cipargamin (KAE609) / Novartis - LARVOL DELTA

PLATINUM: Platform Study to Evaluate the Efficacy and Safety of Anti-malarial Agents in Participants With Uncomplicated Plasmodium Falciparum Malaria (Cohort C2) (clinicaltrials.gov) - P2 | N=120 | Recruiting | Sponsor: Novartis Pharmaceuticals

Monotherapy • New P2 trial • Infectious Disease • Malaria

PLATINUM: Platform Study to Evaluate the Efficacy and Safety of Anti-malarial Agents in Participants With Uncomplicated Plasmodium Falciparum Malaria (Cohort B1) (clinicaltrials.gov) - P2 | N=95 | Completed | Sponsor: Novartis Pharmaceuticals

Monotherapy • New P2 trial • Infectious Disease • Malaria

Targeting Biofilm Formation in Acinetobacter baumannii: In Silico Discovery of Novel Candidate Inhibitors for Acyl-Homoserine Lactone Synthase. (PubMed, Curr Drug Discov Technol) - "These findings suggest that Lovastatin may be a promising drug candidate for AHLS targeting the QS pathway of A. baumannii. The results warrant further experimental validation to explore its potential as an anti-bacterial therapeutic agent."

Journal • Infectious Disease

Assessment of the pharmacodynamic properties of antimalarial drugs. (PubMed, Philos Trans R Soc Lond B Biol Sci) - "Drugs acting on younger circulating ring-stage asexual parasites (artemisinins, cipargamin, ganaplacide) provide rapid parasite clearance, which translates into faster clinical recoveries and a life-saving benefit in severe malaria. Greater availability of drug measurement in malaria-endemic areas would facilitate the field assessment of antimalarial drugs. This article is part of the Theo Murphy meeting issue 'Evaluating anti-infective drugs'."

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

Impacts of Cipargamin on Na+-ATPase and Osmoregulation of Trypanosoma cruzi. (PubMed, Membranes (Basel)) - "ENA-type ATPases (P-type ATPase IID) and ATP-type ATPase do not have structural homologs in mammals, appearing only in plants, fungi, and protozoan parasites, such as Trypanosoma cruzi, Leishmania sp., T. gondii, and P. falciparum. Therefore, this exclusivity points to Na+-ATPases as promising targets for medical projects aiming at new treatments contributing to the academic community."

Journal

Validation of solvent proteome profiling for antimalarial drug target deconvolution. (PubMed, Int J Parasitol Drugs Drug Resist) - "Here, we successfully generated solvent denaturation curves for the P. falciparum proteome, and demonstrated the utility of SPP with five antimalarial compounds: pyrimethamine, atovaquone, cipargamin, MMV1557817 and OSM-S-106. This alternative method simplifies the experimental workflow and includes positive controls to affirm the performance of the experiment. Overall, this study demonstrates that SPP can be successfully applied in both lysate and live-cell treatment conditions to elucidate drug targets in P. falciparum, as well as providing additional information regarding the mechanisms of drug action, offering insights for the optimisation of existing antimalarials and the development of novel therapies."

Journal • Infectious Disease • Malaria • DHFR • TYMS

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

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

Identification of α-Azacyclic Acetamide-Based Inhibitors of P. falciparum Na+ Pump (PfATP4) with Fast-Killing Asexual Blood-Stage Antimalarial Activity by Phenotypic Screening. (PubMed, ACS Infect Dis) - "Resistance selections on P. falciparum parasites with two α-azacyclic acetamide analogs identified mutations in PfATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming PfATP4 as the target. PfATP4 is a well-established antimalarial target, and identification of additional PfATP4 inhibitors provides alternative avenues to disrupt its function."

Journal • Infectious Disease • Malaria

Efficacy and mechanism of action of cipargamin as an antibabesial drug candidate. (PubMed, Elife) - "Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC50 values. Combining CIP with TQ effectively eliminated B. microti infection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance."

Journal • Infectious Disease

Malaria: past, present, and future. (PubMed, Signal Transduct Target Ther) - "The FDA-approved regimens like Artemether-Lumefantrine, Atovaquone-Proguanil, and Primaquine are discussed, and their benefits and limitations are highlighted, especially in terms of drug resistance. Perspectives in the development of novel vaccines and new drugs, such as Sevuparin, Imatinib, and Cipargamin, and combination therapies with promise in overcoming resistance has been proposed. Overall, this review provides a detailed summary of the latest progress in malaria research and emphasizes the need for continuous monitoring and innovation in malaria treatment."

