferably, the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt of any thereof.

More preferably, the NKi inhibitor is aprepitant, fosaprepitant or maropitant, or a pharmaceutically acceptable salt of any thereof.

Most preferably, the NKi inhibitor aprepitant or its prodrug fosaprepitant, or pharmaceutically acceptable salts of either thereof.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.

Aprepitant has the following structure:

Aprepitant is not typically formulated in the form of a pharmaceutically acceptable salt. Thus, preferably the NKi inhibitor used in the present invention is aprepitant.

Fosaprepitant is prodrug of aprepitant and has the following structure:

Fosaprepitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the dimeglumine salt:

Thus, in a further preferred aspect of the invention, the NKi inhibitor used in the present invention is fosaprepitant dimeglumine.

Pharmaceutically acceptable salts of fosaprepitant, such as fosaprepitant dimeglumine, are typically reconstituted in an aqueous solvent, such as saline, prior to administration, thereby providing an aqueous solution comprising fosaprepitant.

Fosaprepitant is converted in vivo to aprepitant. Thus, when administered to a patient, typically intravenously, fosaprepitant is converted to aprepitant. Treatment of malaria

The patient to be treated in the present invention is suffering from malaria. Malaria can easily be diagnosed using routine diagnostic techniques known to those of skill in the art. Similarly, a successful treatment can identified by the absence of symptoms of malaria and/or using routine diagnostic techniques.

Typically the patient to be treated is a mammal. Preferably the patient is a human. Typically, the malaria to be treated is caused by P. berghei, P. vivax, P. falciparum, P. malariae, P. ovale, or P. knowlesi , preferably by P. vivax, P. falciparum, P. malariae,

P. ovale, or P. knowlesi. Most commonly, the malaria to be treated is caused by P.

falciparum, for example P. falciparum Welch. Alternatively, the malaria to be treated is caused by P. berghei, for example P. berghei Vincke and Lipps.

The malaria may be caused by a Plasmodium with or without mutations. For example, the Plasmodium strains above may be unmutated. Alternatively, the Plasmodium strains above may be mutated. For example, P. falciparum may carry the Knobless mutation. As described further below, the present inventors have shown that NKi inhibitors can be used to treat malaria caused by Plasmodium with or without mutations.

The malaria may be caused by a Plasmodium from any geographical origin. It is well known that differences exist between Plasmodium strains with different geographical origins. However, as described further below, the present inventors have shown that NKi inhibitors can be used to treat malaria caused by Plasmodium strains with different geographical origins. For example, activity has been shown against Plasmodium from

Gambia, Honduras, Hainan Island (China) and Kisanga, Katanga (Democratic Republic of the Congo).

Typically, the malaria to be treated in the present invention is severe malaria.

However, mild and moderate malaria can also be treated using the present invention.

Typically, the patient has previously been treated unsuccessfully with an another antimalarial therapy, such as artemisinin-combination therapy (ACT). This may be because the patient’s malaria is treatment-resistant, for example resistant to one or more of artemisins, amodiaquine, lumefantrine, mefloquine, sulfadoxine and pyrimethamine.

Alternatively, the malaria can be resistant to treatment with chloroquine. In some cases, the malaria may even be ACT-resistant. NKi inhibitors, such as aprepitant or

fosaprepitant, or a pharmaceutically acceptable salt thereof, provides a useful strategy for treating such treatment-resistant malaria.

Typically, the patient has suffered an adverse event, or is susceptible to suffering an adverse event, when treated with a conventional antimalarial therapy (such as ACT). For example, the patient may have suffered an adverse event, or be susceptible to suffering an adverse event, when treated with one or more of artemisins, amodiaquine, chloroquine, lumefantrine, mefloquine, sulfadoxine and pyrimethamine. For such patients, treatment with NKi inhibitors, such as aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, provides an alternative approach to treating the malarial infection. An example of such as patient is an immunosuppressed cancer patient.

Treatment may be curative or palliative in nature, i.e. it may aim at curing the patient, achieving complete or partial remission, alleviating or managing symptoms and/or side effects of the disease (without curing the patient). Preferably, however, the treatment is curative.

Pharmaceutical compositions

The present invention provides a pharmaceutical composition that comprises a NK1 inhibitor (the“active ingredient”), which is preferably aprepitant or fosaprepitant or a pharmaceutically acceptable salt thereof, for use in treating malaria. Pharmaceutical compositions according to the invention will typically further comprise one or more pharmaceutically acceptable excipients or carriers.

In general, administration of the pharmaceutical compositions may be oral (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc), by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.), or by inhalation (as a dry powder, a solution, a dispersion, etc.).

The preferred route of administration will depend upon the specific active ingredient to be delivered, and a skilled person can easily choose an appropriate route. For example, aprepitant is preferably delivered orally, whereas fosaprepitant is preferably administered intravenously.

