First-in-Human Study of an Oral Plasmodium Falciparum Plasma Membrane Protein Inhibitor

This is a single site, Phase 1a, first-in-human, oral, primarily single-dose, dose escalation study of (+)-SJ000557733 (SJ733) in healthy adult volunteers. SJ733, is an investigational oral anti-malarial agent is a novel inhibitor of Plasmodium falciparum plasma membrane protein (PfATP4). Subjects meeting eligibility criteria will be enrolled using a leap frog, fixed dose escalation design with an adaptive component where 6 subjects are enrolled per dose cohort.

Following successful completion of the safety and pharmacokinetic (PK) assessment resulting from the single-dose escalation portion of the study, a three-dose cohort study will be undertaken. It includes once per day oral dosing for 3 consecutive days. Both single and multi-dose cohorts of SJ733 in combination with cobicistat (boosted cohorts) will also be completed.

After the study results from the single-dose cohorts of SJ733 in combination with cobicistat (boosted cohorts) were reviewed, multi-dose cohorts of SJ733 in combination with cobicistat (boosted cohorts) were not conducted and Phase 2 study planning initiated.

Inclusion criteria

• Healthy adult (as certified by comprehensive medical assessment including detailed history and complete physical examination), male or female, aged 18 to 55 years of age (inclusive) at screening
• At least 50 kg in weight and body mass index (BMI) between 18 and 34 kg/m^2
• Able and willing to provide informed consent and to be available for follow-up for the planned duration of the study
• If female, then not of child bearing potential (i.e. permanently sterilized hysterectomy or bilateral oophorectomy at least 6 months before screening; proper documentation required] and/or post-menopausal defined as 12 months with no menses without an alternative cause and with an estradiol level of < 30 pg/mL and follicle-stimulating hormone level of > 40 IU/L at screening)
• Sexually active males must agree to be abstinent or use condoms for the duration of the study.
• Screening laboratories (hematology, chemistries, venous methemoglobin level specified in schedule of evaluations) within normal institutional range or if outside the range, not clinically significant in the opinion of the investigator.

Inclusion criteria

for Participants in Single-dose Cohort Only::

• Agrees not to receive any vaccination within 7 days prior to Day 0 and through Day 7.
• Agrees not to use nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to Day 0 and through Day 7. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day.
• Agrees not to use nicotine containing products from screening through Day 7.
• Agrees not to consume alcohol for the 24 hours prior to Day 0 and through Day 7.
• Agrees not to eat pomegranate, grapefruit or other citrus fruits or drink their juices within 7 days prior to Day 0 and through Day 7.
• Agrees to limit caffeine to no more than 200 mg on Day 0.
• Agrees not to eat or drink (except water) for 10 hours before the Day 0 visit and have no water for the hour prior to dosing.

Exclusion criteria

• Presence of a significant medical or psychiatric condition that in the opinion of the investigator precludes participation in the study.
• Clinically significant abnormalities on physical examination that, in the opinion of the investigator, would preclude entry into the study.
• History of having a significant illness within the 2 weeks prior to screening visit. Participants can screen after illness is resolved for two weeks.
• History of clinically significant electrocardiogram abnormalities or clinically significant abnormalities from the screening electrocardiogram.
• G6PD deficiency
• History of hemolytic anemia or methemoglobinemia
• History of severe drug hypersensitivity including a severe allergic reaction, anaphylaxis or convulsions following any medication, vaccination or infusion.
• History of drug or alcohol abuse in the 12 months prior to screening or evidence at screening visit
• Use of nicotine containing products within 30 days prior to screening
• Positive blood test for HBsAg, HCV, or HIV-1
• Participation in a clinical study of another investigational product within 30 days prior to study enrollment, or planning to begin such participation during the study.
• Employment under the direct supervision of the investigators or study staff.
• Receipt of any vaccination within 7 days of dosing.
• Febrile illness within 48 hours of dosing
• Use of any prescription medication within 14 days prior to study drug administration.
• Use of nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to study drug administration. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day.
• Consumption of pomegranate, grapefruit or other citrus fruits or their juices within 7 days prior to study drug administration.
• Use of nicotine containing products from screening to study drug administration.
• Consumption of alcohol within 24 hours prior to study drug administration.

Inclusion criteria

For participants in multi-dose cohort only:

• Agrees not to receive any vaccination within 7 days prior to Day 1 and through Day 10.
• Agrees not to use nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to Day 1 and through Day 10. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day.
• Agrees not to use nicotine containing products from screening through Day 10.
• Agrees not to consume alcohol for the 24 hours prior to Day 1 and through Day 10.
• Agrees not to eat pomegranate, grapefruit or other citrus fruits or drink their juices within 7 days prior to Day 1 and through Day 10.
• Agrees to limit caffeine to no more than 200 mg on Days 1, 2, and 3.
• Agrees not to eat or drink (except water) for 10 hours before the Days 1, 2, and 3 visits and have no water for the hour prior to dosing on each of those days.

Note: As with the single dose study, sexually active must agree to be abstinent or use condoms for the duration of the study (through the Day 14 visit).