Causal chemoprophylactic activity of cabamiquine against Plasmodium falciparum in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands

Plas, Johan L. van der; Kuiper, Vincent P; Bagchus, Wilhelmina; Bödding, Matthias; Yalkinoglu, Özkan; Tappert, Aliona; Seitzinger, Andrea; Spangenberg, Thomas; Bezuidenhout, Deon; Wilkins, Justin; Oeuvray, Claude; Dhingra, Satish K.; Thathy, Vandana; Fidock, David A.; Smidt, Lisanne C A; Roozen, Geert V.T.; Koopman, J.; Lamers, Olivia A. C.; Sijtsma, Jeroen; Schuijlenburg, Roos van; Wessels, Els; Meij, Pauline; Kamerling, Ingrid M C; Roestenberg, Meta; Khandelwal, Akash

doi:10.1016/s1473-3099(23)00212-8

Cited by 13 publications

(5 citation statements)

References 23 publications

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“…31 Ideally, this monitoring against any infection endpoints would be supported through human challenge studies of drug activity against both blood-stage and liver-stage parasites, such as for the recently completed trial for cabamiquine. 32 Natural infection phase 2 studies with highly sensitive PCR endpoints can also be used. Published pharmacokinetic and pharmacodynamic evidence from clinical trials is available for some combination SMC candidates, such as for atovaquone–proguanil plus amodiaquine.…”

Section: Discussionmentioning

confidence: 99%

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

Braunack-Mayer,

Malinga,

Masserey

et al. 2024

The Lancet Global Health

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Section: Discussionmentioning

confidence: 99%

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

Braunack-Mayer,

Malinga,

Masserey

et al. 2024

The Lancet Global Health

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“…31 Ideally this would be supported through human challenge studies of drug activity against both blood and liver stage parasites, such as for the recently completed trial for cabamiquine. 32 Natural infection phase two studies with highly sensitive PCR endpoints can also be used. Published PK/PD evidence from clinical trials is available for some combination SMC candidates, such as for ATV-PG with AQ.…”

Section: Discussionmentioning

confidence: 99%

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

Braunack-Mayer,

Malinga,

Masserey

et al. 2023

Preprint

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BackgroundSeasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to highPlasmodium falciparumtransmission and currently depends on administration of sulfadoxine-pyrimethamine with amodiaquine. However, poor regimenadherence and the increasedfrequencyof sulfadoxine-pyrimethamine resistant parasite mutations may threaten SMC’s effectiveness. We need guidance to de-risk the development of drug compounds for malaria prevention.MethodsWe combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic/pharmacodynamic models. We modelled SMC drug attributes for several possible modes-of-action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions.FindingsModel predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When four SMC cycles are deployed to children under five years with high levels of coverage (69% of children receiving all cycles), drug candidates require a duration of protection half-life of >23 days (elimination half-life >10 days) to achieve >75% clinical incidence and severe disease reductions (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is critical to achieve these targets, requiring >60% of children received all SMC cycles and >90% of children at least one cycle regardless of the drug’s duration.InterpretationWhile efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determiningcycle timing. Explicitlydesigning or selectingdrug properties to increase communityuptake is paramount.FundingBill & Melinda Gates Foundation and the Swiss National Science Foundation.

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“…Recently, several compounds were identified with the ability to selectively target parts of the Plasmodium cytoplasmic translation machinery, including diverse aminoacyl-tRNA synthetase enzymes (reviewed in references 3, 4) and eukaryotic elongation factor 2 (eEF2) (5), most of which display multistage antiplasmodial activity. The eEF2 inhibitor, DDD107498 (also known as M-5717 and currently developed as cabamiquine), has successfully completed phase I trials, with demonstrated efficacy against both liver stage and blood stage Plasmodium falciparum infections in human volunteers (6,7). The promise of compounds targeting Plasmodium protein synthesis has led to increased efforts to identify additional novel compounds and rational drug targets in the Plasmodium cytoplasmic translation apparatus (3,4,8,9,10,11).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of translation inhibitors onPlasmodium bergheiliver stage parasites

McLellan,

Hanson

2024

Life Sci. Alliance

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Increasing numbers of antimalarial compounds are being identified that converge mechanistically at inhibition of cytoplasmic translation, regardless of the molecular target or mechanism. A deeper understanding of how their effectiveness as liver stage translation inhibitors relates to their chemoprotective potential could prove useful. Here, we probed that relationship using thePlasmodium berghei–HepG2 liver stage infection model. After determining translation inhibition EC50s for five compounds, we tested them at equivalent effective concentrations to compare the parasite response to, and recovery from, a brief period of translation inhibition in early schizogony, followed by parasites to 120 h post-infection to assess antiplasmodial effects of the treatment. We show compound-specific heterogeneity in single parasite and population responses to translation inhibitor treatment, with no single metric strongly correlated to the release of hepatic merozoites for all compounds. We also demonstrate that DDD107498 is capable of exerting antiplasmodial effects on translationally arrested liver stage parasites and uncover unexpected growth dynamics during the liver stage. Our results demonstrate that translation inhibition efficacy does not determine antiplasmodial efficacy for these compounds.

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Causal chemoprophylactic activity of cabamiquine against Plasmodium falciparum in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands

Cited by 13 publications

References 23 publications

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

Differential effects of translation inhibitors onPlasmodium bergheiliver stage parasites

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