MMV390048 / Medicines for Malaria Venture - LARVOL DELTA

The ATM Kinase Inhibitor AZD0156 is a Potent Inhibitor of Plasmodium Phosphatidylinositol 4-Kinase (PI4Kβ) and is an Attractive Candidate for Medicinal Chemistry Optimisation Ag…. (PubMed, Angew Chem Int Ed Engl) - "Importantly, a cleaner biochemical profile was measured against human kinases (MAP4K4, MINK1) implicated in embryofoetal developmental toxicity associated with the PfPI4Kβ inhibitor MMV390048. This improved kinase selectivity profile and structural differentiation from other PI4Kβ inhibitors, together with its multistage antiplasmodial activity and favourable pharmacokinetic properties, makes AZD0156 an attractive candidate for target-based drug repositioning against malaria via a medicinal chemistry optimisation approach."

Journal • Ataxia • Immunology • Infectious Disease • Malaria • Movement Disorders • Oncology • Primary Immunodeficiency

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

2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy. (PubMed, J Med Chem) - "These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048...It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria."

Journal • Preclinical • 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

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

Developing kinase inhibitors for malaria: an opportunity or liability? (PubMed, Trends Parasitol) - "The phosphatidylinositol 4-kinase beta inhibitor MMV390048 showed good efficacy in Phase 2a clinical trials, demonstrating the potential of kinase inhibitors for malaria treatment. Here we argue that the potential benefits of Plasmodium kinase inhibitors outweigh the risks, and we highlight the opportunity for designed polypharmacology to reduce the risk of resistance."

Journal • Review • Infectious Disease • Malaria • Oncology

Recent developments in antimalarial drug discovery. (PubMed, Bioorg Med Chem) - "Methods to fight malaria are being diversified, including the use of mosquito nets, the target candidate profiles (TCPs) and target product profiles (TPPs) of medicine for malarial venture (MMV) strategy, the search for newer and potent drugs that could reverse chloroquine resistance, and the use of adjuvants such as rosiglitazone and sevuparin. Although these adjuvants have no antiplasmodial activity, they can help to alleviate the effects which result from plasmodium invasion such as cytoadherence. The list of new antimalarial drugs under development is long, including the out of ordinary new drugs MMV048, CDRI-97/78 and INE963 from South Africa, India and Novartis, respectively."

Journal • Review • Infectious Disease • Malaria

Efficacy, Safety, Tolerability, and Pharmacokinetics of MMV390048 in Acute Uncomplicated Malaria. (PubMed, Am J Trop Med Hyg) - "Mild adverse events, mainly headache and gastrointestinal symptoms, were reported by eight patients. Single-dose MMV390048 (120 mg) rapidly cleared asexual parasites and gametocytes in patients with P. vivax malaria and was well tolerated."

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

Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts. (PubMed, Front Cell Infect Microbiol) - "Meanwhile, an atovaquone (ATO) resistant parasite line was isolated from the group treated with ATO plus azithromycin. Likewise, MMV390048 showed potent inhibition against ATO-resistant parasites. These results provide evidence of PI4K as a viable drug target for the radical cure of babesiosis, which will contribute to designing new compounds that can eradicate parasites."

Journal • Infectious Disease

Susceptibility of Plasmodium falciparum isolates from eastern Uganda to antimalarial compounds under development (ASTMH 2022) - "In general, field isolates were highly susceptible, with median IC50s in the low nM range for compounds targeting PfCYTb (ELQ300, 13 nM); PfDHODH (DSM265, 3.6 nM; DSM421, 20 nM; DSM632, 9.8 nM; DSM705, 11 nM; DSM1049, 22 nM; BRD1331 13 nM), PfEF2 (DDD498, 0.6 nM); PfPheRS (BRD5018, 1.6 nM); and PfPI4K (MMV048, 60 nM; UCT943, 11 nM). Three mutations (N957H, I876V and Y883H) in PfPI4K were associated with slightly decreased susceptibility to MMV048 (median IC50 WT vs mutant: 55 nM vs 74 nM for N957H, 61 nM vs 75 nM for I876V, and 60 nM vs 77 nM for Y883H). Overall, Ugandan P. falciparum isolates were highly susceptible to 11 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 • Malaria

Mass spectrometry identification of biomarkers in extracellular vesicles from Plasmodium vivax liver hypnozoite infections. (PubMed, Mol Cell Proteomics) - "We used P. vivax infected human liver-chimeric (huHep) FRG KO mice treated with the schizonticidal experimental drug MMV048 as hypnozoite infection model...Only one protein fulfilled this stringent top-down selection, a putative filamin domain-containing protein. This study sets the stage to unveil biological features of human liver infections and identify biomarkers of hypnozoite infection associated with extracellular vesicles."

Biomarker • Journal • CNS Disorders • Hepatology • Immunology • Infectious Disease • Inflammation • Malaria • Psychiatry • Schizophrenia

Efficacy of the Antimalarial MMV390048 against Babesia Infection Reveals Phosphatidylinositol 4-Kinase as a Druggable Target for Babesiosis. (PubMed, Antimicrob Agents Chemother) - "At 52 DPI, a parasite relapse (in 1 out of 5 mice) and a mutation in the B. microti PI4K L746S, a MMV390048 resistance-related gene, were detected. Although the radical cure of B. microti infection in immunocompromised host SCID mice was not achieved, results from this study showed that MMV390048 has excellent inhibitory effects on Babesia parasites, revealing a new treatment strategy for babesiosis: targeting the B. microti PI4K."

