Introduction and Background of the Project

1. Introduction

Plasmodium Falciparum malaria remains a leading cause of death in the tropical world, in particular in young children in Sub-Saharan Africa. Malaria control and elimination efforts are under threat because of increasing problems with antimalarial drug resistance against the artemisinins and their partner drugs in artemisinin-based combination therapies (ACTs). The ACTs are globally the first-line treatments for uncomplicated Plasmodium falciparum malaria, and there are currently no alternatives available. Artemisinin partial resistance (ART-R) is now observed widely in the Greater Mekong Subregion of Southeast Asia and has over the last years also emerged in several African countries, including Rwanda and Uganda. Artemisinin partial resistance facilitates the emergence and spread of resistance to the ACT partner drugs, resulting in treatment failure. One important approach to overcome this problem is the development of Triple Artemisinin-based Combination Therapies (TACTs), where the artemisinin derivative is combined with two partner drugs mutually protecting each other. The combination of artemether-lumefantrine-amodiaquine (ALAQ) is the most advanced in its development. A loose combination of AL and AQ has been shown to be efficacious and well tolerated, with no new safety signals identified. Mathematical modelling suggests that the deployment of TACT could reduce the spread of ART-R and of treatment failures as compared to continued use of ACTs. To ensure patient compliance, the final presentation should be a fixed dose combination (FDC) of the three active ingredients. Fosun Pharma has developed recently an ALAQ-FDC and the current project will evaluate this new drug combination in African and Asian malaria endemic countries.

2. Project objective

  1. Evaluate the safety, tolerability and efficacy of ALAQ-FDC developed and produced by FOSUN PHARMA compared to the current first-line treatments AL and ASAQ, in areas with different patterns of antimalarial drug resistance.
  2. Compare the post-treatment prophylactic effect of ALAQ-FDC with AL and ASAQ.
  3. Assess potential drug-drug interactions in ALAQ-FDC in clinical use.
  4. Explore potential strategies for the successful registration, deployment and commercialization of ALAQ-FDC in participating countries.
  5.Explore the marketing positioning of ALAQ-FDC to facilitate the introduction of ALAQ-FDC in malaria endemic countries

3. Project design

The safety, tolerability, efficacy and pharmacokinetic/dynamic aspects of ALAQ-FDC will be studied in a randomized controlled non-inferiority trial comparing ALAQ-FDC to the ACTs artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) (with single-low dose primaquine in some sites) for the treatment of uncomplicated Plasmodium falciparum malaria. The study will be conducted at sites in Rwanda, Uganda, Angola, Nigeria and Thailand.

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

Plasmodium falciparum malaria remains a major health threat throughout the tropical world. In many African countries, progress to reduce the malaria burden has stalled. Partial artemisinin resistance and ACT partner drug resistance could cause a further increase in malaria morbidity and mortality in Africa and could also jeopardize the current malaria elimination efforts in Asia. The threat of partial artemisinin resistance and ACT partner drug resistance has been recognized as a major global health challenge by the WHO and others. Deployment of ALAQ-FDC can be a pivotal component of the global response to this challenge, since ALAQ-FDC will provide a novel antimalarial drug combination to treat and prevent artemisinin- and multidrug resistant P. falciparum malaria.

What sort of innovation are you bringing in your project?

Plasmodium falciparum malaria is currently treated with ACTs, a combination of 2 different antimalarial drugs. As for HIV and TB, we may now need to use triple combinations of currently used drugs to treat Plasmodium falciparum malaria in the context of the increasing problem of antimalarial drug resistance. Our project will be the first time a fixed dose triple ACT be tested and prepared for deployment in malaria endemic countries.

Role and Responsibility of Each Partner

FOSUN PHARMA will develop, manufacture, and commercialize ALAQ-FDC and initiate the application, with MMV’s support, for WHO policy recommendation and WHO-Prequalification. FOSUN PHARMA commits to make ALAQ-FDC accessible and affordable for malaria-endemic countries.

MARUBENI will be responsible for process management of the whole project. Through its corporate social responsibility agenda, MARUBENI aims to make ALAQ-FDC accessible to malaria patients worldwide.

MMV will facilitate interactions with regulators and normative bodies and provide regulatory and CMC/technical support to FOSUN PHARMA for the WHO-Prequalification processes.

MORU will coordinate the clinical trial and be closely involved in running the work package on marketing positioning of the new ALAQ-FDC.

Others (including references if necessary)

1. Triple Artemisinin-Based Combination Therapies for Malaria - A New Paradigm? van der Pluijm RW, Amaratunga C, Dhorda M, Dondorp AM. Trends Parasitol. 2021 Jan;37(1):15-24.

2. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. van der Pluijm RW, Tripura R, Hoglund RM, et al. Lancet. 2020 Apr 25;395(10233):1345-1360.