A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria

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tuberculosis 1 infectiousdiseases
Lyme disease 3 infectiousdiseases
ivermectin 22 infectiousdiseasesdrugs
malaria 59 infectiousdiseases
primaquine 1 infectiousdiseasesdrugs
pyrimethamine 2 infectiousdiseasesdrugs
scabies 1 infectiousdiseases
sulfadoxine 2 infectiousdiseasesdrugs

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Select Drug Character Offset Drug Term Instance
ivermectin 10188 typically treated by 14–21 days of antibiotic treatment, early administration of an endectocide, ivermectin , could be beneficial in some settings. Studies with fluralaner [[32]] in dogs have shown 100% mortality
ivermectin 10630 fluralaner and afoxalaner to kill mosquito vectors for malaria and dengue [[33]]. In human medicine, ivermectin is used to kill the parasites in patients infected with the mite Sarcoptes scabiei, which results in
ivermectin 12059 on the classical endectocides, although the new TCP-6 covers additional scenarios.The experience of ivermectin use in preventing malaria transmissionOver recent years there has been growing interest in the use of
ivermectin 12172 use in preventing malaria transmissionOver recent years there has been growing interest in the use of ivermectin , as a potential endectocide, for a use in malaria. Several clinical studies have been conducted, [[35],
ivermectin 12538 Profile does depend on the proposed deployment; and this report focused on the use case for high-dose ivermectin as a stand-alone mass drug administration (MDA) regimen. This initial research has suggested that the
ivermectin 13036 Tanzania, where efficacies in cattle lasted over 6 months [[47]]. The alternative approach would be to use ivermectin in combination with other malaria control modalities. In another example from Tanzania, addition of
ivermectin 13147 in combination with other malaria control modalities. In another example from Tanzania, addition of ivermectin to long-lasting, insecticidal-treated bed nets (LLINs) resulted in a near-complete collapse of populations
ivermectin 13363 populations of the malaria vector, Anopheles arabiensis, inside large naturalized mesocosms [[48]]. Combining ivermectin with SMC is another option, where 3 days of ivermectin could be given each month with a full treatment
ivermectin 13419 large naturalized mesocosms [[48]]. Combining ivermectin with SMC is another option, where 3 days of ivermectin could be given each month with a full treatment course of anti-malarials [[49], [50]]. This also underscores
ivermectin 13680 in malaria elimination; the possibility that insects could emerge which are no longer sensitive to ivermectin , as is seen for other targeted arthropods [[51]] and helminths [[52]]. In this case, it is always important
ivermectin 13965 control interventions (such as LLINs or IRS) that use insecticides that remain effective even against ivermectin -resistant mosquitoes.A target candidate profile for endectocidal transmission blocking in malariaThis
ivermectin 15206 profile, TCP-6, is described for an endectocide, where the reference molecule is currently elevated-dose ivermectin . The definition of the endectocide in this case is expanded to include existing examples that kill blood-feeding
ivermectin 17718 able to kill rapidly and thus reduce egg laying, as already demonstrated with some formulations of ivermectin when administered to cattle [[43]] and humans [[48]], will also greatly impact the vector population.
ivermectin 18109 need to be extremely convincing, with a wide safety margin. There are, in fact, safety concerns with ivermectin [[54]]. An alternative is to consider these endectocide transmission-blocking candidates primarily for
ivermectin 23151 5–15 years contributing about the same as all older than 15 years [[59]]. For example, modelling studies on ivermectin show that with an increased dose (300 µg/kg daily for 3 days, every month throughout the rainy season
ivermectin 25847 of $0.50 per month has been set, considerably lower than the $1.50–6.00 per day cited in a TCP for ivermectin [[46]].TCP-6 requirements are based on their impact on transmission as predicted by modellingThe impact
ivermectin 27445 on the transmission intensity category (Fig. 3). Interestingly, clinical studies that examined the ivermectin impact on mosquito survival (when dosed at 3 × 300 μg/kg), based on feeding assays post-dose,
ivermectin 27672 the hazard ratio is 4 at day 14 but only 1.1 at day 30 [[49]], but even with this inferior profile ivermectin is still predicted to effect a significant reduction in rate of clinical incidence when used in combination
ivermectin 29233 population) at day 30 post-dosing, due to the decreased fitness and survival of mosquitoes having ingested ivermectin [[35]]. Determining the precise level of the resistance threat which is acceptable for an endectocidal
