MAM01 for Malaria

Overseen By Gates MRI (Toll Free Number)

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Bill & Melinda Gates Medical Research Institute

Must not be taking: Cimetidine, Metoclopramide, Antacids, Kaolin

Disqualifiers: Pregnancy, Autoimmune disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

61 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a First-in-Human (FiH), randomized, 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. Part A will have a double-blind, placebo-controlled design. Part B will randomize participants to one of three open-label MAM01 dose groups; a separate non-randomized group will be enrolled to include participants who will receive no treatment and act as infectivity controls.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use medications known to cause drug reactions with chloroquine or atovaquone-proguanil, such as cimetidine, metoclopramide, antacids, and kaolin.

What data supports the idea that MAM01 for Malaria is an effective treatment?

The available research does not provide specific data supporting the effectiveness of MAM01 for Malaria. The studies mentioned focus on other aspects of malaria treatment, such as the need for new antimalarial drugs due to resistance and the use of scores to predict disease severity. There is no direct evidence or comparison provided for MAM01's effectiveness in treating malaria. ^{1 2 3 4 5}

What safety data is available for the malaria treatment MAM01?

The provided research does not specifically mention MAM01, but it discusses the safety of antimalarial drugs in general. It highlights the need for more safety studies, especially in pregnant women and young children, and the importance of monitoring adverse events in clinical trials. Serious adverse reactions are rare and often identified in post-marketing studies. The research emphasizes the need for standardized guidelines and improved pharmacovigilance to better assess drug safety. ^{6 7 8 9 10}

Is the drug MAM01 a promising treatment for malaria?

Yes, MAM01 is a promising treatment for malaria because it targets a crucial protein called apical membrane antigen 1 (AMA1), which is essential for the malaria parasite to invade red blood cells. This makes it a strong candidate for preventing and treating malaria. ^{11 12 13 14 15}

Research Team

[phone]

Principal Investigator

Bill & Melinda Gates Medical Research Institute

Eligibility Criteria

Healthy adults who can become pregnant must use effective contraception and have a negative pregnancy test. Participants need to be healthy, with a BMI of 18-30 kg/m^2 up to 220 pounds, not in other trials recently, no significant medical conditions or immune system issues, and must have completed their primary COVID vaccine series.

Inclusion Criteria

Body Mass Index (BMI) 18 to 30 kg/m^2 (inclusive) to a maximum of 220 pounds

Participants who are healthy as determined by medical evaluation including medical history, physical examination and laboratory tests

I am a woman capable of becoming pregnant and agree to use birth control from 28 days before joining the study until 10 months after the last treatment.

Exclusion Criteria

I do not have a fever of 99.5°F or higher on the day of treatment.

I have a serious health condition that my doctor is concerned about.

A 5-year cardiovascular risk of ≥10% using the Gaziano nomogram

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Participants receive MAM01 or placebo in a double-blind, placebo-controlled design with dose escalation

Up to 378 days

Multiple visits for dosing and monitoring

Treatment Part B

Participants are randomized to one of three open-label MAM01 dose groups or act as infectivity controls

Up to 280 days

Multiple visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

168 days

Treatment Details

Interventions

• MAM01
• Placebo

Trial Overview The trial is testing MAM01, an antibody against malaria. It's the first time humans are trying it. The study will compare MAM01 with a placebo to see how safe it is and how the body processes it. Some people will get repeat doses under the skin.

Participant Groups

Group I: Part B: Dose Expansion Cohort 6: Group 3: MAM01 Experimental Treatment 1 Intervention

8 participants will receive 900 mg SC dose of MAM01. The dose was selected by applying a PK-PD model from the Part A data to estimate a (data-driven) protection threshold at CHMI.

Group II: Part B: Dose Expansion Cohort 6: Group 2: MAM01 Experimental Treatment 1 Intervention

8 participants will receive a 600 mg SC dose of MAM01. The dose was selected by applying a PK-PD model from the Part A data to estimate a (data-driven) protection threshold at CHMI

Group III: Part B: Dose Expansion Cohort 6: Group 1: MAM01 Experimental Treatment 1 Intervention

6 participants will receive a 450 mg SC dose of MAM01. The dose was selected by applying a PK-pharmacodynamic (PD) model from the Part A data to estimate a (data-driven) protection threshold at Controlled Human Malaria Infection (CHMI).

Group IV: Part A: Single Ascending Dose (SAD): Dose escalation cohort 1: MAM01 and placebo Intravenous (IV) Experimental Treatment 2 Interventions

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.

Group V: Part A: SAD dosing: Dose escalation Cohort 5: MAM01 and placebo IV Experimental Treatment 2 Interventions

7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 40 mg/kg IV or placebo

Group VI: Part A: SAD dosing: Dose escalation Cohort 4: MAM01 and placebo IV Experimental Treatment 2 Interventions

8 participants will be randomly assigned in a 6:2 ratio to receive MAM01 10 mg/kg IV or placebo.

Group VII: Part A: SAD dosing: Dose escalation Cohort 3: MAM01 and placebo IV Experimental Treatment 2 Interventions

7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg IV or placebo.

