Pyronaridine in Healthy Adult Participants Infected With Blood Stage Malaria

Inclusion Criteria: Demography 1. Male or female (non-pregnant, non-lactating) aged 18 to 55 years inclusive who will be contactable and available for the 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 the range 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. Health status 3. Certified as healthy by a comprehensive clinical assessment (detailed medical history and full physical examination). 4. Vital signs at screening (measured after 5 min in the supine position): * Systolic blood pressure (SBP) - 90-140 mmHg, * Diastolic blood pressure (DBP) - 40-90 mmHg, * Heart rate (HR) 40-100 bpm. 5. At Screening and pre-inoculation with the malaria challenge agent: normal standard mean of triplicate 12-lead electrocardiogram (ECG) parameters after 5 minutes resting in supine position in the following ranges: 1. QTcF ≤450 msec (male participants); QTcF ≤470 msec (female participants); 2. QRS 50-120 msec 3. PR interval ≤ 210 msec for both males and females, and 4. Normal ECG tracing unless the PI or delegate considers an ECG tracing abnormality to be not clinically relevant. 6. Women of childbearing potential (WOCBP) who anticipate being sexually active with a male during the trial must agree to the use of a highly effective method of birth control (see below) combined with a barrier contraceptive from the screening visit until 100 days after the last dose of pyronaridine (covering a full menstrual cycle of 30 days starting after 5 half-lives of last dose pyronaridine) and have a negative result on urine pregnancy test performed before inoculation with the malaria challenge agent. Note: a. Highly effective birth control methods include: combined (oestrogen and progestogen containing) oral/intravaginal/transdermal/implantable hormonal contraception associated with inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or sexual abstinence or same sex relationship. b. Female participants who are abstinent (from penile-vaginal intercourse) must agree to start a double method if they start a sexual relationship with a male during the study. Female participants must not be planning in vitro fertilisation within the required contraception period. 7\. Women of non-childbearing potential (WONCBP) are defined as: 1. Natural (spontaneous) post-menopausal defined as being amenorrhoeic for at least 12 months without an alternative medical cause with a screening follicle stimulating hormone level (FSH) \>25 IU/L (or at the local laboratory levels for post-menopause) 2. Premenopausal with irreversible surgical sterilization by hysterectomy and/or bilateral oophorectomy or salpingectomy at least 6 months before screening (as determined by participant medical history) 8. Males who have, or may have, female sexual partners of child bearing potential during the course of the study must agree to use a double method of contraception including condom plus diaphragm, or condom plus intrauterine device, or condom plus stable oral/transdermal/injectable/implantable hormonal contraceptive by the female partner, from the time of informed consent through to 70 days (covering a spermatogenesis cycle) after pyronaridine administration. Abstinent males must agree to start a double method if they begin sexual relationship with a female during the study and up to 70 days after the last dose of pyronaridine. Males with female partners of child-bearing potential that are surgically sterile, or males who have undergone sterilisation and have had testing to confirm the success of the sterilisation, may also be included and will not be required to use above described methods of contraception. Regulations 9. Completion of the written informed consent process prior to undertaking any trial-related procedure. 10\. Must be willing and able to communicate and participate in the whole trial. 11. Agreement to adhere to Lifestyle Considerations (see Section 5.3) throughout trial duration 12. Agreement to provide current contact details (two telephone numbers including a mobile number and a responsible adult as an emergency contact) and a relevant email address. Exclusion Criteria: * Individual who lives alone, OR, does not satisfy the following criteria: Participants who live alone may be included on a case-by-case basis, following discussion with the Principal Investigator. Participants who live alone must identify and provide contact details of a support person who is aware of the participant's participation in the study and is available to provide assistance if required (for example with contacting the participant in the event that study staff are unable to, or with transporting the participant to and from the study site if required). 2\. Known hypersensitivity to pyronaridine, artesunate or any of its derivatives, artemether, lumefantrine or other artemisinin derivatives, proguanil/atovaquone, primaquine, or 4-aminoquinolines. 3\. Haematology, biochemistry or urinalysis results at screening or at the eligibility visit that are outside of Sponsor-approved clinically acceptable laboratory ranges (appendix) or are considered clinically significant by the PI or their delegate. 4\. Participation in any investigational product trial within the 12 weeks preceding pyronaridine administration. 5\. Symptomatic postural hypotension at screening (confirmed on two consecutive readings), irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure ≥20 mmHg within 2-3 min when changing from supine to standing position. 6\. Any history of anaphylaxis or other severe allergic reactions including face, mouth, or throat swelling or any difficulty breathing, or other food or drug allergy that the Investigator considers may impact on participant safety. Participants with seasonal allergies/hay fever or allergy to animals or house dust mite that are untreated and asymptomatic at the time of dosing can be enrolled in the trial. 7\. History of convulsion (including drug or vaccine-induced episodes). A medical history of a single febrile convulsion during childhood (\< 5 years) is not an exclusion criterion. 8\. Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease, diabetes, progressive neurological disease, severe malnutrition, hepatic or renal disease. Acute or progressive hepatic or renal disease, porphyria, psoriasis, rheumatoid arthritis, asthma (excluding childhood asthma, or mild asthma with preventative asthma medication required less than monthly), or epilepsy. 