ivermectin 41699 initial concept and overall development plan to achieve registration. Since the current reference, ivermectin , is widely used as a human medicine, this new class, endectocidal transmission-blocking compounds, will
ivermectin 42012 prequalification route, even if the candidates primarily act on the vectors. The widespread use of ivermectin , and the available safety database may support an abbreviated pathway, but even in this case, there
ivermectin 48574 less attention, but this is changing with recent work on avermectins and isoxazolines.Whether or not ivermectin is ultimately deployed, there is still a role for new compounds, either improving on safety, convenience
primaquine 48353 control through ITNs and IRS, transmission-blocking vaccines, or the deployment of single, low-dose primaquine . The additional approach of using an endectocide to deliver a lethal dose of drug to the insect has
pyrimethamine 22112 success of SMC. In its current implementation, SMC is the use of a full treatment course of sulfadoxine– pyrimethamine and amodiaquine (SP–AQ) to each child aged between 3 and 59 months administered monthly for three
pyrimethamine 44189 study; SMFA, Standard membrane feeding assay; MAD, multiple ascending dose study; SP–AQ, sulfadoxine– pyrimethamine Initial estimates of the relationship between drug concentrations and mosquito mortality will be provided
sulfadoxine 22098 on the success of SMC. In its current implementation, SMC is the use of a full treatment course of sulfadoxine –pyrimethamine and amodiaquine (SP–AQ) to each child aged between 3 and 59 months administered monthly
sulfadoxine 44175 ascending dose study; SMFA, Standard membrane feeding assay; MAD, multiple ascending dose study; SP–AQ, sulfadoxine –pyrimethamineInitial estimates of the relationship between drug concentrations and mosquito mortality
Select Disease Character Offset Disease Term Instance
Lyme disease 9894 reticulatus) in dogs. These treatments are mainly aimed at the parasites that these ticks transmit. Lyme disease in humans is the result of infection by the tick-borne spirochete Borellia burgdorferi, and many more
Lyme disease 10072 Borellia burgdorferi, and many more human tick-borne diseases have been described [[31]]. Although Lyme disease is typically treated by 14–21 days of antibiotic treatment, early administration of an endectocide,
Lyme disease 10431 after oral treatment, which would be sufficiently fast to potentially prevent the primary infection by Lyme disease . A recent study has also highlighted the potential for repurposing the isoxazolines, fluralaner and
malaria 111 Malaria JournalA discovery and development roadmap for new endectocidal transmission-blocking agents in malaria Jeremy BurrowsHannah SlaterFiona MacintyreSarah ReesAnna ThomasFredros OkumuRob Hooft van HuijsduijnenStephan
malaria 409 (pmc-release): 12/2018Publication date (collection): /2018AbstractReaching the overall goal of eliminating malaria requires halting disease transmission. One approach to blocking transmission is to prevent passage of
malaria 1269 profile. Here, using a combination of insights from current endectocides, mathematical models of the malaria transmission dynamics, and known impacts of vector control, a target candidate profile (TCP-6) and a
malaria 1755 three, thereby constituting an ‘endectocidal transmission blocking’ paradigm.BackgroundEradicating malaria : thinking about preventing transmission in addition to treatment optionsMalaria remains one of the leading
malaria 2022 435,000 deaths in 2017, 93% of which were in Africa [[1]]. Between 2010 and 2016, the incidence of malaria infection decreased by 18%. This prevention of infection was largely driven by the deployment of insecticide-treated
malaria 2441 dramatic increase in the deployment of medicines to protect vulnerable populations, including seasonal malaria chemoprevention (SMC) for children under 5 years of age [[3], [4]] and intermittent preventive treatment
malaria 3027 artemisinin combination therapy (ACT, [[6]]), and the switch to injectable artesunate treatment of severe malaria . In 2015, the World Health Organization (WHO) announced its global technical strategy for malaria for
malaria 3125 severe malaria. In 2015, the World Health Organization (WHO) announced its global technical strategy for malaria for 2016–2030, which sets an ambitious target of reducing malaria incidence and mortality by a further
malaria 3193 its global technical strategy for malaria for 2016–2030, which sets an ambitious target of reducing malaria incidence and mortality by a further 90% [[7]]. This strategy has two major pillars, the first of which
malaria 3338 90% [[7]]. This strategy has two major pillars, the first of which is to ensure universal access to malaria prevention, diagnosis and treatment, and the second, to accelerate efforts towards malaria elimination.
