Safety, Tolerability, Pharmacokinetics and Protective Efficacy of MAM01 in Healthy Adults

A Phase 1, Dose Escalation, Double Blind, Placebo Controlled Clinical Trial With Controlled Human Malaria Infections (CHMI) to Evaluate Safety, Tolerability, Pharmacokinetics, and Protective Efficacy of an Anti-Malaria Human Monoclonal Antibody, MAM01, in Healthy, Malaria-Naive Adults

This is a First-in-Human (FiH) double-blind, randomized, placebo-controlled, two-part, dose-escalation trial of MAM01 monoclonal antibody (mAb) targeting the Plasmodium falciparum (Pf) Circumsporozoite Protein (CSP). This study will evaluate the safety, tolerability, pharmacokinetics (PK), and protective efficacy of MAM01, as well as safety and PK of repeat subcutaneous (SC) dosing.

Study Overview

• Status: Recruiting
• Conditions: Malaria
• Intervention / Treatment: Biological: MAM01 1.5 mg/kg; Biological: Placebo; Biological: Placebo; Biological: MAM01 5 mg/kg; Biological: MAM01 5 mg/kg; Biological: MAM01 10 mg/kg; Biological: MAM01 40 mg/kg; Biological: MAM01

• Study Type: Interventional
• Enrollment (Estimated): 61
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Gates MRI; Phone Number: +1 857 702 2108; Email: clinical.trials@gatesmri.org
• Study Contact Backup: Name: Gates MRI (Toll Free Number); Phone Number: +1 866 789 5767

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Recruiting
      • Center for Vaccine Development and Global Health, 685 W. Baltimore Street

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

• Participants who are healthy as determined by medical evaluation including medical history, physical examination and laboratory tests
• Body Mass Index (BMI) 18 to 30 kilograms per square meter (kg/m^2) (inclusive) to a maximum of 220 pounds

• Both males and females are eligible to participate as per the following:

  a. Female participants physically capable of pregnancy, have at least one negative pregnancy test during Screening, on the day of enrollment, prior to Investigational product (IP) administration, prior to CHM and at the start of antimalarial treatment, and who agree to use effective contraception to avoid pregnancy from 28 days before enrollment through 10 months after last administration of investigation product are eligible to participate

• Capable of giving signed Informed Consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and the trial protocol, and completion of a test of understanding if he/she may participate in the CHMI procedure
• Reported completion of primary Coronavirus Disease (COVID) vaccine series is documented

Exclusion criteria:

