Phase 1b MMV367 PK/PD and Safety in Healthy Adult Volunteers Experimentally Infected With Blood Stage P. Falciparum

Inclusion Criteria:

1 Healthy adults aged 18 to 55 years inclusive who will be contactable and available forthe duration of the trial and up to two weeks following the EOS visit. 2. Total body weight greater than or equal to 50 kg, and a body mass index (BMI) within therange of 18 to 32 kg/m2 (inclusive). BMI is an estimate of body weight adjusted for height.It is calculated by dividing the weight in kilograms by the square of the height in metres. 3. Completion of the written informed consent process prior to undertaking anytrial-related procedure. 4. Must be willing and able to communicate and participate in thewhole trial. 5. Agreement to adhere to Lifestyle Considerations (Section 5.3) throughoutthe trial duration. 6. Must be able to provide contact details of a support person (responsible adult) who isaware of the participant's participation in the study and is available to provideassistance if required (for example with contacting the participant in the event that studystaff are unable to, or with transporting the participant to and from the study site ifrequired). Vital signs and ECG parameters 7. Vital signs at screening (measured after 5 min in thesupine position):

• Systolic blood pressure (SBP): 90-140 mmHg,
• Diastolic blood pressure (DBP): 40-90 mmHg,
• Heart rate (HR): 40-100 bpm. Note: Symptomatic postural hypotension will be assessedby measuring SBP and DPB in the standing position (see exclusion criterion 10).

8. At Screening and pre-inoculation with the malaria challenge agent (Day 0), normalstandard mean of triplicate 12-lead electrocardiogram (ECG) parameters after 5 minutesresting in supine position:

• QTcF: ≤450 msec (males) or ≤470 msec (females),
• QRS: 50-120 msec,
• PR interval: ≤ 210 msec,
• Normal ECG tracing unless the Principal Investigator or delegate considers an ECGtracing abnormality to be not clinically relevant. Contraception 9. Women of childbearing potential (WOCBP) who anticipate being sexuallyactive with a male during the trial must agree to use a highly effective method of birthcontrol (see below) combined with a barrier contraceptive from the screening visit until 34days after the last dose of MMV367 (covering a full menstrual cycle of 30 days startingafter 5 half-lives of last dose of MMV367) and have a negative urine pregnancy test resultprior to inoculation with the malaria challenge agent on Day 0.
• Highly effective birth control methods include: combined (oestrogen and progestogencontaining) oral/intravaginal/transdermal/implantable hormonal contraceptionassociated with inhibition of ovulation, progestogen-only oral/injectable/implantablehormonal contraception associated with inhibition of ovulation, intrauterine device,intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomisedpartner, or sexual abstinence or same sex relationship.
• Female participants who are abstinent (from penile-vaginal intercourse) must agree tostart a double method if they start a sexual relationship with a male during thestudy. Female participants must not be planning in vitro fertilisation within therequired contraception period. Women of non-childbearing potential (WONCBP) are defined as:
• Natural (spontaneous) post-menopausal defined as being amenorrhoeic for at least 12months without an alternative medical cause with a screening follicle stimulatinghormone level (FSH) >25 IU/L (or at the local laboratory levels for post-menopause).
• Premenopausal with irreversible surgical sterilization by hysterectomy and/orbilateral oophorectomy or salpingectomy at least 6 months before screening (asdetermined by participant medical history).

10. Males who have, or may have, female sexual partners of childbearing potentialduring the course of the study must agree to use a double method of contraceptionincluding condom plus diaphragm, or intrauterine device, or stableoral/transdermal/injectable/implantable hormonal contraceptive by the female partner,from the time of informed consent through to 94 days after MMV367 administration. Thishas been calculated based on 90 days (one cycle of spermatogenesis) plus 5 half-livesof the IMP (4 days). Abstinent males must agree to start a double method if they begina sexual relationship with a female during the study and up to 94 days after the lastdose of MMV367. Males that are surgically sterile, or who have undergone sterilisationand have had testing to confirm the success of the sterilisation, may also be includedand will not be required to use above described methods of contraception.

Exclusion Criteria: Medical history

1. Known hypersensitivity to artesunate or other artemisinin derivatives, lumefantrine,proguanil/atovaquone, primaquine, or 4-aminoquinolines.
2. Any history of anaphylaxis or other severe allergic reactions, or other food or drugallergy that the Investigator considers may impact on participant safety.
3. History of convulsion (including drug or vaccine-induced episodes). A medical historyof febrile convulsion during childhood (< 5 years) is not an exclusion criterion.
4. Presence of current or suspected uncontrolled chronic diseases that may impactparticipant safety or interpretation of clinical trial results, such as (but notlimited to) cardiac or autoimmune disease, diabetes, progressive neurological disease,severe malnutrition, hepatic or renal disease, epilepsy, or asthma.
5. History of malignancy of any organ system (other than localised basal or squamous cellcarcinoma of the skin or in situ cervical cancer), treated or untreated, within fiveyears of screening, regardless of whether there is no evidence of local recurrence ormetastases.
6. Individuals with history of schizophrenia, bipolar disorder psychoses, attempted orplanned suicide, or any other severe (disabling) chronic psychiatric diagnosisincluding generalised anxiety disorder.
7. History of an episode of depression lasting more than 6 months that requiredpharmacological therapy and/or psychotherapy within the last 2 years.
8. A score of 20 or more on the Beck Depression Inventory-II (BDI-II) and/or a responseof 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation).

