ferroquine/artefenomel / Evotec, Sanofi, Medicines for Malaria Venture - LARVOL DELTA

Recent advances, challenges and updates on the development of therapeutics for malaria. (PubMed, EXCLI J) - "This review is primarily concerned with the description of newly synthesized antimalarial compounds, i.e. Tafenoquine, Cipargamin, Ferroquine, Artefenomel, DSM265, MMV390048 designed to improve the activity of pure antimalarial enantiomers. In this review, we selected the representative malarial drugs in clinical trials, classified them with detailed targets according to their action, discussed the relationship within the human trials, and generated a summative discussion with prospective expectations."

Journal • Review • Infectious Disease • Malaria

Predicting optimal antimalarial drug combinations from a standardized Plasmodium falciparum humanized mouse model (ASTMH 2023) - "Then, using historical data on monotherapy and two small cohorts of Pfalc Hu Mice evaluated with ferroquine plus artefenomel or piperaquine plus artefenomel, we found that only measurements of parasite killing, (i.e., cure of mice) as a function of drug exposure in blood allowed direct estimation of the individual drug contribution to efficacy by using multivariate statistical modelling and intuitive graphic displays. Overall, the analysis of parasite killing in the Pfalc Hu Mouse model is a unique and robust experimental in vivo tool to inform the selection of optimal combinations by pharmacometric PK/PD modelling."

Preclinical • Infectious Disease • Malaria

Predicting Optimal Antimalarial Drug Combinations from a Standardized Plasmodium falciparum Humanized Mouse Model. (PubMed, Antimicrob Agents Chemother) - "Then, using historical data on monotherapy and two small cohorts of PfalcHuMice evaluated with ferroquine plus artefenomel or piperaquine plus artefenomel, we found that only measurements of parasite killing (i.e., cure of mice) as a function of drug exposure in blood allowed direct estimation of the individual drug contribution to efficacy by using multivariate statistical modeling and intuitive graphic displays. Overall, the analysis of parasite killing in the PfalcHuMouse model is a unique and robust experimental in vivo tool to inform the selection of optimal combinations by pharmacometric pharmacokinetic and pharmacodynamic (PK/PD) modeling."

Journal • Preclinical • Infectious Disease • Malaria

Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria. (PubMed, Malar J) - P2a | "The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated."

Journal • P2a data • Infectious Disease • Malaria

Effectiveness of antimalarial drug combinations in treating concomitant urogenital schistosomiasis in malaria patients in Lambaréné, Gabon: A non-randomised event-monitoring study. (PubMed, PLoS Negl Trop Dis) - P2 | "Antimalarial treatments with artesunate-pyronaridine and artemether-lumefantrine reduced the excretion of S. haematobium eggs, comforting the hypothesis that antimalarial drugs could play a role in the control of schistosomiasis."

Journal • Infectious Disease • Malaria

New In Vitro Interaction-Parasite Reduction Ratio Assay for Early Derisk in Clinical Development of Antimalarial Combinations. (PubMed, Antimicrob Agents Chemother) - "Last, our more informative in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g., a concentration-dependent change in the maximum killing effect (E) and the concentration producing 50% of the killing maximum effect (EC) of piperaquine or artefenomel or a directional reduction of the EC of ferroquine by artefenomel and a directional reduction of E of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations for malaria and potentially also in other therapeutic areas."

Journal • Preclinical • Infectious Disease • Malaria

A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria. (PubMed, Malar J) - P2b | "The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1."

Clinical • Journal • P2b data • PK/PD data • Infectious Disease • Malaria • PCR

Lipid Compositions in Infant Formulas Affect the Solubilization of Antimalarial Drugs Artefenomel (OZ439) and Ferroquine during Digestion. (PubMed, Mol Pharm) - "Infant formulas could therefore be designed and used as milk substitutes to tailor the desired level of drug solubilization while circumventing the variability of components in naturally derived milk. The enhanced solubilization of OZ439 was achieved during the digestion of medium-chain triacylglycerols (MCT), indicating the potential applicability of MCT-fortified infant formula powder as a lipid-based formulation for the oral delivery of OZ439 and FQ."

Journal • Infectious Disease • Malaria

Single dose treatment of malaria - current status and perspectives. (PubMed) - "The development of a single dose combination therapy would constitute a breakthrough in the control of malaria. Such an innovative treatment approach would simultaneously close the effectiveness gap of current three-day therapies and revolutionize population based interventions in the context of malaria elimination campaigns."

Journal • Biosimilar

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria. (PubMed, Mol Pharm) - "We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation."

Combination therapy • Journal • Preclinical

SACT: Effect of Artemisinin-based Combination Therapies on Schistosomiasis on Malaria Co-infection (clinicaltrials.gov) - P2; N=54; Completed; Sponsor: Centre de Recherche Médicale de Lambaréné

Combination therapy • New P2 trial

Study to Investigate the Clinical and Parasiticidal Activity and Pharmacokinetics of Different Doses of Artefenomel and Ferroquine in Patients With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2a; N=140; Completed; Sponsor: Sanofi; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • PCR

To Evaluate the Efficacy of a Single Dose Regimen of Ferroquine and Artefenomel in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2b; N=377; Terminated; Sponsor: Sanofi; N=683 ➔ 377; Trial completion date: May 2020 ➔ Sep 2019; Recruiting ➔ Terminated; Trial primary completion date: May 2020 ➔ Sep 2019; All treatment arms met the futility criteria for efficacy during the pre-planned interim analysis, therefore the study was stopped.

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination

Study to Investigate the Clinical and Parasiticidal Activity and Pharmacokinetics of Different Doses of Artefenomel and Ferroquine in Patients With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2a; N=140; Active, not recruiting; Sponsor: Sanofi; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed

To Evaluate the Efficacy of a Single Dose Regimen of Ferroquine and Artefenomel in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2b; N=683; Recruiting; Sponsor: Sanofi; Trial completion date: Apr 2021 ➔ May 2020; Trial primary completion date: Apr 2021 ➔ May 2020

Clinical • Trial completion date • Trial primary completion date

Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination. (PubMed, F1000Res) - "...This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine...Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination."

Journal • Review