• Acute illness or fever ≥99.5°Fahrenheit (F) (or ≥37.5 degrees Celsius) on day of dosing
• Women who are pregnant or breastfeeding
• Evidence and/or history of clinically significant medical condition(s) as judged by the Investigator, including malignancies, diabetes mellitus, and unstable or uncontrolled hypertension
• A 5-year cardiovascular risk of ≥10% using the Gaziano nomogram
• History of any autoimmune disease or immune deficiency or other impairment to the immune system, including but not limited to Human immunodeficiency virus (HIV), autoimmune conditions or immunosuppressive therapy
• Participation in an interventional clinical trial and/or receipt of any investigational drug within 180 days prior to administration of trial drug on Day 1
• Anticipated use of medications known to cause drug reactions with chloroquine or atovaquoneproguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Single Ascending Dose (SAD): Dose escalation cohort 1: MAM01 and placebo Intravenous (IV); 2 sentinel participants will be randomized in a 1:1 ratio to receive MAM01 1.5 milligrams per kilogram (mg/kg) IV or placebo. Following at least a 24-hour safety review period, the 6 remaining participants of Cohort 1 will be randomized in a 5:1 ratio to receive MAM01 1.5 mg/kg IV or placebo.	Biological: MAM01 1.5 mg/kg; 1.5 mg/kg MAM01 will be administered via IV route.; Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.
Experimental: Part A: SAD dosing: Dose escalation Cohort 2: MAM01 and placebo SC; 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg SC or placebo	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01 5 mg/kg; 5 mg/kg MAM01 will be administered via SC route.; Biological: MAM01 5 mg/kg; 5 mg/kg MAM01 will be administered via IV route.
Experimental: Part A: SAD dosing: Dose escalation Cohort 3: MAM01 and placebo IV; 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg IV or placebo.	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01 5 mg/kg; 5 mg/kg MAM01 will be administered via SC route.; Biological: MAM01 5 mg/kg; 5 mg/kg MAM01 will be administered via IV route.
Experimental: Part A: SAD dosing: Dose escalation Cohort 4: MAM01 and placebo IV; 8 participants will be randomly assigned in a 6:2 ratio to receive MAM01 10 mg/kg IV or placebo.	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01 10 mg/kg; 10 mg/kg MAM01 will be administered via IV route.
Experimental: Part A: SAD dosing: Dose escalation Cohort 5: MAM01 and placebo IV; 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 40 mg/kg IV or placebo	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01 40 mg/kg; 40 mg/kg MAM01 will be administered via IV route.
Experimental: Part A: Multiple Ascending Dose (MAD) (Repeat dosing): MAM01 and placebo SC; Participants from Cohort 2 and from Cohort 3 will receive 5 mg/kg MAM01 SC.	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01 5 mg/kg; 5 mg/kg MAM01 will be administered via SC route.; Biological: MAM01 5 mg/kg; 5 mg/kg MAM01 will be administered via IV route.
Experimental: Part B: Dose Expansion Cohort 6: Group 1: MAM01 and placebo SC (optional); 8 participants will receive a single SC dose of either MAM01 or placebo. The dose will be selected by applying a PK-pharmacodynamic (PD) model from the Part A data to estimate a (data-driven) protection threshold.	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01; MAM01 will be administered via SC route.
Experimental: Part B: Dose Expansion Cohort 6: Group 2: MAM01 and placebo SC (optional); 8 participants will receive a single SC dose of either MAM01 or placebo. The dose will be selected by applying a PK-PD model from the Part A data to estimate a (data-driven) protection threshold.	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01; MAM01 will be administered via SC route.
Experimental: Part B: Dose Expansion Cohort 6: Group 3: MAM01 and placebo SC (optional); 8 participants will receive a single SC dose of either MAM01 or placebo. The dose will be selected by applying a PK-PD model from the Part A data to estimate a (data-driven) protection threshold.	Biological: Placebo; Placebo will be administered via IV route.; Biological: Placebo; Placebo will be administered via SC route.; Biological: MAM01; MAM01 will be administered via SC route.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants reporting solicited local and systemic adverse events (AEs) in the SC cohorts	Local injection site solicited AEs will be assessed after dosing and will also be recorded for 7 days from SC recipients only. Systemic solicited AEs will be assessed in all participants after dosing at Visit 1 and recorded for 7 days.	Through 7 days post-dose
Number of participants reporting unsolicited AEs (single dose or multiple dose)	Unsolicited adverse events will be captured after product administration and the CHMI procedure	Through Day 28
Number of participants reporting serious adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs) and adverse events special interest (AESIs)	A SAE is defined as any untoward medical occurrence that, at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or is a medically significant / important event or reaction. SUSARs are adverse event that occur in a clinical trial participant, which is assessed by the Sponsor and or study investigator as being unexpected, serious and as having a reasonable possibility of a causal relationship with the study drug. AESIs are adverse events that the Sponsor wants to monitor carefully and which are subject to expedited reporting	Through 168 days post-dose
Number of re-dosed participants reporting SUSARs, SAEs and AESIs		Through 378 days
Number of participants with safety laboratory assessments by grade (grade 1 and above)	Blood samples will be collected for the analysis of laboratory parameters including hematology and serum chemistry.	Up to 378 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal observed concentration (Cmax) following single and repeat dosing of MAM01	Capillary blood samples via Volumetric Absorptive Microsampling Method (VAMS) will be collected from participants in the Pharmacokinetic (PK) Population for measurement of MAM01 Cmax. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Area under the curve (AUC) from Time=0 to the last measurable concentration (AUC0-t) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 AUC 0-t. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Partial AUC's Time= 0 to the CHMI challenge (AUC0-CHMI) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 AUC0-CHMI. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Concentration at the time of CHMI (CCHMI) following single and repeat dosing of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 CCHMI. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Blood terminal elimination rate constant (λz) following single and repeat dosing of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 λz. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Terminal half life (t1/2) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 t1/2. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Time Frame: Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
AUC from Time=0 extrapolated to infinity (AUC0-infinity) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 AUC0-infinity. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Percentage (%) AUC extrapolated (% AUCext) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 (% AUCext. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Bioavailability of SC formulation following single and repeat dosing of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 bioavailability. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose
Part A: Cohorts 2 and 3: Accumulation ratio (AUC0-168) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 AUC0-168. Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140 and 168 post-dose
Part A: Cohorts 2 and 3: AUC (210-378) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 AUC (210-378). Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Day 210 and up to Day 378
Part A: Cohorts 2 and 3: Accumulation ratio AUC (210-378) of MAM01	Capillary blood samples via VAMS will be collected from participants in the PK Population for measurement of MAM01 Accumulation ratio AUC (210-378). Blood concentrations of MAM01 will be measured using a qualified immunoassay.	Day 210 and up to Day 378
Number of participants with presence or absence of Pf infection assessed by quantitative polymerase chain reaction assay (qRT-PCR) after CHMI	A sensitive qRT-PCR will be used for the detection of Pf parasites in Efficacy Population.	Through Day 27 post CHMI
Time to parasitemia after CHMI in Efficacy Population		Up to Day 378
Part A: Cohorts 1, 4 and 5: Titers of anti-drug antibodies (ADAs) following administration of MAM01 in Immunogenicity Population	Percentage of participants with titers confirmed above the assay cut point will be summarized calculated by treatment group as appropriate.	Up to Day 280
Part A: Cohorts 2 and 3: Titers of ADAs following administration of MAM01 in Immunogenicity Population		Up to Day 378
Part B: Cohort 6: Titers of Number of participants with ADAs following administration of MAM01 in Immunogenicity Population		Up to Day 168

Collaborators and Investigators

• Sponsor: Bill & Melinda Gates Medical Research Institute
• Investigators: Study Director: +1 866 789 5767, Bill & Melinda Gates Medical Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 14, 2023
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: May 26, 2023
• First Submitted That Met QC Criteria: May 26, 2023
• First Posted (Actual): June 6, 2023

Study Record Updates

• Last Update Posted (Actual): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Healthy volunteers; First-in-Human; Prevention; Phase 1; Dose-escalation; Mosquito; Multiple ascending dose; Single ascending dose; Malaria vaccine; Recruiting; MAM01 monoclonal antibody; Gates; Nonprofit
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria
• Other Study ID Numbers: Gates MRI-MAM01-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No