Introduction and Background of the Project

1.Introduction

While two new malaria vaccines are currently being rolled out in Africa, additional tools are still needed to reduce the high burden of P. falciparum malaria, especially among children in sub-Saharan Africa. Interest in malaria monoclonal antibodies (mAbs) as a new prevention intervention has increased significantly over the past several years. In April 2023, the World Health Organization (WHO) published “Monoclonal antibodies for malaria prevention: Preferred product characteristics and clinical development considerations” to incentivize and guide the development of malaria mAbs and inform global policy decisions. ¹

Prophylactic mAbs are different from drugs and vaccines given their potential to confer rapid, high-level protection from infection and/or clinical disease for several months following the administration of a single dose. Our initial use-case is focused on the reduction of disease burden in young African children living in regions associated with highly seasonal transmission, with the potential for future expanded use in additional at-risk populations, most notably pregnant women. Our project’s candidate mAb was isolated from vaccinated/protected volunteers who participated in a clinical trial with the RTS,S/AS01 malaria vaccine.

During the next phase of this project, we plan to complete the remaining preclinical development activities required to prepare the candidate mAb for a first-in-human (FIH) Phase 1 clinical study, focusing on Good Manufacturing Practice (GMP) manufacture and release of a master cell bank and clinical trial material.  

2.Project objective

The objective of this project is to complete GMP drug substance and GMP drug product manufacturing to support the future Investigational New Drug Application (IND) submission to the United States Food and Drug Administration (US FDA) for a proof-of-concept clinical trial that includes controlled human malaria infection. Our long-term goal is to secure a WHO recommendation for a mAb that prevents P. falciparum malaria in young children living in areas of seasonal transmission in sub-Saharan Africa. Milestones for this project include:

1) Manufacture and release of GMP candidate mAb clinical drug substance.

2) Manufacture and release of GMP candidate mAb clinical drug product.

3) Development of reagents for pharmacokinetic (PK) and anti-drug antibody (ADA) assays needed for clinical studies.

4) Preparation of IND and commencement of study preparations for FIH Phase 1 study.

3.Project design

The project is built on our successful completion of the following activities: 1) production and release of a pre-master cell bank for the candidate mAb; 2) development and optimization of the manufacturing process for the candidate mAb to confirm production conditions for Good Laboratory Practice toxicology studies and future scale-up; 3) formulation development to enable stability of the mAb at a high concentration to accommodate potential subcutaneous injection; and 4) a pre-IND meeting with the US FDA on the proposed nonclinical and clinical program, specifically on the adequacy of the nonclinical toxicology studies to support the FIH Phase 1 study.

We will start with the manufacturing and release of the drug substance with viral clearance and reference standard characterization. Once this is complete, we will manufacture and release the drug product to support the FIH study.

We will also generate reagents for the PK and ADA assays to support the FIH study. We will use a panel of anti-idiotype murine antibodies of proper affinity and specificity to detect the candidate mAb in human clinical studies to assess PK and presence of ADAs.

Finally, we will prepare the regulatory package for the FIH study, and all project partners will provide input on the drafting and context.

How can your partnership (project) address global health challenges?

Malaria kills more than 600,000 people each year worldwide and causes illness in at least 200 million more. Although existing interventions have reduced malaria deaths significantly, progress has stalled, highlighting the urgent need for new tools.

Current malaria control interventions, including anti-vector long-lasting insecticidal nets, indoor residual spraying of insecticides, and short-acting antimalarial medications (artemisinin-based combination therapies and 8-aminoquinolines), are at risk of reduced effectiveness because of emerging vector and parasite resistance. In addition, some antimalarial medications can completely cure asymptomatic patients, but mass drug administration campaigns are not logistically or operationally feasible in all settings. Several recent campaigns failed to drive transmission down to zero, with parasite prevalence rebounding when the campaigns ended. Finally, while current malaria vaccines confer relatively high-level protection from clinical malaria (similar to seasonal malaria chemoprevention) when administered prior to the rainy season in highly seasonal settings, three doses are required in the first year of life followed by annual boosting.^2,3 This regimen is challenging for many African populations to complete.

Highly efficacious mAbs represent a potential new class of intervention that could substantially reduce malaria-related illness and deaths in high-risk groups such as children younger than five years of age, under-immunized children, pregnant women, and travelers and migrants who would not be able to attend clinic for repeat vaccine doses.

What sort of innovation are you bringing in your project?

First, a unique innovative advantage of this project is that our mAb candidate was derived from volunteers who was protected from malaria following immunization with RTS,S/AS01. The candidate mAb targets an invariant region of the parasite so will not be subject to immune selection pressure that risks compromising efficacy and associated impact over time. Further, our mAb contains sequence modifications designed to increase both half-life in circulation and potency.

Second, we start with the “end” in mind and bring in a “line of sight” approach by including a cost of goods analysis and the development of an integrated product development and policy plan for mAbs as tools for malaria intervention. This ensures rigorous assessment of the critical value drivers to attain cost-effectiveness and high community acceptance, as well as inform our target product profile. 

Finally, our project combines the experience of a world-class consortium focused on global health impact. The consortium comprises a global non-profit organization (PATH) with unrivaled experience in malaria and product development; two biopharmaceutical companies (Eisai and GSK) with deep commitments to global health, extensive malaria and monoclonal research, and development and commercialization experience; and a premier academic malaria research partner (Ehime University). 

Role and Responsibility of Each Partner

PATH brings extensive experience in product development and project management to oversee the grant, including financial administration. In addition, PATH will support the preparation of the modules for an IND application for a future FIH study.

Eisai will contribute expertise from the manufacture of the toxicology batch to support GSK’s GMP manufacturing efforts as a key thought partner. Eisai will also prepare the sections of the IND that are relevant to the toxicology batch, namely the process development, analytical, and formulation development sections.

GSK will manufacture and formulate the GMP clinical trial material, produce reagents for the human PK and ADA to support future critical clinical assays, lead preparation of the regulatory materials and meetings for the FIH study, and conduct other preparatory activities for the study.

Ehime University has a 20-year history of working on malaria protein biochemistry and will be responsible for troubleshooting assays to evaluate the ligand binding potency of the mAb.

Others (including references if necessary)

1. World Health Organization website. Publications page. WHO meeting on preferred product characteristics for monoclonal antibodies for malaria prevention. https://www.who.int/publications/i/item/9789240060401. Accessed November 30, 2022.

2. Datoo MS, Dicko A, Tinto H, et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. The Lancet. 2024;403(10426):533–544. DOI: 10.1016/S0140-6736(23)02511-4.

3. Dicko A, Ouedraogo J, Issaka Z, et al. Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial. The Lancet: Infectious Diseases. 2024;24(1):75–86. DOI: 10.1016/S1473-3099(23)00368-7.