For oral administration, the pharmaceutical compositions of the present invention may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g.

pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.

For administration by injection, the pharmaceutical compositions typically take the form of an aqueous injectable solution. Examples of suitable aqueous carriers that may be employed in the injectable pharmaceutical compositions of the invention include water, buffered water and saline. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.

For administration by inhalation, the pharmaceutical composition may take the form of a dry powder, which will typically comprise the active ingredient and a carrier such as lactose, and be delivered via an inhaler. Alternatively, the pharmaceutical composition may for example be formulated as aqueous solutions or suspensions and be delivered as an aerosol from a pressurised metered dose inhaler, with the use of a suitable liquefied propellant. Suitable propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydro fluoroalkanes.

Pharmaceutical compositions comprising of the invention may be prepared by any suitable method known to those of skill in the art.

Pharmaceutical compositions of the invention may comprise additional active ingredients, such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects. However, it is generally preferred that the compositions of the invention do not contain any further active ingredients (i.e. the pharmaceutical

compositions contain only a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof.

Dosages and dosage regimes

Suitable dosages of the active ingredients used in the present invention may easily be determined by a skilled medical practitioner.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

Administration may be in single or multiple doses. Multiple doses may be administered via the same or different routes and to the same or different locations.

Dosage and frequency may vary depending on the half-life of the drugs in the patient and the duration of treatment desired.

Typically, the NKi inhibitor, such as aprepitant or fosaprepitant, or a

pharmaceutically acceptable salt thereof, is administered 1 to 5 time per day, for example 3 times per day.

Typically, the total amount of the NKi inhibitor, such as aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, administered per day is 500 mg to 4000 mg per day, preferably 500 to 3000 mg per day.

Typically, the total amount of the NKi inhibitor administered per day is 1 to 50 mg/kg body weight, for example 2 to 40 mg/kg body weight or 10 to 40 mg/kg body weight, such as 2.5, 10, 30 or 40 mg/kg body weight. A preferred range is 10 to 30 mg/kg body weight per day. These ranges are particularly preferred for fosaprepitant when administered intravenuously.

Exemplary doses of aprepitant that may be useful in the invention include about 570 mg, about 1425 mg or about 2850 mg per day. These later doses may conveniently be administered by way of three separate doses (e.g. 250, 160 and 160 mg = 570mg; 445, 445, and 535 mg = 1425 mg; 935, 935 and 980 mg = 2850 mg).

Determination of the proper dosage for particular situations is within the skill of the person skilled in the art. The present invention is explained in more detail in the following by referring to the Examples, which are not to be construed as limiting.

EXAMPLES

Example 1 - off-label treatment of a patient with malaria

A patient was a 60 year old male with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL). The patient presented with immunosuppression, and had low leukocyte counts, platelet counts and red blood cell (RBC) counts low. For this reason, we had to be wary of anaemia and internal bleeding/bruises, and give supplements and coagulants as and when necessary.

Given that the patient had lymphoma which is refractory to conventional treatments, off-label treatment with aprepitant was started as a compassionate use. The details of that treatment and the patient’s progress are set out below.

Day 1: 250mg, 160 mg, 160 mg three time per day (tds) aprepitant were given to the patient. No dose limiting toxicity was observed. Fever in the evening with chills upwards of 100 degree Fahrenheit was observed. An antipyretic and water dressing of head was prescribed. Diagnostic tests for malaria were also ordered, with positive result for malaria.

Day 2: 250mg, 160 mg, 160 mg tds aprepitant were given to the patient. No dose limiting toxicity was observed.

Day 3: 250mg, 160 mg, 160 mg tds aprepitant were given to the patient. No dose limiting toxicity was observed. No fever.

Day 4: 250mg, 160 mg, 160 mg tds aprepitant were given to the patient. No dose limiting toxicity was observed. No fever.

Day 5: 250mg, 160 mg, 160 mg tds aprepitant were given to the patient. No dose limiting toxicity was observed. Patient complained of fatigue and stomach pain managed by rest and warm bottle respectively. Antimalarial IV was given. Day 6: 250mg, 160 mg, 160 mg tds aprepitant were given to the patient. Patient was taken to emergency ward, due to suspected internal bleeding during evening. Tranexamic acid IV was prescribed every 8 hours. Antimalarial IV discontinued.

Day 7: 250mg, 160 mg, 160 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Patient stable,

Day 8: 445, 445 and 535 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Patient stable. Patient complain of heartburn. Ranitidine prescribed symptomatically.

Day 9: 445, 445 and 535 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Heartburn that goes away with Ranitidine reported. Patient stable.

Day 10: 445, 445 and 535 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Patient stable. Heartburn that goes away with Ranitidine reported.

