cabamiquine (M5717) / Medicines for Malaria Venture, EMD Serono - LARVOL DELTA

Overview and vision of Cabamiquine clinical drug development (ASTMH 2025) - No abstract available

Clinical • Infectious Disease

Seeing is believing-Plasmodium falciparum translation in action. (PubMed, Structure) - "Using cryoelectron tomography and cryoelectron microscopy, ten ribosomal states are resolved, five previously unseen in eukaryotes, providing a more comprehensive parasite translation elongation cycle. The work describes parasite-specific translation dynamics, showing how the antimalarial cabamiquine disrupts elongation."

Journal • Infectious Disease

135 - Cabamiquine: A Decade of Antimalarial Drug Development (ASTMH 2025) - "• Modelling and clinical trial simulation Cabamiquine:Pyronaridine was evaluated with mathematical models to allow trial simulations at population level to assess the potential impact in a chemoprevention use case and compared with standard of care (SPAQ). #InfectiousDisease #Therapeutics #Prevention #ClinicalResearch #MNCH"

Infectious Disease • Malaria

Cytoplasmic and nuclear NFATc3 cooperatively contributes to vascular smooth muscle cell dysfunction and drives aortic aneurysm and dissection. (PubMed, Acta Pharm Sin B) - "Cabamiquine-targets eEF2 and inhibits protein synthesis-inhibited AAD development and progression in VSMC-NFATc3-overexpressing mice. VSMC-NFATc3 promoted VSMC switch and ECM degradation while exacerbating AAD development, making it a novel potential therapeutic target for preventing and treating AAD."

Journal • Cardiovascular • MMP2 • MMP9 • NFATC1 • NFATC3

The non-artemisinin antimalarial drugs under development: a review. (PubMed, Clin Microbiol Infect) - "Although attrition remains a possibility, several promising candidate drugs with novel modes of action are advancing through clinical development. Many are expected to become available for treating uncomplicated and severe malaria within the next decade. These new antimalarials could significantly enhance malaria treatment, reduce resistance, and support global health effort toward malaria control, elimination, and, potentially, eradication."

Journal • Review • Infectious Disease • Malaria

Efficacy, Safety, and PK of M5717 in Combination With Pyronaridine as Chemoprevention in Adults and Adolescents With Asymptomatic Plasmodium Falciparum Infection (CAPTURE-2) (clinicaltrials.gov) - P2 | N=192 | Completed | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Recruiting ➔ Completed

Trial completion • Infectious Disease • Malaria

Phase IIa Proof of Concept Study of M5717-Pyronaridine in Adults and Adolescents With Acute Uncomplicated Plasmodium Falciparum Malaria (CAPTURE 1) (clinicaltrials.gov) - P2 | N=38 | Completed | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ May 2024 | Trial primary completion date: Dec 2024 ➔ May 2024

Trial completion • Trial completion date • Trial primary completion date • Infectious Disease • Malaria

Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic Plasmodium berghei. (PubMed, ACS Infect Dis) - "The drug combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma Cav0-24/EC50 ratio >2 for ganaplacide and >5 for cabamiquine was achieved. These findings demonstrate that chemoprevention using a combination of cabamiquine and ganaplacide has the potential to target the asymptomatic liver stage of Plasmodium infection and prevent the development of parasitemia."

Journal • Infectious Disease • Malaria

Minimum Inoculum of Resistance Studies to Support Antimalarial Drug Discovery (ASTMH 2024) - "Here, we present our MIR studies on five different targets: dihydroorotate dehydrogenase (PfDHODH), ATPase4 (PfATP4), translation elongation factor 2 (PfeEF2), acetyl CoA synthetase (PfACS), and phosphatidylinositol-4 kinase (PfPI4K), targeted by the compounds DSM265, KAE609, M5717, MMV019721 and MMV390048, respectively. Data from these results can be used to predict whether resistance would be quickly selected in the field. Compounds with robust MIR data can be used as a positive control for studies to assess the resistance liabilities of candidate therapeutics."