malaria 3429 access to malaria prevention, diagnosis and treatment, and the second, to accelerate efforts towards malaria elimination. To achieve this, it will be important to continue the investments to develop new generations
malaria 3655 interventions described above, particularly for vector control and case management.Basic concepts of malaria transmission controlThe theoretical analysis of disease eradication can be summarized as the need to
malaria 8350 entomopathogenic fungi, and use of endectocides among others (reviewed in [[27]]).Current case management of malaria patients may leave significant gametocytaemiaClinically, transmission can be reduced either by decreasing
malaria 8617 their ability to be transmitted, thus lowering the proportion of infective bites, b. Existing anti- malaria l treatments differ significantly in their capacity to reduce gametocyte carriage, because they were
malaria 9114 clearance and gametocytaemia during follow-up. All new pre-clinical development candidates in the global malaria portfolio (http://www.mmv.org; [[29]]) are now routinely tested for their transmission-blocking activity
malaria 9342 standard membrane feeding assays (SMFAs; [[30]]), but case management is unlikely to greatly impact malaria transmission for the moment.Endectocides used in transmission blockingA remaining possibility is the
malaria 10584 potential for repurposing the isoxazolines, fluralaner and afoxalaner to kill mosquito vectors for malaria and dengue [[33]]. In human medicine, ivermectin is used to kill the parasites in patients infected
malaria 10980 between drug exposure and how this shortens the lifespan of the insect becomes particularly relevant for malaria transmission [[35]–[39]]. Even under optimal climatic situations, Plasmodium falciparum requires 10–12 days
malaria 12088 endectocides, although the new TCP-6 covers additional scenarios.The experience of ivermectin use in preventing malaria transmissionOver recent years there has been growing interest in the use of ivermectin, as a potential
malaria 12225 there has been growing interest in the use of ivermectin, as a potential endectocide, for a use in malaria . Several clinical studies have been conducted, [[35], [41]–[45]], and the WHO has published a Meeting
malaria 12362 have been conducted, [[35], [41]–[45]], and the WHO has published a Meeting Report on Ivermectin for malaria transmission control [[46]]. The definition of the Target Product Profile does depend on the proposed
malaria 13073 over 6 months [[47]]. The alternative approach would be to use ivermectin in combination with other malaria control modalities. In another example from Tanzania, addition of ivermectin to long-lasting, insecticidal-treated
malaria 13272 long-lasting, insecticidal-treated bed nets (LLINs) resulted in a near-complete collapse of populations of the malaria vector, Anopheles arabiensis, inside large naturalized mesocosms [[48]]. Combining ivermectin with SMC
malaria 13493 option, where 3 days of ivermectin could be given each month with a full treatment course of anti- malaria ls [[49], [50]]. This also underscores an additional risk in use of endectocides in malaria elimination;
malaria 13584 of anti-malarials [[49], [50]]. This also underscores an additional risk in use of endectocides in malaria elimination; the possibility that insects could emerge which are no longer sensitive to ivermectin,
malaria 14066 ivermectin-resistant mosquitoes.A target candidate profile for endectocidal transmission blocking in malaria This paper explores the use case for an ideal medicine for blocking transmission through endectocidal
malaria 14729 formulations, and combinations required for the ideal product.TCPs have been developed for other types of anti- malaria l medicine, and help define the screening cascade, and the supportive data required [[53]]. Profiles
malaria 16461 blood at day 28 after administration at a concentration sufficient to decrease the mean lifespan of malaria -competent female Anopheles that take a blood meal, since this is also the administration period for
malaria 16859 Poor potency may result in high dosing (> 10 mg/kg), difficulties in co-formulation with other anti- malaria ls, problems when formulating fixed-dose combinations, and high cost of goods. Therefore, during the
malaria 17241 the mechanism of action and the mosquito tissue distribution. There is a risk of transmission in a malaria -endemic region with every blood meal. Any compound that is long-lasting in the vertebrate host but is
malaria 19407 including strains with known insecticide resistanceActivity on all four major Anopheles species with malaria relevance in AfricaDrug–drug interactionsNo unsurmountable risks with potential anti-malarial partners,
malaria 19502 with malaria relevance in AfricaDrug–drug interactionsNo unsurmountable risks with potential anti- malaria l partners, especially those under consideration for SMCNo interactions with other anti-malarial, anti-retroviral
malaria 19597 anti-malarial partners, especially those under consideration for SMCNo interactions with other anti- malaria l, anti-retroviral or tuberculosis medicinesSafetySafety margin > tenfold between therapeutic exposure
malaria 20332 endemic countries. No food effect.Cost of active ingredient in final medicineSimilar to current anti- malaria ls: ≤ $0.5 for adults, $0.1 for infants under 2 yearsSimilar to older anti-malarials: < $0.25
malaria 20421 current anti-malarials: ≤ $0.5 for adults, $0.1 for infants under 2 yearsSimilar to older anti- malaria ls: < $0.25 for adults, $0.05 for infants under 2 yearsEstimated stability of final product under
