MMV390048 POC in Patients With P. Vivax and P. Falciparum Malaria

An Open Label Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose of MMV390048 in Adult Patients With Acute, Uncomplicated Plasmodium Vivax or Falciparum Malaria Monoinfection Over a 35 Day Period

The present proof-of-concept Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human Induced Blood-Stage Malaria (IBSM) challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub-type. The results of this trial will identify active, well-tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial.

The present Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human IBSM human challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub type.

The results of this trial will identify active, well tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial.

Preclinical studies using SCID mice inoculated with P. falciparum-infected red blood cells link doses and exposures to the efficacy of MMV390048.38 The active dose in the SCID model causing maximum effect (ED90) against the parasites is 1 mg/kg/day. The MPC derived from the SCID data was 39 ng/ml.39 A human dose for the treatment of P. falciparum was sought that could maintain blood concentrations above 39 ng/ml (100 nM) for 8 days. Assuming linear pharmacokinetics and based on observed data from the Phase I exploratory formulation study in human volunteers, a dose of approximately 20 mg would be estimated to achieve the pharmacodynamic target drug concentration in humans based on the preclinical efficacy data generated in the SCID mice model. For new antimalarial drugs the translation of a predicted efficacious dose from the SCID mouse to the human challenge model and in turn to the treatment of acute, uncomplicated P. vivax or P. falciparum is unknown. To minimise the risk to patients and to ensure the highest probability of success, the maximum safe dose (as determined in healthy volunteers) that maintains a toxicokinetic safety margin to the repeat dose studies was selected for the first cohort in this study. This dose is expected to exceed the predicted MPC on Day 8 and provide significant target coverage at the site of action.

Inclusion Criteria:

• Body weight between 40 kg and 90 kg inclusive
• Presence of P. vivax or P. falciparum monoinfection confirmed by:
• Fever, as defined by axillary temperature ≥37.5°C or oral/rectal/tympanic temperature ≥38°C, or history of fever in the previous 48 hours for P. vivax and 24 hours for P. falciparum and,
• Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite count/µL blood
• Written informed consent provided by the patient in accordance with local practice. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations.
• Ability to swallow oral medication
• The patient is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned
• Willing to be hospitalized for at least 72 hours or until malarial parasites are not detected by microscopy on 2 consecutive occasions whichever comes later and return to clinic for all follow-up visits
• Women must be of non-childbearing potential (WNCBP) as per one of the following definitions:
• postmenopausal defined as having age-appropriate, natural (spontaneous) amenorrhea for at least 12 months prior to screening in the absence of an alternative medical cause for the amenorrhea, or
• premenopausal with irreversible surgical sterilization by hysterectomy and/or bilateral oophorectomy or salpingectomy at least 6 months prior to screening (as determined by subject medical history)
• Sexually active men must agree to comply with strict appropriate contraception rules (barrier contraception, e.g. condom) or complete abstinence when this is in line with the preferred and usual lifestyle of the patient. The contraception coverage in this situation should ensure full elimination of MMV390048, i.e. until 120 days after MMV390048 administration to the enrolled male patient (covering a full sperm cycle of 90 days starting after 5 x t½ of the drug). Abstinent patients must agree to use the above-mentioned contraceptive methods if they start sexual relationships during the study, and to continue these methods until 120 days after study medication.

Exclusion Criteria:

• Patients with signs and symptoms of severe / complicated malaria according to the World Health Organisation Criteria 2012
• Mixed Plasmodium infection
• Vomiting more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or diarrhea equivalent to three or more watery stools per day
• Women who are nursing (lactating)
• Presence of other serious or chronic clinical condition requiring hospitalisation
• Severe malnutrition (defined as a body mass index [BMI] of less than 16 kg/m2 as per local guidelines)
• Presence of concurrent febrile illness (e.g. typhoid fever)
• Known history or evidence of clinically significant:
• cardiovascular disease (including arrhythmia, QTcF interval >450 msec, personal or family history of long QT syndrome, PR interval >200msec; any relevant intra-ventricular heart block [QRS >120msec]),
• respiratory conditions (including active tuberculosis),
• history of jaundice or other hepatic dysfunction,
• renal insufficiency,
• gastrointestinal disorder, or any condition that may affect absorption of the study medication (e.g. vomiting or diarrhea),
• immunological disorders (including known pre-existing HIV infection),
• endocrine disorders (including any type of diabetes mellitus whether controlled or not, diabetes insipidus, uncontrolled hypo- or hyperthyroidism, endocrine reproductive disorders not requiring concurrent medication, disorders of adrenal function),
• infectious conditions (other than minor skin or soft tissue infections or confirmed minor lower urinary tract infection),
• malignancy,
• psychiatric or neurological disorders (including a history of convulsions, major head trauma, focal neurological signs, psychosis, bipolar or major depressive disorder), or
• any other disorder or condition that in the opinion of the investigator may render the patient unfit for participation in the trial, may limit his/her ability to provide informed consent, may interfere with protocol adherence or place the patient at increased risk through participation in the study
• Known to have any of the following markers of active hepatitis:
• Hepatitis A IgM (HAV-IgM),
• Hepatitis B surface antigen (HBsAg), or
• Hepatitis C antibody (HCV Ab) and HCV RNA
• Have received any antimalarial treatment (alone or in combination) during the following periods before screening (list of prohibited medication is provided in Appendix 2):
• Piperaquine, mefloquine, naphthoquine or sulphadoxine-pyrimethamine within 6 weeks prior to screening
• Amodiaquine, chloroquine, pyronaridine or tafenoquine within 4 weeks prior to screening
• Any artemisinin derivative (artesunate, artemether, arteether or dihydroartemisinin), quinine, halofantrine, lumefantrine and any other anti-malarial treatment or antibiotic with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones and azithromycin) within 14 days prior to screening
• Any herbal products or traditional medicines during the 7 days prior to screening
• Receipt of an investigational drug within 8 weeks or 5 half-lives (whichever is longer) prior to screening
• Current participation in any other clinical trial
• A history of regular abuse of alcohol, or use of drugs of abuse during the past 6 months, or any clinical signs of substance abuse
• Neutrophil count <1,000/µL
• Elevated liver function tests as follows:
• AST/ALT >2 x the upper limit of normal (ULN), regardless of the level of total bilirubin
• AST/ALT >1.5 and ≤2 x ULN and total bilirubin >ULN
• AST/ALT >ULN and ≤1.5 x ULN
• and total bilirubin >1.5 and ≤2 x ULN,
• and conjugated bilirubin ≥35% of the total bilirubin
• Total bilirubin >2 x ULN, regardless of the level of AST/ALT
• Hb level <8g/dL
• Serum creatinine levels >2 x ULN
• Platelet level <50,000/mm3.