Infectious Disease • Malaria

Plasmodium falciparum field isolates to guide clinically relevant dose ratios for Cabamiquine: Pyronaridine combination using translational modeling (ASTMH 2024) - "Finally, we were able to generate a range of EC50s for the two drugs, both as monotherapy and combination, that could then be translated into human doses. This study innovatively used P. falciparum field isolates data, modeling and simulation techniques to assess cabamiquine and pyronaridine combination selection and reducing animal testing in pre-clinical studies."

Clinical • Infectious Disease

A high content imaging assay for identification of specific inhibitors of native Plasmodium liver stage protein synthesis. (PubMed, Antimicrob Agents Chemother) - "We identified only two hits; both of which are parasite-specific quinoline-4-carboxamides, and analogs of the clinical candidate and known inhibitor of blood and liver stage protein synthesis, DDD107498/cabamiquine. We further show that these compounds have strikingly distinct relationships between their antiplasmodial and translation inhibition efficacies. These results demonstrate the utility and reliability of the P. berghei liver stage OPP HCI assay for the specific, single-well quantification of Plasmodium and human protein synthesis in the native cellular context, allowing the identification of selective Plasmodium translation inhibitors with the highest potential for multistage activity."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Infectious Disease • Liver Cancer • Malaria • Solid Tumor

Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data. (PubMed, Nat Commun) - "In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development."

Journal • Infectious Disease

Absence of developmental and reproductive toxicity in rats, rabbits, and zebrafish embryos exposed to antimalarial drug cabamiquine. (PubMed, Birth Defects Res) - "The results obtained in a full set of reproductive toxicity studies did not provide evidence of detrimental effects on the conceptuses and progeny at maternally nontoxic doses and exposures, still representing a multiple of the anticipated systemic exposures in women of childbearing potential (WOCBP). Cabamiquine can therefore be considered a suitable therapeutic option for WOCBP and pregnant women living in malaria-endemic regions by significantly reducing maternal and infant malaria death rates."

Journal • Preclinical • Infectious Disease • Malaria

Phase IIa Proof of Concept Study of M5717-Pyronaridine in Adults and Adolescents With Acute Uncomplicated Plasmodium Falciparum Malaria (CAPTURE 1) (clinicaltrials.gov) - P2 | N=38 | Active, not recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Recruiting ➔ Active, not recruiting | N=137 ➔ 38

Enrollment change • Enrollment closed • Infectious Disease • Malaria

Efficacy, Safety, and PK of M5717 in Combination With Pyronaridine as Chemoprevention in Adults and Adolescents With Asymptomatic Plasmodium Falciparum Infection (CAPTURE-2) (clinicaltrials.gov) - P2 | N=192 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Trial completion date: Apr 2024 ➔ Nov 2024 | Trial primary completion date: Apr 2024 ➔ Nov 2024

Combination therapy • Trial completion date • Trial primary completion date • Infectious Disease • Malaria

A high content imaging assay for identification of specific inhibitors of native Plasmodium liver stage protein synthesis. (PubMed, bioRxiv) - "We identified only two hits, both of which are parasite-specific quinoline-4-carboxamides, and analogues of the clinical candidate and known inhibitor of blood and liver stage protein synthesis, DDD107498/cabamiquine. We further show that these compounds have strikingly distinct relationships between their antiplasmodial and translation inhibition efficacies. These results demonstrate the utility and reliability of the P. berghei liver stage OPP HCI assay for specific, single-well quantification of Plasmodium and human protein synthesis in the native cellular context, allowing identification of selective Plasmodium translation inhibitors with the highest potential for multistage activity."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Infectious Disease • Liver Cancer • Malaria • Solid Tumor

Differential effects of translation inhibitors on Plasmodium berghei liver stage parasites. (PubMed, Life Sci Alliance) - "We also demonstrate that DDD107498 is capable of exerting antiplasmodial effects on translationally arrested liver stage parasites and uncover unexpected growth dynamics during the liver stage. Our results demonstrate that translation inhibition efficacy does not determine antiplasmodial efficacy for these compounds."