Day 11: 445, 445 and 535 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Heartburn that goes away with Ranitidine reported. Patient stable.

Day 12: 445, 445 and 535 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Patient stable. Heartburn that goes away with Ranitidine reported.

Day 13: 445, 445 and 535 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Patient stable. Heartburn that goes away with Ranitidine reported.

Day 14: 445, 445 and 535 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Heartburn that goes away with Ranitidine reported. Patient stable.

Day 15: 935, 935 and 980 mg tds aprepitant was given to the patient. No dose limiting toxicity observed. Heartburn that goes away with Ranitidine and stomach ache that was managed by warm bottle reported. Patient stable Day 16: 935, 935 and 980 mg tds aprepitant was given to the patient. A range of symptoms similar to a mild form of tumour lysis syndrome were observed - diarrhoea, lack of appetite, lethargy, blood in the urine, muscle cramps etc. IV fluids and medications to prevent serious manifestations were prescribed. Blood tests during the treatment to manage this prophylactic ally were necessary.

Day 17: 935, 935 and 980 mg tds aprepitant was given to the patient. Patient stable, only minor pain, heart burn and cramps reported. Patient stable but IV fluids continued. Day 18: 935, 935 and 980 mg tds aprepitant was given to the patient. Patient stable and smile for the first time since treatment. No untoward symptom except heart burn managed by Ranitidine. IV fluids continued.

Day 19: 935, 935 and 980 mg tds aprepitant was given to the patient. Patient stable, IV fluids continued. Heart burn and fatigue reported, and managed by ranatidine and supplements.

Day 20: 935, 935 and 980 mg tds aprepitant was given to the patient. IV fluids continued. Patient was stable and show signs of improved well-being.

Day 21: 935,935 and 980 mg tds aprepitant was given to the patient. IV fluids continued. No dose limiting toxicity observed. Patient stable.

Based on the above report, the prevent inventors believe that the patient’s malaria was effectively treated by the aprepitant. In particular, the patient’s malaria was treated despite the antimalarial medications being discontinued at Day 6, following an adverse event following their administration at Day 5. Aprepitant was shown to be non-toxic at the doses administered.

Further, without wishing to be bound by theory, the present inventors believe that aprepitant is able to treat malaria either by directly causing lysis of plasmodium parasite cells in large numbers and/or by activating immune system.

Specifically, the symptoms at day 16 (which are similar to those observed with tumour lysis syndrome) suggest that aprepitant may be causing lysis of plasmodium parasite cells in large numbers, and thereby treating the malaria infection in the patient. Similarly, the patient’s overall progression suggests that the initial immunosuppression is overcome, and that the patient’s immune system is reactivated.

Example 2 - NKi inhibitors are effective in the treatment of malaria in vitro

Briefly, parasites in blood stage of Plasmodium were cultured in human erythrocytes with a concentration corresponding to a haematocrit of 10% and in RPMI- 1640 medium supplemented with 2mM L-glutamine, 50mg / L hypoxanthine, 25m M NaHCCb at 0.225%, gentamicin 10 mg / L or ATCC® Medium 2196 -Malaria medium, complete-, according to the provider's instructions. The parasites in culture were kept at 37° C under ambient conditions of 5% O2, 5% CO2 and 90% N2, adapted from what has been previously published (Trager 1976, Science 193 (4254), 673-675; Trager 1981, Proc. Natl. Acad. Sci. USA, Vol. 78, No. 10, 6527-6530, Microbiology; Rocha 2013, Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 108(4): 501-507).

Cultures were monitored by methanol fixed and deposited on slides as cytological extensions. After Giemsa staining, they were observed with light microscopy. Briefly, a standard thin culture smear was fixed with methanol (100%) for 10 min and stained with Giemsa working solution (Merck KGaA, Darmstadt, Germany), for 10 min. Slides were observed using a model CX30 light microscope (Olympus, Tokyo, Japan).

The characteristics of the lines used were those reflected in Table 1.

15 laboratory culture plates were seeded with the same concentration of every parasite type. That was verified by cytological study. Cytological slides were observed using a model CX30 light microscope (Olympus, Tokyo, Japan).

A group of 3 plates (Group 1) was treated with a dose of aprepitant at concentration of 5 micromolar, another group of 3 plates (Group 2) was treated with a dose of aprepitant at concentration of 10 micromolar, a third group (Group 3) was treated with a dose of aprepitant at concentration of 20 micromolar and a fourth group (Group 4) was treated with a dose of aprepitant at concentration of 40 micromolar. In all cases, Aprepitant was dissolved in DMSO and in parallel, 3 culture plates (Control Group) was treated under identical conditions with only DMSO, but without Aprepitant.

