Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria

Quique Bassat,Jerôme Clain,Oumou Maïga-Ascofaré,Abdoulaye Djimde,Mirjam Groger,Johannes Mischlinger,Ayôla A Adegnika,Ghyslain Mombo-Ngoma,Michael Ramharter,Jürgen May,Asaap And Multimal Consortia ,Jean-Claude Dejon Agobé

doi:10.1186/s12936-022-04079-9

Abstract

The addition of a third anti-malarial drug matching the pharmacokinetic characteristics of the slowly eliminated partner drug in artemisinin-based combination therapy (ACT) has been proposed as new therapeutic paradigm for the treatment of uncomplicated falciparum malaria. These triple artemisinin-based combination therapy (TACT) should in theory more effectively prevent the development and spread of multidrug resistance than current ACT. Several clinical trials evaluating TACT—or other multidrug anti-malarial combination therapy (MDACT)—have been reported and more are underway. From a regulatory perspective, these clinical development programmes face a strategic dilemma: pivotal clinical trials evaluating TACT are designed to test for non-inferiority of efficacy compared to standard ACT as primary endpoint. While meeting the endpoint of non-inferior efficacy, TACT are consistently associated with a slightly higher frequency of adverse drug reactions than currently used ACT. Moreover, the prevention of the selection of specific drug resistance—one of the main reasons for TACT development—is beyond the scope of even large-scale clinical trials. This raises important questions: if equal efficacy is combined with poorer tolerability, how can then the actual benefit of these drug combinations be demonstrated? How should clinical development plans be conceived to provide objective evidence for or against an improved management of patients and effective prevention of anti-malarial drug resistance by TACT? What are the objective criteria to ultimately convince regulators to approve these new products? In this Opinion paper, the authors discuss the challenges for the clinical development of triple and multidrug anti-malarial combination therapies and the hard choices that need to be taken in the further clinical evaluation and future implementation of this new treatment paradigm.

Highlights

Since the Second World War monotherapy constituted the universal treatment paradigm for falciparum malaria [1]
*Correspondence: ramharter@bnitm.de 7 Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany Full list of author information is available at the end of the article region, a new anti-malarial drug was evaluated in clinical trials against a failing first-line therapy demonstrating superior efficacy and replacing it as standard treatment for uncomplicated malaria [1,2,3]. This process occurred in similar ways for the major anti-malarials of the twentieth century—chloroquine, sulfadoxine-pyrimethamine, and mefloquine—until no replacement drug was Bassat et al Malaria Journal (2022) 21:61 readily available for clinical testing [4, 5]. The spread of these drug resistant Plasmodium falciparum isolates throughout sub-Saharan Africa was paralleled by a dramatic increase in malaria-related mortality, highlighting the impact of drug resistance from a public health perspective [6]
To address this vicious cycle of drug development and emergence of drug resistance, and mimicking what had been historically proposed for other infectious diseases, such as tuberculosis (TB) or HIV, a new treatment paradigm emerged at the turn of the century by proposing artemisinin-based combination therapy (ACT) as standard of care for uncomplicated malaria [4]