The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance.

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

Safety biomarkers for development of vaccines and biologics: Report from the safety biomarkers symposium held on November 28-29, 2017, Marcy l'Etoile, France.

Vaccines prevent infectious diseases, but vaccination is not without risk and adverse events are reported although they are more commonly reported for biologicals than for vaccines. Vaccines and biologicals must undergo vigorous assessment before and after licensure to minimise safety concerns. Potential safety concerns should be identified as early as possible during the development for vaccines and biologicals to minimize investment risk. State-of-the art tools and methods to identify safety concerns and biomarkers that are predictive of clinical outcomes are indispensable. For vaccines and adjuvant formulations, systems biology approaches, supported by single-cell microfluidics applied to translational studies between preclinical and clinical studies, could improve reactogenicity and safety predictions. Next-generation animal models for clinical assessment of injection-site reactions with greater relevance for target human population and criteria to define the level of acceptability of local reactogenicity at vaccine injection sites in pre-clinical animal species should be assessed. Advanced in silico machine-learning-based analytics, species-specific cell or tissue expression, receptor occupancy and kinetics and cell-based assays for functional activity are needed to improve pre-clinical safety assessment of biologicals. The in vitro MIMIC® system could be used to compliment preclinical and clinical studies for assessing immune-toxicity, immunogenicity, immuno-inflammatory and mode of action of biologicals and vaccines. Sanofi Pasteur brought together leading experts in this field to review the state-of-the-art at a unique 'Safety Biomarkers Symposium' on 28-29 November 2017. Here we summarise the proceedings of this symposium. This unique scientific meeting confirmed the importance for institutions and industrial organizations to collaborate to develop tools and methods needed for predicting reactogenicity and immune-inflammatory reactions to vaccines and biologicals, and to develop more accuracy, reliability safety biomarkers, to inform decisions on the attrition or advancement of vaccines and biologicals.

Oversulfated chondroitin sulfate and OSCS-contaminated heparin cause dose- and route-dependent hemodynamic effects in the rat.

During 2007-2008, serious adverse events were reported following iv administration of certain batches of commercially available heparin in humans. Anaphylactoid reactions with acute hypotension were the hallmark of these cases. Subsequently, it was shown that a contaminant, oversulfated chondroitin sulfate (OSCS), was responsible for these adverse events. The present study was undertaken to further elucidate the risks related to OSCS-contaminated heparin preparations. Using an anesthetized rat hemodynamic model, marked diastolic blood pressure drops were induced with a single iv injection of a contaminated heparin (1000 IU/kg; 34% wt/wt OSCS). OSCS alone (0.8 and 20 mg/kg) or in combination (0.8-1.7 mg/kg) with uncontaminated heparin produced a similar hypotensive effect, whereas heparin spiked with 0.2 or 0.4 mg/kg OSCS produced no hemodynamic changes. In conscious rats, acute hypotensive effects were seen following single iv administration of OSCS-spiked heparin (1.7 or 3.0 mg/kg). Conversely, no hemodynamic effects were observed with same doses when administered sc. Pretreatment with a bradykinin-2 receptor antagonist (HOE140) fully abolished the hypotensive response after iv OSCS (1.7 mg/kg) administration, whereas pretreatment with the histamine (H1) receptor antagonist cetirizine did not. In vitro, OSCS (25 and 250 µg/ml) induced a robust, dose-related increase in kallikrein activity in rat and human plasma with a lower amplitude of response in dog and pig. The data suggest that the adverse events associated with OSCS-contaminated heparin are dependent upon the concentration of contaminant and its route of administration. Furthermore, the kallikrein-kinin system plays a pivotal role in the initiation of OSCS-related vascular effects.

The isolated rabbit heart and Purkinje fibers as models for identifying proarrhythmic liability.

INTRODUCTION: Delayed ventricular repolarization is associated with rare, but often fatal, polymorphic tachyarrhythmias named Torsades de Pointes. ICH S7B guideline recommends an integrated approach for cardiovascular preclinical evaluation of new drug candidates, including action potential assays (as a Purkinje fiber test) but also proarrhythmia models. The aim of this preliminary study was to compare the respective value of two preclinical in vitro rabbit cardiac preparations-the Purkinje fiber and the isolated perfused heart (Langendorff method)-based on effects of dofetilide, a selective IKr inhibitor. METHODS: Transmembrane action potentials from rabbit Purkinje fibers were recorded using a conventional intracellular glass microelectrode. Electrocardiograms from rabbit isolated hearts were evaluated for QRS, QT and T wave durations (Tpeak-Tend). The pacing protocol was the same for both preparations (basal rate of 80 bpm and pacing of 40, 60 and 140 bpm). Dofetilide was tested in both systems at concentrations of 1, 3 and 10 nmol/L. RESULTS: In Purkinje fibers dofetilide induced a concentration- and reverse use-dependent increase in action potential durations measured at 50 and 90% of repolarization. At 10 nmol/L, only 3/10 fibers showed early after depolarizations. In the isolated heart model, dofetilide also induced a similar concentration- and reverse use-dependent increase in QT-interval. From 3 nmol/L, major changes in T wave morphology, R-on-T extrasystoles and TdP were observed, mainly at low rate. Prior to arrhythmias, T wave shape and duration were markedly altered suggesting an increase in the heterogeneity of cardiac ventricular repolarization. CONCLUSIONS: The effects of dofetilide were comparable in the two models for delayed repolarization but the isolated heart appears to be a better predictor for arrhythmias and a unique in vitro model to assess arrhythmogenic potential of QT prolonging compounds at least when associated with IKr/hERG inhibition.