Antimalarial compounds in Phase II clinical development

Held, Jana; Jeyaraj, Sankarganesh; Kreidenweiss, Andrea

doi:10.1517/13543784.2015.1000483

Cited by 45 publications

(24 citation statements)

References 99 publications

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“…In a similar fashion, dichloracetate may be effective at reducing plasma lactate levels [34], however, it seems unlikely to be an effective adjuvant reducing the underlying causes of tissue hypoxia and mortality. Several of the current experimental adjuvant or supporting treatments are aiming at an improvement of the microcirculation in severe malaria, including nitric oxide donors [35, 36], and compounds affecting cytoadhesion and sequestration [15, 37]. Our results suggest that improvement in blood or plasma lactate concentrations over time is an adequate endpoint for trials evaluating these interventions.…”

Section: Discussionmentioning

confidence: 80%

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

et al. 2017

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BackgroundClinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria.MethodsThree datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures.ResultsImprovements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery.ConclusionsThe relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

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Section: Discussionmentioning

confidence: 80%

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

et al. 2017

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“…) . This compound, a pipeline drug molecule known as KAF156 is an imidazolopiperazine and is being clinically developed by a team led by Novartis. This compound displayed high activity against the malaria parasites P. falciparum and P. vivax .…”

Section: Chemical Compounds Effective Against Various Life Stagesmentioning

confidence: 99%

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

Poonam

Gupta

et al. 2018

Medicinal Research Reviews

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Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large-scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.

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“…This blue dye was discovered for antiplasmodial applications in 1891, when its mode of action on the redox equilibrium was not comprehended, and it was used for the treatment of malaria in humans until the launching of the more effective drug chloroquine in the 1950s (65). Methylene blue, which is still the drug of choice in the treatment of methemoglobinemia, has recently regained interest for its antiplasmodial activities (66)(67)(68), especially as a companion drug in combination therapies (69,70) or as a potential transmission-blocking agent (17). Similar to benzylmenadiones, methylene blue seems to exert its antiplasmodial activity by causing a redox imbalance (9,71).…”

Section: Discussionmentioning

confidence: 99%

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Ehrhardt

Deregnaucourt

Goetz

et al. 2016

Antimicrob Agents Chemother

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Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.M alaria remains one of the most severe infectious diseases that disproportionately affects the public health and economic welfare of the world's poorest communities. The causative agents of malaria are protozoan parasites of the genus Plasmodium. Among the five Plasmodium species that can cause malaria in humans (Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi), P. falciparum is the most virulent and is responsible for severe clinical outcomes and most of the deaths associated with malaria. Until the development of an effective vaccine, chemotherapy remains a major frontline strategy for the control and possible future elimination of malaria. The emergence and rapid spread of drug-resistant parasites undermine efforts at reducing the global disease burden and emphasize the need for drugs with novel chemical entities that exploit new molecular targets while overcoming established drug resistance mechanisms. Ideally, such drugs should quickly kill the pathogenic asexual blood stages of P. falciparum and, in addition, be effective against other developmental stages, in particular the sexual stages that transmit the infection from the human to the mosquito host (1, 2).Previously, we presented the chemical design and synthesis of a novel class of compounds, the 3-[substituted-benzyl]-menadiones, that exhibit potent activities against P. falciparum blood stages in vitro and moderate activities in v...

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Antimalarial compounds in Phase II clinical development

Cited by 45 publications

References 99 publications

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

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