Journal • Genetic Disorders • Immunology • Infectious Disease • Primary Immunodeficiency

Malarial PI4K inhibitor induced diaphragmatic hernias in rat: Potential link with mammalian kinase inhibition. (PubMed, Birth Defects Res) - "Deciphering if the EFD effects are dependent on PI4K inhibition, and/or via inhibition of other off-target kinases will require the generation of novel, more potent, and more specific PI4K inhibitors."

Journal • Preclinical • Cardiovascular • CNS Disorders • Gastroenterology • Infectious Disease • Malaria • Psychiatry • Schizophrenia • PIK3CG

Research progress of phosphatidylinositol 4-kinase and its inhibitors in inflammatory diseases. (PubMed, Eur J Pharmacol) - "PI4K-related inhibitors have been found to have the effects of inhibiting virus replication, anti-cancer, treating malaria and reducing rejection in organ transplants, among which MMV390048, an anti-malaria drug, has entered phase II clinical trial. This review discusses the classification, structure, distribution and related inhibitors of PI4K and their role in the progression of cancers, viral replication, and other inflammation induced diseases to explore their potential as therapeutic targets."

Journal • Review • Immunology • Infectious Disease • Inflammation • Malaria • Oncology • Transplantation

Application of Vinamidinium Salt Chemistry for a Palladium Free Synthesis of Anti-Malarial MMV048: A "Bottom-Up" Approach. (PubMed, Org Lett) - "MMV390048 (1) is a clinical compound under investigation for antimalarial activity. A new synthetic route was developed which couples two aromatic fragments while forming the central pyridine ring over two steps. This sequence takes advantage of raw materials used in the existing etoricoxib supply chain and eliminates the need for palladium catalysts, which were projected to be major cost-drivers."

Journal • Infectious Disease

Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance. (PubMed, Antimicrob Agents Chemother) - "When comparing the three infection experiments, we identified different relationships of parasite clearance with dose, and different maximum parasite clearance rates: in P. berghei-NMRI mouse infections we estimated a maximum parasite clearance rate of 0.2 [1/h]; in P. falciparum-SCID mouse infections 0.05 [1/h]; while in human volunteer infection studies with P. falciparum, we found a maximum parasite clearance rate of 0.12 [1/h] and 0.18 [1/h] after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-parasite driven processes account for up to 25% of variance in parasite clearance for medium-high doses of antimalarials. Although there are limitations in translating parasite clearance rates across these experiments, they provide insight into characterising key parameters of drug action and dose response, and assist in decision-making regarding dosage for further drug development."

Journal • Infectious Disease • Malaria

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments. (PubMed, Molecules) - "One of these, MMV390048, is a plasmodial kinase inhibitor...This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored."

Journal • Review • Infectious Disease • Malaria

MMV390048 POC in Patients With P. Vivax and P. Falciparum Malaria (clinicaltrials.gov) - P2; N=8; Terminated; Sponsor: Medicines for Malaria Venture; N=102 ➔ 8; Suspended ➔ Terminated; Due to a Medicines for Malaria Venture (MMV) strategic business decision

Clinical • Enrollment change • Trial termination • Infectious Disease • Malaria

Exploring the Anti-Plasmodial 2-Aminopyridines as Potential Anti-Trypanosomal Agents. (PubMed, ChemMedChem) - "This compound had previously been identified as a potent and selective antiplasmodial agent, where a focused optimization campaign, resulted in a medium-sized library of compounds, with favorable drug-like properties, one of which (MMV048, 2, 5-(4-(methylsulfonyl)phenyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-2-amine) is currently undergoing clinical trials for malaria...Our study has identified several structural features important for anti-trypanosomal activity, which are distinct from those required for anti-plasmodial activity. Results from this study can be exploited to develop potent anti-trypanosomal agents."

Journal • Infectious Disease • Malaria

The development process for discovery and clinical advancement of modern antimalarials. (PubMed, J Med Chem) - "In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. 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."

Clinical • Journal • Infectious Disease • Malaria • Ophthalmology

MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants (clinicaltrials.gov) - P1; N=6; Terminated; Sponsor: Medicines for Malaria Venture; Completed ➔ Terminated; Inconsistent and unpredictable exposures were observed. Drug needed to be reformulated.

Clinical • Trial termination • Infectious Disease • Malaria

MMV390048 POC in Patients With P. Vivax and P. Falciparum Malaria (clinicaltrials.gov) - P2; N=102; Suspended; Sponsor: Medicines for Malaria Venture; Trial completion date: Dec 2020 ➔ Jun 2021; Trial primary completion date: May 2020 ➔ May 2021

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

A phase 1, placebo controlled, randomised, single ascending dose study and a volunteer infection study to characterize the safety, pharmacokinetics and antimalarial activity of the Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048. (PubMed, Clin Infect Dis) - "The safety, pharmacokinetics, and pharmacodynamics of MMV390048 support its further development as a partner drug of a single-dose combination therapy for malaria."

Clinical • Journal • P1 data • PK/PD data

Safety, tolerability, pharmacokinetics and antimalarial activity of the novel Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048 in healthy volunteers. (PubMed, Antimicrob Agents Chemother) - "Overall, the results of this study suggest that MMV390048 is well tolerated in humans and the pharmacokinetic properties of the compound indicate that it has the potential to be used for antimalarial prophylaxis or inclusion in a single-dose cure. MMV390048 is currently being tested in a phase 2a study in Ethiopian adults with acute, uncomplicated falciparum or vivax malaria mono-infection."

Clinical • Journal • PK/PD data

Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination. (PubMed, F1000Res) - "...This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine...Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination."

Journal • Review