ganaplacide (KAF156) / Novartis - LARVOL DELTA

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

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

KALUMI - A Phase II trial to evaluate the efficacy, safety and tolerability of the novel anti-malarial drug ganaplacide/lumefantrine in pediatric patients (ASTMH 2024) - P2 | "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 ® (artemether-lumefantrine). A summary of results for KALUMI will be presented at the ASTMH 2024 Annual Meeting. The study is part of the EDCTP WANECAM-II program supported by the European Union (RIA2017T-2018) and financially supported by MMV and Novartis"

Clinical • Late-breaking abstract • P2 data • Infectious Disease • Malaria • Pediatrics

KALUMI - An adaptive run-in cohort of a Phase II trial to evaluate food-effects of ganaplacide/lumefantrine in adolescent patients (ASTMH 2024) - P2 | "A summary of results including PK will be presented at the 2024 ASTMH Annual Meeting. The study is part of the EDCTP WANECAM-II program supported by the European Union (RIA2017T-2018) and financially supported by MMV and Novartis"

Clinical • Late-breaking abstract • P2 data • Infectious Disease • Malaria • Pediatrics

Transposon mutagenesis of Plasmodium knowlesi reveals determinants of antimalarial susceptibility (ASTMH 2024) - "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."

Infectious Disease • Malaria • Targeted Protein Degradation

Lumefantrine performance in Africa - a review of literature (ASTMH 2024) - "Due to their synergistic effect against P. falciparum, Lumefantrine was combined with Artemether and consist of one of the most popular Artemisinin-Combination Therapy (ACT) being used to treat non-complicated malaria in Africa (Artemether-Lumefantrine, AL)...Additionally, because Lumefantrine and Amodiaquine exert opposite genetic forces on the parasite, they could potentially lead to incompatible resistance mechanisms if combined...Furthermore, Lumefantrine is also being rescued into a non-artemisinin combination, along with Ganaplacide (KAF156). 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."

Review • CNS Disorders • Infectious Disease • Malaria • Psychiatry • Schizophrenia • ABCB1

Ex vivo susceptibilities to new antimalarials under development and associations with genotypes in P. falciparum isolates from Burkina Faso (ASTMH 2024) - "Among novel compounds under development as potential antimalarials are inhibitors of the proteins PfATP4 (KAE609, SJ733, PA92), PfPI4K (MMV1901539, EQV620), and resistance mediators PfCARL, PfACT and PfUGT (ganaplacide). Our results indicate that malaria parasites circulating in Burkina Faso are generally susceptible to inhibitors under development. We identified several polymorphisms in potential drug targets and resistance mediators, and a natural occurring mutation in PfATP4 was associated with modestly decreased ex vivo inhibitor susceptibility."

Preclinical • Infectious Disease • Malaria

Results of the KALUMI study: effect of food on exposure of ganaplacide-lumefantrine SDF combination. Early indicators of transmission blocking and effect in K13 mutated parasites (ASTMH 2024) - No abstract available

Infectious Disease • Malaria

Methods to assess P. falciparum dynamics of selection of drug resistance markers of the new a non-artemisinin-based combination therapy (KAF156) (ASTMH 2024) - No abstract available

Combination therapy • Infectious Disease • Malaria

Capacity building and methods for assessment of transmission blocking activities of the new non-artemisinin-based combination therapy (KAF156) in a phase 3 multi-country study (ASTMH 2024) - No abstract available

Combination therapy • P3 data • Infectious Disease • Malaria

89 - Ganaplacide (KAF156) A Next-Generation, Non-Artemisinin, for the Treatment of P. falciparum Malaria (ASTMH 2024) - "The symposium will open with an overview of the past and current malaria treatment options. Talks, delivered on behalf of the WANECAM2 consortium members, then describe the EDCTP2-funded WANECAM2 consortium’s capacity building in clinical research and its efforts for the clinical development of a novel combination therapy consisting of ganaplacide (KAF156) and lumefantrine – solid dispersion formulation ((LUM-SDF)."

Infectious Disease • Malaria

2 - Can We Expect Triple/Multiple Artemisinin-Based Combination Therapies for Malaria in the Near Future? (ASTMH 2024) - "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’s evaluation of clinical efficacy and transmission blocking potential of AL+atovaquone-proguanil in five African countries will be presented...."

Combination therapy • Infectious Disease • Malaria • Pediatrics

Efficacy, safety and tolerability of KAF156 in combination with LUM-SDF in pediatric population with uncomplicated Plasmodium falciparum malaria Efficacité, sécurité et tolérabilité du KAF156 en association avec la LUM-SDF dans une population pédiatrique atteinte de paludisme non compliqué à Plasmodium falciparum (clinicaltrialsregister.eu) - P2 | N=220 | Sponsor: Novartis Pharma AG

Combination therapy • New P2 trial • Infectious Disease • Malaria • Pediatrics

Plasmodium SEY1 is a novel druggable target that contributes to imidazolopiperazine mechanism of action. (PubMed, Res Sq) - "The precise mode of action of ganaplacide (KAF156), a phase III antimalarial candidate, remains elusive...We also confirm that SEY1 is an essential gene in P. falciparum . These data suggest that SEY1 may contribute to the mechanism of action of imidazolopiperazines and is a new and attractive druggable target."

