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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Malaria

Intervention / Treatment
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* Biological: MAM01
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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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 in this 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Single Ascending Dose (SAD): Dose escalation cohort 1: MAM01 and placebo Intravenous (IV)<br>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<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part A: SAD dosing: Dose escalation Cohort 2: MAM01 and placebo SC<br>7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg SC or placebo | Biological: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part A: SAD dosing: Dose escalation Cohort 3: MAM01 and placebo IV<br>7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg IV or placebo. | Biological: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part A: SAD dosing: Dose escalation Cohort 4: MAM01 and placebo IV<br>8 participants will be randomly assigned in a 6:2 ratio to receive MAM01 10 mg/kg IV or placebo. | Biological: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part A: SAD dosing: Dose escalation Cohort 5: MAM01 and placebo IV<br>7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 40 mg/kg IV or placebo | Biological: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part A: Multiple Ascending Dose (MAD) (Repeat dosing): MAM01 and placebo SC<br>Participants from Cohort 2 and from Cohort 3 will receive 5 mg/kg MAM01 SC. | Biological: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part B: Dose Expansion Cohort 6: Group 1: MAM01 and placebo SC (optional)<br>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: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part B: Dose Expansion Cohort 6: Group 2: MAM01 and placebo SC (optional)<br>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: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|
| Experimental: Part B: Dose Expansion Cohort 6: Group 3: MAM01 and placebo SC (optional)<br>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: MAM01<br>* MAM01 will be administered via IV or SC route<br>Biological: Placebo<br>* Placebo will be administered via IV or SC route.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants reporting solicited local and systemic adverse events (AEs) in the SC cohorts |  | Through 7 days post-dose | 
| Number of participants reporting unsolicited AEs (single dose or multiple dose) |  | Through Day 28 | 
| Number of participants reporting serious adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs) and Adverse Events Special Interest (AESIs) |  | Through 168 days post-dose | 
| Number of re-dosed participants reporting SUSARs, SAEs and AESIs |  | Through 336 days | 
| Number of participants with safety laboratory assessments by grade (grade 1 and above) |  | Up to 336 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal observed blood concentration (Cmax) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Area under the curve (AUC) from Time=0 to the last measurable concentration (AUC0-t) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Partial AUC's Time= 0 to the CHMI challenge (AUC0-CHMI) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Concentration at the time of CHMI (CCHMI) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Blood terminal elimination rate constant (λz) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Terminal half life (t1/2) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| AUC from Time=0 extrapolated to infinity (AUC0-infinity) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Percentage (%) AUC extrapolated (% AUCext) following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Bioavailability of SC formulation following single and repeat dosing of MAM01 |  | Pre-dose, Day 28 and Day 84 post-dose | 
| Part A: Cohorts 2 and 3: Accumulation ratio (AUC0-168) following single and repeat dosing of MAM01 |  | Pre-dose and up to Day 168 | 
| Part A: Cohorts 2 and 3: AUC (169-336) following single and repeat dosing of MAM01 |  | Day 169 and up to Day 336 | 
| Number of participants with presence or absence of Pf infection assessed by quantitative polymerase chain reaction assay (qRT-PCR)) after CHMI |  | Through Day 27 post CHMI | 
| Time to parasitemia after CHMI |  | Up to Day 336 | 
| Part A: Cohorts 1, 4 and 5: Number of participants with anti-drug antibodies (ADAs) following administration of MAM01 |  | Up to Day 280 | 
| Part A: Cohorts 2 and 3: Number of participants with ADAs following administration of MAM01 |  | Up to Day 336 | 
| Part B: Cohort 6: Number of participants with ADAs following administration of MAM01 |  | Up to Day 168 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, MAM01 monoclonal antibody, First-in-Human, Dose-escalation, Single ascending dose, Multiple ascending dose