Journal • Review • Infectious Disease • Malaria

Revisiting Plasmodium falciparum P-type ATPase 4 in malarial: ADMET, mutation effect, and molecular simulation studies of potential inhibitors. (PubMed, J Biomol Struct Dyn) - "Pharmacokinetic analyses revealed that Concanamycin A, Maduramicin, and GNF-Pf4492 exhibit low gastrointestinal absorption, while Brefeldin A, MMV396719, MMV006239, and Cipargamin can cross the blood-brain barrier...In conclusion, (+)-SJ733 and MMV665878 demonstrate strong potential as PfATP4 inhibitors, with different interaction profiles. Further in vivo and pharmacometric studies are required to validate their efficacy and determine optimal dosing strategies for malaria treatment."

Journal • Infectious Disease • Malaria

Identification of α-azacyclic acetamide-based inhibitors of P. falciparum Na + pump ( Pf ATP4) with fast-killing asexual blood-stage antimalarial activity by phenotypic screening. (PubMed, bioRxiv) - "Resistance selections on P. falciparum parasites with two α-azacyclic acetamide analogs identified mutations in Pf ATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming Pf ATP4 as the target. Pf ATP4 is a well-established antimalarial target, and identification of additional Pf ATP4 inhibitors provides alternative avenues to disrupt its function."

Journal • Infectious Disease • Malaria

Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4. (PubMed, J Med Chem) - "Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na+-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in aPlasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy."

Journal • Infectious Disease

Nickel-Catalyzed Asymmetric Homobenzylic Hydroamidation of Aryl Alkenes to Access Chiral β-Arylamides. (PubMed, J Am Chem Soc) - "The reaction exhibits a high functional group tolerance and utilizes readily available starting materials of vinylarenes to react with dioxazolone as a robust amidating source. Notably, this approach was successfully applied to the synthesis of pharmaceutical compounds and natural products, such as Clobenzorex, Direx, Selegiline, Sacubitril, and Cipargamin."

Journal

Deciphering antimalaria drugs’ modes of action by Protein Thermal Profiling (PTP). (ASTMH 2024) - "We validated the CETSA approach by identifying several well-established antimalaria targets, such as PfDHFR for pyrimethamine and, most recently, subunits of bc1-complex for atovaquone or PfATP4 for cipargamin using the recently optimized detergent-assisted (DA) CETSA, which can detect drug interactions with the membrane-associated protein targets. Here, we show the utility of the developed CETSA-AlphFold2 pipeline not only for target identification but also for subsequent structure-function-based optimizations of a lead compound using medicinal chemistry. As the key results here, we will present a list of more than a dozen new putative antimalaria drug targets identified by the prediction pipeline that warrant further explorations."

Late-breaking abstract • 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

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

Evaluation of a Bayesian hierarchical pharmacokinetic-pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs. (PubMed, Antimicrob Agents Chemother) - "This simulation study demonstrates the viability of our PK-PD model to predict parasitological outcomes in Phase 2 volunteer infection studies. This work will inform the dose-effect relationship of cipargamin, guiding decisions on dosing regimens to be evaluated in Phase 3 trials."

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

First-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending doses clinical study to assess the safety, tolerability, and pharmacokinetics of cipargamin administered intravenously in healthy adults. (PubMed, Antimicrob Agents Chemother) - P1 | "This first-in-human study assessed safety, tolerability, and pharmacokinetics (PK) of cipargamin (intravenous) in healthy adults. However, these results should be interpreted with caution due to inadequate Fridericia's QT correction. This study is registered with ClinicalTrials.gov as NCT04321252."

Clinical • Journal • P1 data • PK/PD data • Gastrointestinal Disorder • Infectious Disease • Malaria

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

PLATINUM: Platform Study to Evaluate the Efficacy and Safety of Anti-malarial Agents in Patients With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2 | N=327 | Recruiting | Sponsor: Novartis Pharmaceuticals | N=207 ➔ 327 | Trial completion date: Oct 2025 ➔ May 2026

Enrollment change • Trial completion date • Infectious Disease • Malaria

PLATINUM: Platform Study to Evaluate the Efficacy and Safety of Anti-malarial Agents in Patients With Uncomplicated Plasmodium Falciparum Malaria (clinicaltrials.gov) - P2 | N=207 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Monotherapy • Infectious Disease • Malaria

Search for novel Plasmodium falciparum PfATP4 inhibitors from the MMV Pandemic Response Box through a virtual screening approach. (PubMed, J Biomol Struct Dyn) - "Sodium ATPase (PfATP4) of Plasmodium has been recently explored as a suitable target for new antimalarials such as Cipargamin...Our analysis identified new molecules from the PRB library that showed affinity for distinct binding sites including the previously known G358 site, several of which are clinically used anti-bacterial (MMV1634383, MMV1634402), antiviral (MMV010036, MMV394033) or antifungal (MMV1634494) agents. Therefore, this study highlights the possibility of exploiting PRB molecules against Malaria through abrogation of PfATP4 activity.Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease • Malaria