Percentage of parasitemia (% parasitemia) of experimental cultures was determined at three days in the Giemsa stained blood smears that were examined under light microscope Percentage parasitemia was estimated using the formula: Number of infected Red Blood Cells x 100 / Total number of Red Blood Cells.

Percentage (% suppression) of suppression of the parasitemia was calculated using the formula: (Average % parasitemia of infected untreated cultures - Average %

parasitemia of infected treated cultures) / Average % parasitemia of infected untreated cultures x 100.

The suppression percentages of each group with respect to the control group are shown in Table 2.

Table 2

Example 3 - Fosaprepitant is effective in the treatment of malaria in vivo

15 laboratory mice with 6-8 weeks old were used in this example. All subjects were administered a millilitre of intraperitoneal solution with the same concentration of parasites. The parasite was Plasmodium berghei Vincke and Lips (ATCC 30090) - Geographical origin: Kisanga, Katanga. That was verified by cytological study. Cytological slides were observed using a model CX30 light microscope (Olympus, Tokyo, Japan).

Subsequently, from days 3 to 7, a group of 3 mice (Group 1) was administered an oral dose of fosaprepitant intraperitoneal at 2.5 mg/kg body weight per day, another group of 3 mice (Group 2) was administered an intraperitoneal dose of 10 mg/kg body weight per day, a third group (Group 3) was administered an intraperitoneal dose of 30 mg/kg body weight per day and a fourth group (Group 4) was administered an intraperitoneal dose of 40mg/kg body weight per day. In parallel, 3 mice were kept under identical conditions but were not administered any treatment (Control Group).

On day 7 of the experiment ah animals were euthanized and necropsied. A blood sample was obtained from the heart. A blood sample was obtained from the heart. In this blood sample, the percentage of parasitemia (% parasitemia) was measured in ah mice in ah groups in the experiment.

Table 3

Example 4 - Maropitant is effective in the treatment of malaria in vivo

15 laboratory mice with 6-8 weeks old were used in this example. Ah subjects were administered a mililitre of intraperitoneal solution with the same concentration of parasites. The parasite was Plasmodium berghei Vincke and Lips (ATCC 30090) - Geographical origin: Kisanga, Katanga-. That was verified by cytological study.

Citologycal slides were observed using a model CX30 light microscope (Olympus, Tokyo, Japan).

Subsequently, from days 3 to 7, a group of 3 mice (Group 1) was administered an oral dose of Maropitant intraperitoneal at 1 mg/kg body weight per day, another group of 3 mice (Group 2) was administered an intraperitoneal dose of 5 mg/kg body weight per day, a third group (Group 3) was administered an intraperitoneal dose of 10 mg/kg body weight per day and a fourth group (Group 4) was administered an intraperitoneal dose of 20mg/kg body weight per day. In parallel, 3 mice were kept under identical conditions but were not administered any treatment (Control Group).

On day 7 of the experiment ah animals were euthanized and necropsied. A blood sample was obtained from the heart. A blood sample was obtained from the heart. In this blood sample, the percentage of parasitemia (% parasitemia) was measured in all mice in all groups in the experiment.

Table 3

Claims

1. A NKi inhibitor for use in treating malaria.

2. The NKi inhibitor for use according to claim 1, wherein the NKi inhibitor is

aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt thereof.

3. The NKi inhibitor for use according to claim 2, wherein the NKi inhibitor is

aprepitant, fosaprepitant or maropitant, or a pharmaceutically acceptable salt thereof.

4. The NKi inhibitor for use according to claim 3, wherein the NKi inhibitor is

aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof.

5. The NKi inhibitor for use according to claim 4, wherein the NKi inhibitor is

aprepitant.

6. The NKi inhibitor for use according to claim 4, wherein the NKi inhibitor is

fosaprepitant dimeglumine.

7. The NKi inhibitor for use according to any one of the preceding claims, wherein the malaria is caused by P. berghei, P. vivax, P. falciparum, P. malariae, P. ovale or P. knowlesi, preferably by P. vivax, P. falciparum, P. malariae, P. ovale or P. knowlesi

8. The NKi inhibitor for use according to claim 7, wherein the malaria is caused by P. falciparum.

9. The NKi inhibitor for use according to any one of the preceding claims, wherein the malaria is resistant to one or more of artemisins, amodiaquine, chloroquine, lumefantrine, mefloquine, sulfadoxine and pyrimethamine.

10. A method of treating malaria as defined in any one of claims 1 and 7 to 9 in a

patient in need thereof, which method comprises administering to said patient a NKi inhibitor as defined in any one of claims 1 to 6.

1. Use of a NKi inhibitor as defined in any one of claims 1 to 6, in the manufacture of a medicament for the treatment of malaria as defined in any one of claims 1 and 7 to 9 .