Group VIII: Part A: SAD dosing: Dose escalation Cohort 2: MAM01 and placebo SC Experimental Treatment 2 Interventions

7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg SC or placebo

Group IX: Part A: Multiple Ascending Dose (MAD) (Repeat dosing): MAM01 Experimental Treatment 1 Intervention

Participants from Cohort 2 and from Cohort 3 will receive 5 mg/kg MAM01 SC.

Group X: Internal Infectivity Controls Experimental Treatment 1 Intervention

6 participants will be enrolled into a non-randomized group prior to CHMI. These participants will receive no treatment and act as infectivity controls

Who Is Running the Clinical Trial?

Bill & Melinda Gates Medical Research Institute

Lead Sponsor

Trials

15

Recruited

30,900+

Findings from Research

Current clinical trials for adjunctive therapies in severe falciparum malaria are often underpowered, making it difficult to demonstrate their effectiveness due to the large participant numbers needed to assess mortality outcomes.

To improve trial design and outcomes, researchers suggest using risk stratification and surrogate endpoints, such as biomarkers of immune response and microcirculatory dysfunction, to identify high-risk patients who may benefit most from adjunctive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trials to assess adjuvant therapeutics for severe malaria. Varo, R., Erice, C., Johnson, S., et al.[2021]

In a study of 485 African children with Plasmodium falciparum malaria, the simplified multi-organ dysfunction score (sMODS) was found to be a reliable indicator of disease severity and duration, particularly in children who could walk or sit unaided.

A sMODS score of 16 or higher was associated with prolonged disease duration, showing high sensitivity and specificity, which suggests that this scoring system can be used for early prognostic evaluation in pediatric malaria cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simplified multi-organ dysfunction score predicts disability in African children with Plasmodium falciparum malaria. Helbok, R., Issifou, S., Matsiegui, PB., et al.[2006]

The multi-organ dysfunction score (MODS) was found to be a reliable tool for assessing the severity of uncomplicated Plasmodium falciparum malaria in 22 patients, showing strong correlations with important clinical markers like tumor necrosis factor-alpha and symptom duration.

The MODS can be quickly applied in under three minutes, making it a practical method for healthcare providers to evaluate malaria severity and potentially improve patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of the multi-organ dysfunction score as a tool to discriminate different levels of severity in uncomplicated Plasmodium falciparum malaria. Helbok, R., Dent, W., Nacher, M., et al.[2007]

Malaria is still a major global health issue, with half of the world's population at risk, and there is a pressing need for new antimalarial drugs due to the rising resistance to current treatments like artemisinin-based therapies.

Several promising new antimalarial compounds and therapeutic targets are being developed, including artefenomel and tafenoquine, which could help combat drug resistance and contribute to malaria elimination efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination. Mathews, ES., Odom John, AR.[2020]

Tumor necrosis factor (TNF) plays a dual role in malaria, promoting the killing of malaria parasites while also contributing to the severity of the disease, indicating a complex relationship between immune response and disease outcome.

Recent discoveries have identified other members of the TNF family that influence immune responses and disease pathology in malaria, highlighting the need for further research to understand these mechanisms and their implications for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TNF family members and malaria: old observations, new insights and future directions. Randall, LM., Engwerda, CR.[2010]

The emergence of drug-resistant Plasmodium parasites highlights the urgent need for new, safe, and effective antimalarial drugs, as current treatments are becoming less effective.

While there is substantial safety data for antimalarial drugs in older children and adults, more comprehensive studies are needed for pregnant women and young children, especially for combination therapies that are crucial in combating drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of safety of the major antimalarial drugs. Chattopadhyay, R., Mahajan, B., Kumar, S.[2019]

A monitoring system for adverse events in antimalarial trials was developed in Uganda, evaluating 5,614 treatments across 4,876 patients from 2002 to 2007, highlighting the need for standardized guidelines for safety assessment in malaria studies.

The study identified limitations in the adverse event monitoring system, emphasizing the necessity for new guidelines to effectively detect and report serious adverse events and those related to treatment adherence in antimalarial trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring antimalarial safety and tolerability in clinical trials: a case study from Uganda. Staedke, SG., Jagannathan, P., Yeka, A., et al.[2021]

A new series of benzimidazole derivatives showed strong antimalarial activity against both asexual blood stages and sexual stages of the malaria parasite, with some compounds achieving submicromolar effectiveness.

In vivo studies in mice infected with Plasmodium berghei demonstrated that the leading compound reduced parasitemia by 98% at an oral dose of 4 × 50 mg/kg, while also showing low toxicity to mammalian cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and In Vivo Oral Efficacy Studies. Dziwornu, GA., Coertzen, D., Leshabane, M., et al.[2021]

A study analyzing 104 reports of adverse effects from antimalarial drugs revealed that the majority of patients were over 13 years old, with 77.8% using artemisinin-based combination therapies (ACTs).

