ganaplacide (KAF156) / Novartis - LARVOL DELTA

Eschweilenol C and subfractions from Terminalia plants disrupt haemoglobin metabolism, inhibiting Plasmodium falciparum growth at rings and trophozoite stages. (PubMed, Malar J) - "This study identifies eschweilenol C as a promising candidate for malaria drug discovery efforts and its significance for further exploration in the context of the emergence of artemisinin-resistant parasites in Africa."

Journal • Infectious Disease • Malaria

PLATINUM: Platform Study to Evaluate the Efficacy and Safety of Anti-malarial Agents in Participants With Uncomplicated Plasmodium Falciparum Malaria (Cohort B2) (clinicaltrials.gov) - P2 | N=60 | Completed | Sponsor: Novartis Pharmaceuticals

Monotherapy • New P2 trial • Infectious Disease • Malaria

Prevalence and impact of parasite mutations in pediatric patients in Africa with uncomplicated Plasmodium falciparum malaria in a Phase II clinical evaluation of ganaplacide-lumefantrine (ASTMH 2025) - "Here we report the results from a recently completed phase II trial investigating the efficacy, safety, and tolerability of ganaplacide (KAF156), in combination with Lumefantrine-solid dispersible formulation (SDF) compared to artemether-lumefantrine (Coartem).The study was conducted from 2021 to 2024 in 295 patients aged 6 months to < 18 years diagnosed with uncomplicated Plasmodium falciparum malaria at 10 sites across 5 African countries: Burkina Faso, Côte d'Ivoire, DR Congo, Gabon and Mali. Selection of resistance markers post treatment in recurrent infections will be assessed. Both drug combinations demonstrated high efficacy in this study as previously presented."

Clinical • P2 data • Infectious Disease • Malaria • Pediatrics • ABCB1 • FUBP1

KALUMA - A pivotal Phase III trial to evaluate the efficacy, safety and tolerability of the novel anti-malarial drug ganaplacide-lumefantrine (KLU156) in uncomplicated malaria (ASTMH 2025) - P3 | "Patients were randomized 1:1 to treatment with the fixed-dose combination of ganaplacide-lumefantrine solid dispersion formulation (KLU156), or the artemether-lumefantrine control arm. A summary of results of the core phase of KALUMA will be presented at the ASTMH 2025 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 • P3 data • Infectious Disease • Malaria

An investigation of single dose treatment of uncomplicated malaria using a non-artemisinin triple combination of KLU156 (ganaplacide and lumefantrine) and KAE609 (cipargamin) versus 3 day standard of care with artemether-lumefantrine (ASTMH 2025) - "Final results will be presented at the forthcoming conference. The outcomes from this part of the study should support further investigations in younger patients, down to the age of 2 years."

Hematological Disorders • Infectious Disease • Malaria

149 - Next-generation Antimalarial Drug Resistance: Molecular Approaches, New Determinants, and Implications for the Field (ASTMH 2025) - "A variety of next generation antimalarial medicines (e.g., ganaplacide and cipargamin) are in late-stage clinical development. The speakers will present advances within the field of antimalarial drug discovery, including the characteristics of drug resistance genes and alleles in malaria-endemic regions, the features that distinguish drug resistance alleles from phenotypically silent alleles in resistance genes, and methods for rapid identification of resistance-conferring mutations preceding their appearance in clinical settings. Throughout this session we will discuss promising avenues to accelerate the development of new treatments and debate how to gain additional insights into the mechanisms driving antimalarial drug resistance."

Infectious Disease • Malaria

Results of the KALUMA study: Phase 3 study results of ganaplacide-lumefantrine SDF combination (ASTMH 2025) - No abstract available

P3 data • Infectious Disease • Malaria

197 - Towards the First Non-artemisinin Combinations for falciparum Malaria: Phase 3 Results, Capacity-Building in WANECAM2 and Beyond (ASTMH 2025) - "Creative Format Description The symposium will open with an overview on the clinical trial capacity building within WANECAM2 as exemplified by the Niger trial site, followed by a presentation of the results of the the KAMUMA phase 3 trial of a novel combination therapy, the ganaplacide (KAF156) -lumefantrine (LUM) – SDF (solid dispersion formulation)...The symposium will conclude with a Q&A session. #falciparummalaria #drugresistance #clinicaltrial #capacitybuilding #transmissionblocking""

P3 data • Infectious Disease • Malaria

Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling. (PubMed, J Clin Immunol) - "Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy."

Journal • Aicardi Goutieres Syndrome • Genetic Disorders • Inflammation • Interferonopathies • IFIH1 • IFNA1 • OASL

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