Malaria: Relative Bioavailability and Food Effect of DSM265

The objective of this study is to compare the relative bioavailability of oral DSM265-TPGS 34% SDD formulation with that of a reference 25% SDD powder for suspension used in previous clinical trials. Another objective of the study is to evaluate the effect of food on bioavailability of the DSM265-TPGS 34% SDD formulation.

The current 25% SDD powder for suspension clinical formulation is a suspension which requires reconstitution/administration in 240 mL sucralose based vehicle (for a 400 mg adult dose). This volume is too large for paediatric patients with malaria (e.g., translates into a 30 mL volume for 0.5-2 yr old patients); also, the dosing vehicle is not commercially viable. The new formulation dissolves in a smaller volume of a more common vehicle, water (40 mL for 400 mg adult dose).

• Subjects or their legally authorized representative must voluntarily sign and date each informed consent, approved by an Independent Ethics Committee(IEC) / Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
• Male or female between 18 and 55 years of age inclusive at the time of screening.
• Body Mass Index (BMI) is ≥ 18.0 to ≤ 29.9 kg/m2 after rounding to the tenths decimal. BMI is calculated as weight in kg divided by the square of height measured in meters.
• Females must be of Non-Childbearing Potential as defined below

Females do not need to use birth control during or following study drug treatment if considered of non-childbearing potential due to meeting any of the following criteria:

• Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an follicle stimulating hormone (FSH) level > 40 IU/L.
• Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
• Female who is not pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 120 days after the last dose of study drug.
• Male subjects who are sexually active with a female partner of childbearing potential, must agree to use condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through 120 days after the last dose of study drug. His female partner(s) must also use at least one of the following methods of birth control:

• Combined (oestrogen and progestogen containing) hormonal birth control (oral, intravaginal, injectable, transdermal) associated with inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.
• Progestogen-only hormonal birth control (oral, injectable, implantable) associated with inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.
• Bilateral tubal occlusion/ligation.
• Intrauterine device (IUD).
• Intrauterine hormone-releasing system (IUS).
• Male who is not considering fathering a child or donating sperm during the study or for approximately 120 days after the last dose of study drug.
• Laboratory values meet the following criteria:

• Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ the upper limit of normal (ULN) at the Screening Visit and upon initial confinement.
• Negative test result for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody (Ab) and human immunodeficiency virus (HIV) at screening visit.
• Negative screen for drugs of abuse, alcohol or cotinine at screening and upon initial confinement.
• For non-postmenopausal female subjects, a negative urine pregnancy test at the screening visit and a negative serum pregnancy test upon initial confinement and prior to the first dose of study drug.
• No other laboratory results that the investigator determines are clinically significant.
• Platelets greater than or equal to the lower limit of normal.
• No clinically significant ECG abnormalities including

• No evidence of 2nd or 3rd degree AV block at screening visit and upon initial confinement.
• QT interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) is ≤ 430 msec (males) or ≤ 450 msec (females) at screening visit and upon initial confinement.
• A condition of general good health, based upon the results of a medical history, physical examination, vital signs, laboratory profile and a 12-lead ECG.
• No history of: epilepsy, any clinically significant cardiac, respiratory (except mild asthma as a child), renal, hepatic, gastrointestinal, hematologic or psychiatric disease or disorder, or any uncontrolled medical illness.
• No history of any clinically significant sensitivity or allergy to any medication or food.
• No history of or active medical condition(s) or surgical procedure(s) that might affect gastrointestinal motility, pH, or absorption [e.g., Crohn's disease, celiac disease, gastroparesis, short bowel syndrome, gastric surgery (except pyloromyotomy for pyloric stenosis during infancy), cholecystectomy, vagotomy, bowel resection].
• No evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other than successfully treated non-metastatic cutaneous squamous cell, basal cell carcinoma or localized carcinoma in situ of the cervix.
• No history of any clinically significant illness/infection/major febrile illness, hospitalization, or any surgical procedure within 30 days prior to the first dose of study drug.
• Has not donated blood (including plasmapheresis), lost ≥ 550 mL blood volume, or received a transfusion of any blood product within 8 weeks prior to study drug administration.
• No consumption of alcohol, grapefruit products, Seville oranges, starfruit products or quinine/tonic water within the 72-hour period prior to study drug administration.
• No use of tobacco or nicotine-containing products within 180 days prior to the first dose of study drug.
• No history of clinically significant (per Investigator's judgment) drug or alcohol abuse within the last 6 months.
• Is not currently enrolled in another interventional clinical study.
• Has not been previously enrolled in this study.
• In the opinion of the investigator, this subject is a suitable candidate for enrollment in the study.
• Subjects must not have been treated with any investigational drug within 30 days or 5 half-lives of the drug (whichever is longer) prior to the first dose of study drug.
• Subject must not have received any live vaccine within 4 weeks prior to the first dose of study drug, or expected need of live vaccination during study participation including at least 4 weeks after the last dose of study drug.
• Subject must not require any over-the-counter and/or prescription medication, vitamins and/or herbal supplements, with the exception of contraceptives or hormonal replacement therapies for females, on a regular basis.
• Subject must not use any medications within the 2-week period prior to study drug administration.
• Receipt of any drug by injection within 30 days or within a period defined by 5 half-lives, whichever is longer, prior to study drug administration.
• No use of known inhibitors (e.g., ketoconazole) or inducers (e.g., carbamazepine) of cytochrome P450 3A (CYP3A) within 1 month prior to study drug administration.
• No exposure to DSM265 within the past 90 days prior to first dose of study drug.