Journal • CNS Disorders • Infectious Disease • Psychiatry • Schizophrenia

Phase IIa Proof of Concept Study of M5717-Pyronaridine in Adults and Adolescents With Acute Uncomplicated Plasmodium Falciparum Malaria (CAPTURE 1) (clinicaltrials.gov) - P2 | N=137 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Trial completion date: Nov 2023 ➔ Sep 2024 | Trial primary completion date: Nov 2023 ➔ Sep 2024

Trial completion date • Trial primary completion date • Infectious Disease • Malaria

2,4-disubstituted 6-fluoroquinolines as potent antiplasmodial agents: QSAR, homology modeling, molecular docking and ADMET studies. (PubMed, J Taibah Univ Med Sci) - "Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target. QSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target."

Journal • Infectious Disease • Malaria

Efficacy, Safety, and PK of M5717 in Combination With Pyronaridine as Chemoprevention in Adults and Adolescents With Asymptomatic Plasmodium Falciparum Infection (CAPTURE-2) (clinicaltrials.gov) - P2 | N=192 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Not yet recruiting ➔ Recruiting | Phase classification: P2a ➔ P2 | Initiation date: Aug 2023 ➔ Nov 2023

Combination therapy • Enrollment open • Phase classification • Trial initiation date • Infectious Disease • Malaria

Phase IIa Proof of Concept Study of M5717-Pyronaridine in Adults and Adolescents With Acute Uncomplicated Plasmodium Falciparum Malaria (CAPTURE 1) (clinicaltrials.gov) - P2 | N=137 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Phase classification: P2a ➔ P2

Phase classification • Infectious Disease • Malaria

Understanding Lead Discovery Antimalarial Drugs Resistance Translation from Lab to Field Parasites Toward Sustainable Malaria Elimination (ASTMH 2023) - "Thus,for chloroquine, atovaquone, pyrimethamine and the current frontline artemisinin, major investigations have not been made at early discovery stage to identify which gene, mutations or conditions will cause drug resistance and can translate into field parasites...In a proof of concept study, we demonstrated that some key mutations found in lab parasites translate into field parasite conferring field parasites drug resistance Merck M5717 antimalarial drug candidate...We report that when exposed to GNF179 (Imidazolopiperazine: IPZ), close analogue of KAF156, recrudescent field parasites were detected which is being investigated for resistance purpose. This approach allows us to study the presence of resistant genes in field strains and predict resistance to antimalarial drugs, in order to anticipate therapeutic combinations before the new molecules are deployed."

Infectious Disease • Malaria

Efficacy, Safety, and PK of M5717 in Combination With Pyronaridine as Chemoprevention in Adults and Adolescents With Asymptomatic Plasmodium Falciparum Infection (CAPTURE-2) (clinicaltrials.gov) - P2a | N=192 | Not yet recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Combination therapy • New P2a trial • Infectious Disease • Malaria

Assessment of the transmission blocking activity of antimalarial compounds by membrane feeding assays using natural Plasmodium falciparum gametocyte isolates from West-Africa. (PubMed, PLoS One) - "Methylene-blue, MMV693183, DDD107498, atovaquone and P218 showed potent transmission-blocking activity in the TB-DMFA, and both atovaquone and the novel antifolate P218 were potent inhibitors of sporogonic development in the SPORO-DMA. This work establishes a pipeline for the integral use of field isolates to assess the transmission-blocking capacity of antimalarial drugs to block transmission that should be validated in future studies."

Journal • Infectious Disease • Malaria

The delayed bloodstream clearance of Plasmodium falciparum parasites after M5717 treatment is attributable to the inability to modify their red blood cell hosts. (PubMed, Front Cell Infect Microbiol) - "Using in vitro models, we demonstrated that M5717 treated ring/trophozoite stage iRBCs became less rigid, and cytoadhered less well compared to untreated iRBCs. This indicates that in vivo persistence of M5717 treated iRBCs in the bloodstream is likely due to reduced cytoadherence and splenic clearance."

Journal • Infectious Disease