Most reported adverse effects were mild, but significant associations were found between ACT use and central nervous system and gastro-enterological disorders, highlighting the need for active surveillance of ACTs to ensure safety in real-world use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse effects of antimalarial drugs spontaneously reported to pharmacovigilance national center in Burkina Faso: descriptive study and factors associated]. Diallo, I., Ouédraogo, S., Zongo, RFE., et al.[2019]

Serious adverse reactions to malaria chemoprophylaxis drugs like pyrimethamine/sulfadoxine, pyrimethamine/dapsone, and amodiaquine are rare but can occur independently of dosage, making them difficult to predict during initial drug screening.

To better identify and manage these rare reactions, ongoing Phase IV post-marketing studies and improved data collection methods are essential, as current deficiencies in surveillance hinder the understanding of risks associated with these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ascertainment of risk of serious adverse reactions associated with chemoprophylactic antimalarial drugs. Phillips-Howard, PA., Bjorkman, AB.[2022]

WM382, a dual inhibitor of the aspartic proteases Plasmepsin IX and X, effectively blocks multiple stages of the Plasmodium life cycle, showing promise as a new treatment for malaria.

In studies with mice, WM382 not only cured infections caused by P. berghei but also prevented blood infections from the liver and was effective against P. falciparum, indicating its potential for both treatment and prevention of malaria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle. Favuzza, P., de Lera Ruiz, M., Thompson, JK., et al.[2020]

The study highlights that the PfAMA1 protein is critical for the growth of the malaria parasite Plasmodium falciparum, as attempts to disrupt its gene were unsuccessful, indicating its essential role in blood-stage development.

Introducing a transgene from Plasmodium chabaudi (PcAMA1) into P. falciparum allowed for partial functional complementation, demonstrating that PcAMA1 can support about 35% of PfAMA1's function and enhance the parasite's ability to invade murine red blood cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apical membrane antigen 1 plays a central role in erythrocyte invasion by Plasmodium species. Triglia, T., Healer, J., Caruana, SR., et al.[2019]

In a study involving 47 malaria-naïve adult volunteers, vaccination with the AMA1 antigen induced a significant humoral response, with about half of the antibodies cross-reacting with different allelic variants, which is important for broad vaccine efficacy.

The choice of adjuvant influenced the strength of the antibody response, with AS02 yielding the highest responses, while the functional capacity of the antibodies was consistent across different strains of Plasmodium falciparum, indicating potential effectiveness against various malaria strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Humoral immune responses to a single allele PfAMA1 vaccine in healthy malaria-naïve adults. Remarque, EJ., Roestenberg, M., Younis, S., et al.[2021]

The study found that the apical membrane antigen 1 (AMA-1) from the chimpanzee malaria parasite Plasmodium reichenowi shares similar molecular structure and processing characteristics with the 83-kDa form of AMA-1 from Plasmodium falciparum, suggesting potential for cross-reactivity in vaccine development.

In vitro assays demonstrated that antibodies targeting Pf AMA-1 can inhibit the growth of P. reichenowi, indicating that targeting AMA-1 could be a viable strategy for developing malaria vaccines that are effective against multiple malaria species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular characterisation of Plasmodium reichenowi apical membrane antigen-1 (AMA-1), comparison with P. falciparum AMA-1, and antibody-mediated inhibition of red cell invasion. Kocken, CH., Narum1, DL., Massougbodji, A., et al.[2019]

Malaria remains a significant global health challenge, particularly due to the ongoing issue of drug resistance, highlighting the urgent need for new treatments.

Recent research has focused on targeting apical membrane antigen 1 (AMA1), a key protein that allows malaria parasites to invade red blood cells, as a promising strategy for developing new antimalarial drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimalarial drug discovery targeting apical membrane antigen 1. Devine, SM., MacRaild, CA., Norton, RS., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Clinical trials to assess adjuvant therapeutics for severe malaria. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Simplified multi-organ dysfunction score predicts disability in African children with Plasmodium falciparum malaria. [2006]

3. United States pubmed.ncbi.nlm.nih.gov

Use of the multi-organ dysfunction score as a tool to discriminate different levels of severity in uncomplicated Plasmodium falciparum malaria. [2007]

4. England pubmed.ncbi.nlm.nih.gov

Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

TNF family members and malaria: old observations, new insights and future directions. [2010]

6. England pubmed.ncbi.nlm.nih.gov

Assessment of safety of the major antimalarial drugs. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Monitoring antimalarial safety and tolerability in clinical trials: a case study from Uganda. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and In Vivo Oral Efficacy Studies. [2021]

9. Mali pubmed.ncbi.nlm.nih.gov

[Adverse effects of antimalarial drugs spontaneously reported to pharmacovigilance national center in Burkina Faso: descriptive study and factors associated]. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Ascertainment of risk of serious adverse reactions associated with chemoprophylactic antimalarial drugs. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Apical membrane antigen 1 plays a central role in erythrocyte invasion by Plasmodium species. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Humoral immune responses to a single allele PfAMA1 vaccine in healthy malaria-naïve adults. [2021]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Molecular characterisation of Plasmodium reichenowi apical membrane antigen-1 (AMA-1), comparison with P. falciparum AMA-1, and antibody-mediated inhibition of red cell invasion. [2019]

15. England pubmed.ncbi.nlm.nih.gov

Antimalarial drug discovery targeting apical membrane antigen 1. [2023]