Journal • Infectious Disease

Pharmacokinetics of Ganaplacide and Lumefantrine in Adults, Adolescents, and Children with Plasmodium falciparum Malaria Treated with Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Analysis of Data from a Multinational Phase 2 Study. (PubMed, J Clin Pharmacol) - P2 | "Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (Cmax and AUC0-24 h) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions."

Journal • P2 data • PK/PD data • Infectious Disease • Malaria

Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2 | N=296 | Completed | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Completed

Combination therapy • Trial completion • Infectious Disease • Malaria • Pediatrics

In vitro evaluation of ganaplacide/lumefantrine combination against Plasmodium falciparum in a context of artemisinin resistance. (PubMed, J Antimicrob Chemother) - "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."

Journal • Preclinical • Infectious Disease • Malaria • ABCB1

Ex vivo susceptibilities to ganaplacide and diversity in potential resistance mediators in Ugandan Plasmodium falciparum isolates. (PubMed, Antimicrob Agents Chemother) - "Overall, Ugandan P. falciparum isolates were mostly highly susceptible to ganaplacide. Known resistance mediators were polymorphic, but mutations previously selected with in vitro drug pressure were not seen, and mutations identified in the Ugandan isolates were generally not associated with decreased ganaplacide susceptibility."

Journal • Preclinical • Infectious Disease • Malaria

Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention. (PubMed, bioRxiv) - "Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156."

Journal • Infectious Disease • Malaria

Imidazolopiperazine (IPZ)-Induced Differential Transcriptomic Responses on Plasmodium falciparum Wild-Type and IPZ-Resistant Mutant Parasites. (PubMed, Genes (Basel)) - "Imidazolopiperazine (IPZ), KAF156, a close analogue of GNF179, is a promising antimalarial candidate...Thus, in wild-type parasites only, GNF179 treatment affected enzymes leading lipid metabolism, transport, and synthesis. Lastly, our data revealed that IPZs did not perturb known IPZ resistance genes markers pfcarl, pfact, and pfugt regulations, which are all instead possibly involved in the drug resistance that disturb membrane transport targeted by IPZ."

Journal • Infectious Disease • Malaria • Metabolic Disorders

Susceptibility of Plasmodium falciparum isolates from eastern Uganda to ganaplacide and phosphatidylinositol 4-kinase inhibitors (ASTMH 2023) - "Median IC 50 s for two lead Pf PI4K inhibitors, MMV048 and UCT943, were 65 and 11 n M, respectively. No mutations were observed in Pf ACT or Pf UGT. Overall, Ugandan P. falciparum isolates were highly susceptible to these compounds under development as next-generation antimalarials, consistent with a lack of pre-existing or novel resistance-conferring mutations in circulating Ugandan parasites."

Infectious Disease

Transcriptomic Approach Towards Understanding the Molecular Mechanisms of Imidazolopiperazine (IPZ) in the Malaria Parasite Plasmodium falciparum (ASTMH 2023) - "Imidazolopiperazine (IPZ), KAF156, a close analogue of GNF179 is a promising antimalarial candidate...Finally, our data report that genes involved lipid metabolism are associated to IPZs resistance.These transcriptomic data constitute a great advance to identify the mechanism of action and resistance of IPZs. It's essential to perform q PCR to validate level of the differentially expressed genes in this study and perform antibody experiments to target key genes which have been validated by q PCR"

CNS Disorders • Infectious Disease • Malaria • Metabolic Disorders • Psychiatry • Schizophrenia

Transcriptomic Approach Towards Understanding the Molecular Mechanisms of Imidazolopiperazine (IPZ) in the Malaria Parasite Plasmodium falciparum (ASTMH 2023) - "Imidazolopiperazine (IPZ), KAF156, a close analogue of GNF179 is a promising antimalarial candidate...Finally, our data report that genes involved lipid metabolism are associated to IPZs resistance.These transcriptomic data constitute a great advance to identify the mechanism of action and resistance of IPZs. It's essential to perform q PCR to validate level of the differentially expressed genes in this study and perform antibody experiments to target key genes which have been validated by q PCR"

CNS Disorders • Infectious Disease • Malaria • Metabolic Disorders • Psychiatry • Schizophrenia

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 Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2 | N=295 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2023 ➔ Jun 2024 | Trial primary completion date: Sep 2023 ➔ May 2024

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