ZY-19489 / Zydus Lifesci - 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

A novel mutation in Plasmodium falciparumchloroquine resistance transporter mediates in vitro resistance to the antimalarial candidate drug ZY19489 (ASTMH 2024) - "One such molecule is ZY19489, a fast-killing triaminopyrimidine presently in Phase 2 trials in combination with ferroquine...Studies with purified PfCRT reconstituted in proteoliposomes provided evidence that ZY19489 can impede mutant PfCRT-mediated efflux of tritiated chloroquine, CQ, from the digestive vacuole, DV, in CQ-resistant lines, suggesting that ZY19489 can compete with CQ for mutant PfCRT-mediated drug transport. Notably, 72-hour parasite survival assays showed significant sensitization of Dd2 Dd2 N246H parasites to DV-acting drugs including CQ, piperaquine and desethylamodiaquine but not lumefantrine or atovaquone...This was confirmed by metabolomics, which revealed a reduction in levels of Hb-derived short peptides in ZY19489-treated parasites. These data strongly implicate inhibition of Hb degradation and a novel mutation in PfCRT as central to ZY19489 action and resistance."

Late-breaking abstract • Preclinical • Infectious Disease

A Study to Determine Safety, Tolerability, and Pharmacokinetics of Different Orally Administered Regimens of the Combination ZY19489-Ferroquine in Adult Asymptomatic Plasmodium Falciparum Carriers (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Zydus Lifesciences Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Malaria

Exploring antimalarial potential: Conjugating organometallic moieties with organic fragments for enhanced efficacy. (PubMed, Bioorg Chem) - "The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases."

Journal • Review • Infectious Disease • Malaria

A pH Fingerprint Assay to Identify Inhibitors of Multiple Validated and Potential Antimalarial Drug Targets. (PubMed, ACS Infect Dis) - "Here, we designed a "pH fingerprint" assay that robustly identifies PfATP4 inhibitors while simultaneously allowing the detection of (and discrimination between) inhibitors of the lactate:H+ transporter PfFNT, which is a validated antimalarial drug target, and the V-type H+ ATPase, which was suggested as a possible target of the clinical candidate ZY19489...The pH fingerprint assay also has the potential to identify protonophores, inhibitors of the acid-loading Cl- transporter(s) (for which the molecular identity(ies) remain elusive), and compounds that act through inhibition of either the glucose transporter PfHT or glycolysis. The pH fingerprint assay therefore provides an efficient starting point to match a proportion of antiplasmodial compounds with their mechanisms of action."

Journal • Infectious Disease • Malaria

A Study to Determine Safety, Tolerability, and Pharmacokinetics of Different Orally Administered Regimens of the Combination ZY19489-Ferroquine in Adult Asymptomatic Plasmodium Falciparum Carriers (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: Zydus Lifesciences Limited | Trial completion date: May 2024 ➔ May 2025 | Initiation date: Jul 2023 ➔ Apr 2024 | Trial primary completion date: Feb 2024 ➔ Feb 2025

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

Insights into the Mode of Action and a Novel Mutant PfCRT-Mediated Mechanism of Resistance to the Antimalarial Clinical Candidate ZY-19489 (ASTMH 2023) - "One such molecule is ZY-19489, a fast-killing triaminopyrimidine currently in Phase II trial in combination with ferroquine (FQ)...This study aimed to leverage in vitro selection and whole genome analysis (IVSWGA), quantitative trait loci (QTL) analysis, stage-specificity experiments and transport studies using P. falciparum lines expressing wildtype (Dd2 Dd2 ) or mutant P. falciparum chloroquine resistance transporter (pfcrt) alleles to characterize the mechanisms of resistance to ZY-19489...No change in susceptibility was observed for lumefantrine or atovaquone...Stage-specificity tests showed that ZY-19489 is most potent against schizonts and rings, the latter recently shown to be the initial assembly stage of the parasite's Hb processing machinery. These data implicate Pf CRT N246H mutation in mediating ZY-19489 resistance."

Clinical • CNS Disorders • Infectious Disease • Psychiatry • Schizophrenia

A Study to Determine Safety, Tolerability, and Pharmacokinetics of Different Orally Administered Regimens of the Combination ZY19489-Ferroquine in Adult Asymptomatic Plasmodium Falciparum Carriers (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: Zydus Lifesciences Limited

New P1 trial • Infectious Disease • Malaria

A Study Of Zy-19489 Administered Via Oral Route To Investigate The Safety, Tolerability And Pharmacokinetics In Healthy Adult Human Subjects (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Cadila Healthcare Limited | Recruiting ➔ Completed | Trial completion date: May 2022 ➔ Jan 2022

Trial completion • Trial completion date • Infectious Disease • Malaria

Effect of novel antimalarial ZY-19489 on Plasmodium falciparum viability in a volunteer infection study. (PubMed, Lancet Infect Dis) - No abstract available

Journal • Infectious Disease

Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study. (PubMed, Lancet Infect Dis) - "The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy."

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

A Study Of Zy-19489 Administered Via Oral Route To Investigate The Safety, Tolerability And Pharmacokinetics In Healthy Adult Human Subjects (clinicaltrials.gov) - P1; N=32; Recruiting; Sponsor: Cadila Healthcare Limited

New P1 trial • Infectious Disease • Malaria

Simultaneous estimation of ZY-19489 and its active metabolite ZY-20486 in human plasma using LC-MS/MS, a novel antimalarial compound. (PubMed, Bioanalysis) - "Assay was reproducible, selective and devoid of matrix effect. The validated assay was implemented for clinical sample analysis derived from healthy human subjects and parasitemia-induced subjects."

Journal • Infectious Disease