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

Malaria Journal

Mirjam Groger¹  Johannes Mischlinger¹  Jürgen May¹  Michael Ramharter²  Ghyslain Mombo-Ngoma²  Jean-Claude Dejon Agobé³  Ayôla A. Adegnika⁴  Quique Bassat⁵  Oumou Maïga-Ascofaré⁶  Abdoulaye Djimde⁷  Jerôme Clain⁸ 

[1] Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany;German Center for Infection Research, Partner Site Hamburg- Lübeck-Borstel-Riems, Hamburg- Lübeck-Borstel-Riems, Germany;Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany;German Center for Infection Research, Partner Site Hamburg- Lübeck-Borstel-Riems, Hamburg- Lübeck-Borstel-Riems, Germany;Centre de Recherches de Lambaréné, Lambaréné, Gabon;Centre de Recherches de Lambaréné, Lambaréné, Gabon;Centre de Recherches de Lambaréné, Lambaréné, Gabon;Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany;ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain;Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique;ICREA, Passeig de Lluís Companys 23, 08010, Barcelona, Spain;Pediatrics Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Barcelona, Spain;Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain;Kumasi Center for Collaborative Research, Kumasi, Ghana;Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany;German Center for Infection Research, Partner Site Hamburg- Lübeck-Borstel-Riems, Hamburg- Lübeck-Borstel-Riems, Germany;Malaria Research and Training Centre (MRTC), Faculty of Pharmacy, Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali;Université de Paris, Centre National de Référence du Paludisme, Hôpital Bichat- Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris, France;

关键词: Malaria;    Artemisinin-based combination therapy;    Falciparum;    Regulatory pathway;   

DOI  :  10.1186/s12936-022-04079-9

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY