ganaplacide (KAF156) / Novartis 
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  • ||||||||||  ganaplacide (KAF156) / Novartis
    KALUMI - A Phase II trial to evaluate the efficacy, safety and tolerability of the novel anti-malarial drug ganaplacide/lumefantrine in pediatric patients (Convention Center - Room 391/392 (3rd Floor); In-Person-Only) -  Oct 26, 2024 - Abstract #ASTMH2024ASTMH_3876;    
    P2
    All these in vitro results evidence that multi-drug resistant parasites currently in circulation in the field might not affect KAF156 efficacy, and are encouraging signs for KAF156 use in a triple ACT to preserve the use of artemisinins for as long as possible. The dose tested in this part of the study was 400mg KAF156/480mg LUM-SDF given once daily with a light meal for three days for patients > 35kg body weight and adapted for children with four body-weight bands as for Coartem
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Transposon mutagenesis of Plasmodium knowlesi reveals determinants of antimalarial susceptibility (Convention Center - Room 352 (3rd Floor); In-Person-Only) -  Oct 11, 2024 - Abstract #ASTMH2024ASTMH_3428;    
    Selection with the ganaplacide analog, GNF179, enriched 1000-fold for mutants containing insertions in an acetyl-CoA transporter 1 gene, whose deletion confers GNF179-resistance in P. falciparum...My comments are an informal communication and represent my own best judgement. These comments do not bind or obligate FDA.
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Lumefantrine performance in Africa - a review of literature (Convention Center - Hall I-1 (1st Floor); In-Person-Only) -  Oct 11, 2024 - Abstract #ASTMH2024ASTMH_2012;    
    This combination is currently the most advanced new generation antimalarial therapy in development. In this study, we review the state of art, regarding Lumefantrine potential decreased performance, the mechanisms and factors that could be associated with its decreased performance in Africa and its recycling into new therapeutic alternatives.
  • ||||||||||  2 - Can We Expect Triple/Multiple Artemisinin-Based Combination Therapies for Malaria in the Near Future? (Convention Center - Hall I-2 (1st Floor)) -  Sep 15, 2024 - Abstract #ASTMH2024ASTMH_178;    
    Talks, delivered on behalf of the WANECAM2 consortium members, then describe the EDCTP2-funded WANECAM2 consortium Artemether-lumefantrine (AL) is the most widely used ACT, accounting for >70% of ACT use...New antimalarial drugs may not come to the market within the next 5 years and one of the leading candidates, ganaplacide, is currently combined with lumefantrine...The Development of Triple Artemisinin-based Combination Therapies (DeTACT project), the ArteSunate-Amodiaquine-Atovaquone-Proguanil (ASAAP) consortium and the Multi-drug combination therapies to prevent Malaria drug resistance (MULTIMAL) consortium have been working TACTs and MDACTs to be primarily deployed in pediatric populations in African countries...The DeTACT clinical trial is complete and final results on safety, tolerability and efficacy of AL+amodiaquine (AL+AQ) and artesunate-mefloquine+piperaquine from eight African countries will be presented...The ASAAP consortium
  • ||||||||||  ganaplacide (KAF156) / Novartis, M5717 / EMD Serono
    Understanding Lead Discovery Antimalarial Drugs Resistance Translation from Lab to Field Parasites Toward Sustainable Malaria Elimination (4 Grand Ballrm CDSouth/E/F - BRLevel(East)LIVSTRM) -  Aug 25, 2023 - Abstract #ASTMH2023ASTMH_232;    
    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.
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Journal:  Comparative Susceptibility of Plasmodium ovale and Plasmodium falciparum Field Isolates to Reference and Lead Candidate Antimalarial Drugs in Ghana. (Pubmed Central) -  Jun 19, 2023   
    Furthermore, we identified strong inhibition of P. ovale using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drugs currently in clinical phase II testing...Here, we provided experiment data that were lacking to guide P. ovale treatment and disease control policy makers using reference antimalarial drugs. We also provided key experimental data for 2 clinical candidate drugs that can be used for prioritization selection of lead candidate's identification for clinical development.
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Trial completion, Enrollment change:  Drug-drug Interaction Study of Ganaplacide and Lumefantrine With Efavirenz (clinicaltrials.gov) -  Jan 12, 2023   
    P1,  N=14, Completed, 
    We also provided key experimental data for 2 clinical candidate drugs that can be used for prioritization selection of lead candidate's identification for clinical development. Recruiting --> Completed | N=60 --> 14
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Enrollment open, Enrollment change, Trial completion date, Trial primary completion date:  Drug-drug Interaction Study of Ganaplacide and Lumefantrine With Efavirenz (clinicaltrials.gov) -  Nov 4, 2022   
    P1,  N=60, Recruiting, 
    Recruiting --> Completed | N=60 --> 14 Not yet recruiting --> Recruiting | N=20 --> 60 | Trial completion date: Jun 2022 --> Nov 2022 | Trial primary completion date: Jun 2022 --> Nov 2022
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Keeping eye on non-falciparum species Plasmodium ovale and Plasmodium malariae infections to achieve disease control and elimination goals (Convention Center - Hall 4A (4th Floor); In-Person-Only) -  Oct 9, 2022 - Abstract #ASTMH2022ASTMH_1492;    
    In this regard, we identified strong inhibition of P. malariae and P. ovale using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae, P. ovale and P. falciparum.
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Analysis of the prevalence of molecular markers in PfCarl associated with resistance to Ganaplacide (KAF156) in field samples from Africa (Convention Center - Hall 4A (4th Floor); In-Person-Only) -  Oct 9, 2022 - Abstract #ASTMH2022ASTMH_462;    
    In the former set of infections we have also preliminarily analysed the hypothesis of lumefantrine driven selection of pfcarl SNPs by genotyping the baseline (n=266) and the recurrent infections (n = 37) of an Artemether-Lumefantrine (AL) efficacy trial. We did not find evidence for the presence of any of the aforementioned mutations that have been associated with resistance to KAF156, leading to the conclusion that if present they should be at frequencies significantly below 1%.
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Trial completion:  Drug-drug Interaction Study of Ganaplacide and Lumefantrine With Itraconazole (clinicaltrials.gov) -  Jun 14, 2022   
    P1,  N=19, Completed, 
    We did not find evidence for the presence of any of the aforementioned mutations that have been associated with resistance to KAF156, leading to the conclusion that if present they should be at frequencies significantly below 1%. Recruiting --> Completed
  • ||||||||||  Preclinical, Journal:  Ex vivo susceptibility to new antimalarial agents differs among human-infecting Plasmodium species. (Pubmed Central) -  Jan 7, 2022   
    Several promising antimalarial drugs are currently being tested in human trials, such as artefenomel, cipargamin, ferroquine and ganaplacide...However, using our in vitro adapted line, we demonstrated recently that P. knowlesi is significantly less susceptible than P. falciparum to some new antimalarial drugs (e.g., cipargamin and DSM265), and more susceptible to others (e.g., ganaplacide)...Our findings highlight the need to ensure cross species susceptibility profiles are determined early in the drug development pipeline. Our data can also be used to inform further drug development, and illustrate the utility of the P. knowlesi in vitro model as a scalable approach for predicting the drug susceptibility of non-falciparum malaria species in general.
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Enrollment open:  Drug-drug Interaction Study of Ganaplacide and Lumefantrine With Itraconazole (clinicaltrials.gov) -  Dec 15, 2021   
    P1,  N=24, Recruiting, 
    Our data can also be used to inform further drug development, and illustrate the utility of the P. knowlesi in vitro model as a scalable approach for predicting the drug susceptibility of non-falciparum malaria species in general. Not yet recruiting --> Recruiting
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Journal:  Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway. (Pubmed Central) -  Jul 29, 2020   
    IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models...In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.
  • ||||||||||  Clinical, Journal:  The development process for discovery and clinical advancement of modern antimalarials. (Pubmed Central) -  Jun 26, 2020   
    Additionally, the mechanism of action and lifecycle stage-specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
  • ||||||||||  ganaplacide (KAF156) / Novartis
    Journal:  An efficient, stereocontrolled and versatile synthetic route to bicyclic partially saturated privileged scaffolds. (Pubmed Central) -  May 22, 2020   
    Herein, we describe the development of a simple, high yielding and stereocontrolled strategy for the synthesis of a series of triazolopiperazines and other biologically relevant fused scaffolds from optically active amino acids. This route was applied to the synthesis of 22 scaffolds containing new, previously inaccessible vectors and used to access a novel analogue of ganaplacide.