Efficacy of SJ733 in Adults With Uncomplicated Plasmodium Falciparum or Vivax Malaria

An Open Label Phase 2a Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of (+)-SJ000557733 (SJ733) With or Without Cobicistat in Adult Patients With Acute, Uncomplicated Malaria Over a 42 Day Period

This Phase 2a trial recruits adult patients with uncomplicated P. vivax or P. falciparum blood-stage malaria mono-infection. The study drug SJ733 will be administered to examine its antimalarial efficacy, safety, and tolerability. This study also evaluates whether or not a fixed dose of the pharmacoenhancer cobicistat when given in combination with SJ733 significantly improves drug efficacy.

This is an adaptive open label Phase 2a study to examine the antimalarial efficacy, safety, and tolerability of SJ733 in adult patients with uncomplicated P. vivax or P. falciparum blood-stage malaria monoinfection. SJ733 will be administered orally once every day for three consecutive days, with or without a fixed dose of the pharmacoenhancer cobicistat. The Phase 1 clinical data (completed under a US IND) and PK/PD models suggest that SJ733 is most likely to be curative as a 3-daily-dose pharmacoenhanced therapy, due to its moderately rapid clearance. There will be 1-3 cohorts with each cohort containing two treatment arms, P. falciparum (a) and P. vivax (b). Cohort progression will be managed independently for each treatment arm. Interim analysis will determine whether the data for a given treatment arm meets the success criteria, is inconclusive, or meets the failure criteria. Antimalarial efficacy will be examined over the period of 42 days. Additional aims are to characterize the safety and pharmacokinetics of SJ733. The results of this trial will identify active, well-tolerated doses for investigation in a larger Phase 2b clinical trial.

Inclusion Criteria:

1. Male or female, aged 18 to 70 years of age (inclusive) at screening.

2. Body weight between 45 kg and 90 kg inclusive

3. Presence of mono-infection of P. falciparum or P. vivax confirmed by:

   1. Fever, as defined by axillary temperature ≥ 37.5°C or oral/rectal/tympanic temperature ≥ 38°C, or history of fever in the previous 24 hours (history of fever must be documented) and,
   2. Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite count/µL blood

4. Written informed consent provided by participant, in accordance with local practice. If the participant is unable to write, witnessed consent is permitted according to local ethical considerations.

5. Ability to swallow oral medication.

6. Ability and willingness to participate and to comply with the study requirements

7. Agreement to hospitalization for at least 102 hours and/or until malarial parasites are not detected by microscopy on 2 consecutive occasions.

8. Agreement to come back to the hospital on Days 7, 10 or 11, 14, 17 or 18, 21, 24 or 25, 28, 35, and 42.

9. Women of child-bearing potential, has a negative pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study drug:

   1. Use of oral, implantable, or injectable hormonal contraceptive, either combined or progestogen alone used in conjunction with barrier method as defined below.
   2. Use of an intrauterine device with a documented failure rate of <1% per year.
   3. Barrier method consisting of either condom or diaphragm.
   4. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female.
   5. Complete abstinence from intercourse for 2 weeks prior to administration of study drug, throughout the study and for a period of 90 days after stopping study drug.

Exclusion Criteria:

1. Signs and symptoms of severe/complicated malaria according to the World Health Organization Criteria 2010 (Attachment 1: Definition of Severe Malaria)

2. Mixed Plasmodium infection.

3. Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the study, or severe diarrhea defined as 3 or more watery stools per day.

4. Severe malnutrition (defined as the weight-for-height being below -3 standard deviation or less than 70% of median of the NCHS/WHO normalized reference values)

5. Presence of a significant medical or psychiatric condition, or any other serious or chronic clinical condition requiring hospitalization, or any other condition that in the opinion of the investigator precludes participation in the study.

6. Female patients must not be either lactating or pregnant as demonstrated by a negative serum point-of-care pregnancy test pre-dose (the result of the pre-dose assessment must be confirmed negative prior to dosing).

7. Employment under the direct supervision of the investigators or study staff.

8. Clinically significant alterations to hematologic or clinical chemistry parameters that in the opinion of the investigator precludes participation in the study, including:

   1. AST/ALT > 3 x upper limit of normal range (ULN) and total bilirubin is normal
   2. AST/ALT > 2 x ULN and total bilirubin is >1 and <1.5 x ULN and conjugated bilirubin is > 35% of the total bilirubin
   3. Total bilirubin > 1.5 x ULN
   4. Serum creatinine levels > 2 x ULN
   5. Hb level < 8 g/dL
   6. Platelet level < 50,000/mm3

9. Participation in a clinical study of another investigational small molecule within 30 days or investigational biologic within 90 days prior to study enrollment or planning to begin such participation during the study.

10. Have received any antimalarial treatment (alone or in combination) in the past containing:

    1. Piperaquine, mefloquine, naphthoquine or sulphadoxine / pyrimethamine within the previous 6 weeks
    2. Amodiaquine or chloroquine within the previous 4 weeks
    3. Any artemisinin (artesunate, artemether, arteether or dihydroartemisinin) quinine, halofantrine, lumefantrine and any other anti-malarial treatment or antibiotics with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) within the past 14 days

11. Any medication from the list of prohibited medications.