• The BDI-II will be used as a validated tool for the assessment of depression atscreening. Participants that meet criterion 8 will be referred to a generalpractitioner or medical specialist as appropriate. Participants with a BDI-II score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have ahistory of the psychiatric conditions mentioned in criterion 6 and their mental stateis not considered to pose additional risk to the health of the participant during thetrial or to the execution of the trial and interpretation of the data gathered.

9. History of splenectomy.
10. Symptomatic postural hypotension at screening (confirmed on two consecutive readings),irrespective of the decrease in blood pressure, or asymptomatic postural hypotensiondefined as a decrease of SBP of ≥20 mmHg after 3 min standing and/or a decrease of DBPof ≥10 mmHg after 3 min standing. This 3 min standing period will commence after thevolunteer has rested for 5 min in the supine position.
11. Cardiac/QT risk:

• Family history of sudden death or of congenital prolongation of the QTc intervalor known congenital prolongation of the QTc interval or any clinical conditionknown to prolong the QTc interval.
• History of symptomatic cardiac arrhythmias or of clinically relevant bradycardia.

12. Evidence of increased cardiovascular disease risk (defined as >10%, 5-year risk forthose greater than 35 years of age, as determined by the Australian AbsoluteCardiovascular Disease Risk Calculator [http://www.cvdcheck.org.au/]). Risk factorsinclude sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDLcholesterol (mmol/L), and reported diabetes status.
13. Presence of clinically significant infectious disease or fever (e.g., sublingualtemperature ≥38°C) within the five days prior to inoculation. Prior medications and treatments
14. Any COVID-19 vaccine within 14 days of malaria inoculation, any other vaccinationwithin 28 days of IMP dosing, and any vaccination planned during the study.
15. Use of prescription drugs (excluding contraceptives), investigational medicalproducts, or nonprescription drugs or herbal supplements, that in the opinion of theinvestigator may potentially interfere with study interventions, within 14 days orfive half-lives (whichever is longer) prior to inoculation. Requirements forconcomitant medication use (from inoculation until the end of study) are specified inSection 6.5.
16. Individual who has ever received a blood transfusion. Malaria exposure
17. Any history of malaria or participation in a previous malaria challenge trial ormalaria vaccine trial.
18. Must not have had malaria exposure that is considered by the Principal Investigator ortheir delegate to be significant. This includes but is not limited to: history ofhaving travelled to or lived (>2 weeks) in a malaria-endemic region during the past 12months or planned travel to a malariaendemic region during the course of the trial;history of having lived for >1 year in a malariaendemic region in the past 10 years;history of having ever lived in a malaria-endemic region for more than 10 yearsinclusive. For endemic regions see https://malariaatlas.org/explorer/#/, Bali is notconsidered a malaria-endemic region. Alcohol use and smoking
19. History or presence of alcohol abuse (regular alcohol consumption in males >21 unitsper week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40%spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type), or drughabituation, or any prior intravenous usage of an illicit substance.
20. Any individual who currently smokes cigarettes on a daily basis (includinge-cigarettes, vaping, and other nicotine use). Blood donation
21. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to admission in the clinical unit on Day 8.
22. Individual unwilling to defer blood donations for at least twelve months after the EOSvisit. Laboratory results
23. Haematology, biochemistry or urinalysis results at screening or at the eligibilityvisit (Day -1 to Day -3) that are outside of the standard clinically acceptablelaboratory ranges (Appendix 12.2) or are considered clinically significant by thePrincipal Investigator.
24. Positive result for: hepatitis B surface antigen (HBs Ag), anti-hepatitis B coreantibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-humanimmunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab), COVID-19 byPCR at Screening or RAT on Day 0, red blood cell alloantibodies.
25. Positive urine drug test. Any drug listed in the urine drug screen unless there is anexplanation acceptable to the Investigator (e.g., the participant has stated inadvance that they consumed a prescription or over-the-counter product that containedthe detected drug) and the participant has a negative urine drug screen on retest bythe pathology laboratory.
26. G6PD deficiency (result below the lower limit of the laboratory reference range forquantitative G6PD test).
27. Positive alcohol breath test.
28. Positive serum pregnancy test at screening or eligibility visit, positive urinepregnancy test on Day 0. Other
29. Individual who, in the judgement of the Investigator, is likely to be non-compliantduring the trial
30. Individual who is an Investigator, research assistant, pharmacist, trial coordinator,or other staff thereof, directly involved in conducting the trial.
31. Individual without good peripheral venous access.
32. Individual who is breastfeeding or lactating.