9\. History of malignancy of any organ system (other than localised basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within five years of screening, regardless of whether there is evidence of local recurrence or metastases. 10\. Individuals with history of schizophrenia, bipolar disorder psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis including generalised anxiety disorder. 11\. Individuals who have been hospitalised within five years prior to enrolment for either a psychiatric illness or due to danger to self or others. History of an episode of mild/moderate depression lasting more than 6 months that required pharmacological therapy and/or psychotherapy within the last 5 years; or any episode of major depression. The Beck Depression Inventory-II (BDI-II) will be used as a validated tool for the assessment of depression at screening. In addition to the conditions listed above, participants with a score of 20 or more on the BDI-II and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) will not be eligible for participation. These participants will be referred to a general practitioner or medical specialist as appropriate. Participants with a BDI-II score of 17 to 19 may be enrolled at the discretion of an Investigator if they do not have a history of the psychiatric conditions mentioned in this criterion and their mental state is not considered to pose additional risk to the health of the participant or to the execution of the trial and interpretation of the data gathered. 13\. History of recurrent headache (e.g. tension-type, cluster, or migraine) with a frequency of ≥2 episodes per month on average and severe enough to require medical therapy, during the 2 years preceding screening. 14\. Presence of clinically significant infectious disease or fever (e.g., sublingual temperature ≥38.5°C) within the five days prior to inoculation. 15\. 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. 16\. History or presence of alcohol abuse (alcohol consumption more than 40 g/4 units/4 standard drinks per day), or drug habituation, or any prior intravenous usage of an illicit substance. 17\. Any individual who currently (within 14 days prior to inoculation) smokes \>5 cigarettes/day. 18\. Breastfeeding or lactating; positive serum pregnancy test at screening, positive urine pregnancy test upon admission or at other time points as specified by schedule of activities tables. 19\. Any COVID-19 vaccine within 14 days of inoculation, any other vaccination within 28 days of IMP intake, and any vaccination (including COVID-19 initial or second dose) planned up to the final follow-up visit. 20\. Any corticosteroids, anti-inflammatory drugs (excluding commonly used over-the-counter anti-inflammatory drugs such as ibuprofen, acetylsalicylic acid, diclofenac), immunomodulators or anticoagulants within the past three months. Any individual currently receiving or having previously received immunosuppressive therapy (including systemic steroids, adrenocorticotrophic hormone or inhaled steroids) at a dose or duration potentially associated with hypothalamic-pituitary-adrenal axis suppression within the past year. 21\. Use of prescription drugs (excluding contraceptives) or non-prescription drugs or herbal supplements (such as St John's Wort), within 14 days or five half-lives (whichever is longer) prior to inoculation. Limited use of other non-prescription medications or dietary supplements, not believed to affect participant safety or the overall results of the trial, may be permitted on a case-by-case basis following approval by the Sponsor in consultation with the PI. Participants are requested to refrain from taking non-approved concomitant medications from recruitment until the conclusion of the trial. 22\. Cardiac/QT risk: Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. 23\. Any history of malaria or participation in a previous malaria challenge trial or malaria vaccine trial. 24\. Must not have had malaria exposure that is considered by the PI or their delegate to be significant. This includes but is not limited to: history of having travelled to or lived (\>2 weeks) in a malaria-endemic region during the past 12 months or planned travel to a malaria-endemic region during the course of the trial; history of having lived for \>1 year in a malaria-endemic region in the past 10 years; history of having ever lived in a malaria-endemic region for more than 10 years inclusive. For endemic regions see https://malariaatlas.org/explorer/#/, Bali is not considered a malaria-endemic region. 25\. Has evidence of increased cardiovascular disease risk (defined as \>10%, 5-year risk for those greater than 35 years of age, as determined by the Australian Absolute Cardiovascular Disease Risk Calculator \[http://www.cvdcheck.org.au/\]). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L), and reported diabetes status. 26\. History of splenectomy. 27. Individual unwilling to defer blood donations to the Blood Service for at least twelve months after the EOS visit. 28\. Individual who has ever received a blood transfusion. 29. Any recent (\<6 weeks) therapy with an antibiotic or drug with potential antimalarial activity (e.g. chloroquine, piperaquine phosphate, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, doxycycline etc.). General conditions 30. Any individual who, in the judgement of an Investigator, is likely to be non-compliant during the trial, or is unable to cooperate because of a language problem or poor mental development. 31\. Any individual in the exclusion period of a previous trial according to applicable regulations. 32\. Any individual who is an Investigator, research assistant, pharmacist, trial coordinator, or other staff thereof, directly involved in conducting the trial. 33\. Any individual without good peripheral venous access. Biological status 34. Positive result on any of the following tests: hepatitis B surface antigen (HBs Ag), anti-hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab). 35\. Positive urine drug test. Any drug listed in the urine drug screen unless there is an explanation acceptable to an Investigator (e.g., the participant has stated in advance that they consumed a prescription or over-the-counter product that contained the detected drug) and the participant has a negative urine drug screen on retest by the pathology laboratory. 36\. Severe G6PD deficiency. 37. Positive alcohol breath test. 38. Positive for SARS-CoV-2 by PCR. NPA testing is to occur between Day -3 to Day -1 but only in the event that there is community transmission in South East Queensland (see section 8.3.7) 39. Positive for red cell antibodies