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

NCT02661373 | Completed Phase 1 FDA Drug

• 1 other identifier: BUZZOFF
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

Malaria is an infectious disease caused by a parasite that is passed to humans when an infected mosquito bites a person. About 3.4 billion people live in areas of the world where malaria is regularly found. In many countries, malaria is one of the leading causes of illness and death. Despite this, there are a limited number of drugs, called antimalarials, that can be used to treat malaria and increasing reports of resistance to existing antimalarials. The purpose of this research study is to test a new experimental antimalarial drug called SJ733 to first assess its safety, tolerability and blood levels in healthy adult volunteers. Single-dose, multi-dose and boosted-dose cohorts (both single and multi-dose) will be studied. The pharmacoenhancer (booster), cobicistat, will be given in combination with SJ733 in the boosted dose-cohorts. PRIMARY OBJECTIVES:

• To assess the preliminary safety and tolerability of escalating doses of antimalarial SJ733 in healthy human volunteers.
• To investigate the pharmacokinetic (PK) profile of escalating doses of antimalarial SJ733 and its metabolite in healthy human volunteers.
• To identify a dose of SJ733 that can be tested in a separate Phase 1b human malaria challenge study.
• To assess the preliminary safety and tolerability of SJ733 in healthy adult volunteers after multiple oral dosing.
• To assess the pharmacokinetics of SJ733 and its metabolite SJ506 after multiple dosing of SJ733 in healthy adult volunteers.
• To assess the preliminary safety and tolerability of escalating single oral doses of SJ733 in combination with cobicistat among healthy adult volunteers.
• To assess the pharmacokinetics of SJ733 and its metabolite SJ506 after single oral doses of SJ733 in combination with cobicistat among healthy adult volunteers.
• To assess the preliminary safety and tolerability of SJ733 in combination with cobicistat in healthy adult volunteers after multiple oral dosing.
• To assess the pharmacokinetics of SJ733 and its metabolite SJ506 after multiple dosing of SJ733 in combination with cobicistat among healthy volunteers. SECONDARY OBJECTIVE:
• To assess the impact of food intake on the pharmacokinetic profile of antimalarial SJ733.

Conditions

Malaria

Keywords

Antimalarial; First-in-Human; Pharmacokinetic

Outcome Measures

Primary Outcomes (9)

• Dose limiting toxicity (DLT)

  Number of DLT events will be described at each study dose level. DLT is defined as possibly, probably, or definitely related Grade 4 event, possibly, probably or definitely related Grade 3 event, or possibly, probably, or definitely related Grade 2 methemoglobinemia or anemia (attributed to hemolysis) events.

  From baseline up to minimum of 7 days post-dose

• Maximum tolerated dose (MTD)

  MTD is defined as the dose level prior to the dose cohort that 2 or more Grade 2 methemoglobinemia or anemia (attributed to hemolysis) OR any related Grade 3 OR any Grade 4, study drug adverse event (AE) occurred in.

  7 days after the last dose administration

• Drug absorption

  Drug absorption of SJ733 and its metabolite will be reported.

  From baseline through 7 days post-dose

• Drug clearance

  Drug clearance of SJ733 and its metabolite will be reported.

  From baseline through 7 days post-dose

• Drug volume of distribution

  Drug volume of distribution of SJ733 and its metabolite will be reported.

  From baseline through 7 days post-dose

• Area under the curve (AUC)

  AUC of SJ733 and its metabolite will be reported.

  From baseline through 7 days post-dose

• Time above threshold concentration

  Time above threshold concentration of SJ733 and its metabolite will be reported.

  From baseline through 7 days post-dose

• Maximum drug concentration (Cmax)

  Cmax of SJ733 and its metabolite will be reported.

  From baseline through 7 days post-dose

• Dose level of SJ733

  The dose chosen for the phase 1b trial will be no greater than the MTD and provide an exposure (AUC and time above threshold concentration) that equates (using applicable scaling) with those that provided maximum parasitological effect in the gold standard rodent model.

  14 days after the last dose administration

Secondary Outcomes (6)

• Drug absorption in the fed cohort

  From baseline through 7 days post-dose

• Drug clearance in the fed cohort

  From baseline through 7 days post-dose

• Drug volume of distribution in the fed cohort

  From baseline through 7 days post-dose

• Area under the curve (AUC) in the fed cohort

  From baseline through 7 days post-dose

• Time above threshold concentration in the fed cohort

  From baseline through 7 days post-dose

Study Arms (1)

Treatment Arm

EXPERIMENTAL

Participants will receive SJ733, an investigational drug developed at St. Jude Children's Research Hospital, and cobicistat.

Drug: SJ733; Drug: Cobicistat

Interventions

SJ733 DRUG

SJ733 is an oral, novel inhibitor of Plasmodium Falciparum plasma membrane protein PFATP4. It will be administered as a single, multi, or boosted oral dose.

Also known as: (+)-SJ000557733

Treatment Arm

Cobicistat DRUG

Commercially available cobicistat 150 mg tablets will be used. It will be administered as a single oral dose together with SJ733.

Also known as: Tybost®

Treatment Arm

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Medicines for Malaria Venture: collaborator
• Eisai Inc.: collaborator
• Global Health Innovative Technology Fund: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Publications (2)

• Gaur AH, Panetta JC, Smith AM, Dallas RH, Freeman BB 3rd, Stewart TB, Tang L, John E, Branum KC, Patel ND, Ost S, Heine RN, Richardson JL, Hammill JT, Bebrevska L, Gusovsky F, Maki N, Yanagi T, Flynn PM, McCarthy JS, Chalon S, Guy RK. Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development. EBioMedicine. 2022 Jun;80:104065. doi: 10.1016/j.ebiom.2022.104065. Epub 2022 May 19.

  PMID: 35598441 DERIVED

• Gaur AH, McCarthy JS, Panetta JC, Dallas RH, Woodford J, Tang L, Smith AM, Stewart TB, Branum KC, Freeman BB 3rd, Patel ND, John E, Chalon S, Ost S, Heine RN, Richardson JL, Christensen R, Flynn PM, Van Gessel Y, Mitasev B, Mohrle JJ, Gusovsky F, Bebrevska L, Guy RK. Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial. Lancet Infect Dis. 2020 Aug;20(8):964-975. doi: 10.1016/S1473-3099(19)30611-5. Epub 2020 Apr 8.

  PMID: 32275867 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Malaria

Interventions

SJ733; Cobicistat

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Aditya H. Gaur, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 19, 2016
• First Posted: January 22, 2016
• Study Start: March 1, 2016
• Primary Completion: March 9, 2018
• Study Completion: March 9, 2018
• Last Updated: January 2, 2019

Record last verified: 2018-12

Locations

US (1)