malaria 22299 administered monthly for three or four months throughout the rainy season in areas of highly seasonal malaria . SMC has been enormously successful in reducing the incidence of clinical malaria infection and deaths
malaria 22381 of highly seasonal malaria. SMC has been enormously successful in reducing the incidence of clinical malaria infection and deaths in the Sahel [[56]], with over 13 million children protected in 2016. Unfortunately,
malaria 23373 [[49]], rather than a single 150 µg/kg dose) a significant additional decrease in incidence of clinical malaria can be obtained when given with SMC up to the age of 10 years (HS, unpublished observation). Broader
malaria 23804 non-teratogenic.Demonstration of efficacy of an endectocide in reducing incidence rates of symptomatic malaria when added to SMC could then be followed by measurements of the impact on asymptomatic malaria, or even
malaria 23899 symptomatic malaria when added to SMC could then be followed by measurements of the impact on asymptomatic malaria , or even parasite prevalence. The initial modelling suggests that treating only children under 10 years
malaria 24931 coverage of SMC and a TCP-6 compound in all children under 10. The clinical case incidence of symptomatic malaria on the Y-axis for the left-hand figures is the incidence in children 0–10 years of age. The PCR-measured
malaria 25280 public health agenda, and therefore the high-level customers are the health ministries, the national malaria control programmes and the national vector-borne disease programmes. Therefore, four factors are critically
malaria 26053 modellingThe impact of endectocidal transmission-blocking was assessed using an existing transmission model of malaria [[58], [60], [61]]. Here the impact of dosing a TCP-6 compound in conjunction with the current gold
malaria 26220 compound in conjunction with the current gold standard for SMC was measured on the incidence of clinical malaria and parasite prevalence in children 0–10 years of age. These simulations have allowed for the coverage
malaria 28497 TCP6 lasting in the blood for 30 daysFig. 3Percentage reduction in clinical incidence of symptomatic malaria in children < 10 years old (left panel) and annual PCR prevalence in all ages (right)Protecting
malaria 30474 transmission-blocking strategyThe new drug may not produce an immediate benefit, in terms of protection from malaria for the individuals enrolled in a treatment campaign, although there will be some effects on other ectoparasites
malaria 35499 compound optimization is described below and in Fig. 4, and is aligned with that described previously for malaria and other neglected diseases [[72]]. This cascade has a number of critical components:Fig. 4Screening
malaria 37043 required for mosquitocidal activity.The next stage is to demonstrate adequate potency against the main malaria -transmitting Anopheles species in Africa: Anopheles gambiae, Anopheles coluzzii, Anopheles arabiensis,
malaria 37357 vectors (Aedes species) as well as ticks and lice would give valuable information for uses outside malaria .Once potency across laboratory species has been confirmed, efficacy against highly insecticide-resistant
malaria 40812 compound as part of a SMC campaign. Use in combination as an add-on to an ACT for MDA or as a tool for malaria control and/or elimination could build from this initial application. Irrespective of the targeted use
malaria 41282 subsequently lead to WHO-Prequalification and facilitate National Regulatory Authorities approval in malaria -endemic countries.No drugs are currently approved for such a transmission-blocking strategy; hence no
malaria 42724 extending SMC to 5–10 year olds, as is already the case in Senegal, due to the increasing burden of malaria in this age group [[4]]. This add-on approach could be applicable to other, future approved treatment
malaria 43003 and III for a TCP-6 that is added on top of SMC would measure incidence rate reduction in symptomatic malaria , with entomological endpoints being proposed as supportive endpoints. Collecting the secondary entomological
malaria 43795 standard.Fig. 5Draft TCP-6 clinical development plan for a novel TCP-6 added to SP–AQ for seasonal malaria chemoprevention in asymptomatic subjects < 10 years of age. *West and Central Africa as required:
malaria 46539 sub-clinical P. falciparum infection (symptomatic patients are treated with the local standard of care anti- malaria l combination). The objectives of these studies are to confirm good safety or tolerability by cautious
malaria 47023 III).The primary efficacy endpoint will be the cumulative incidence rate reduction (IRR) of symptomatic malaria cases, however secondary endpoints, such as asexual parasite prevalence and additional supportive entomological
malaria 47532 cluster randomized study to demonstrate, as for Phase III, statistical superior IRR of symptomatic malaria cases of TCP-6 plus SP–AQ versus SP–AQ alone, and also to measure an effect on the total human population,
malaria 47722 the total human population, rather than just those treated on population prevalence of symptomatic malaria cases, positive parasitaemia and gametocytes, to demonstrate an impact on transmission. Theoretically,
malaria 47964 this study could be expanded to subjects > 10 years of age.ConclusionsThe continued drive towards malaria elimination requires a combination of better and more extensive deployment of existing tools, and the
scabies 10742 is used to kill the parasites in patients infected with the mite Sarcoptes scabiei, which results in scabies [[34]].When the parasites that vectors spread are the more relevant target, rather than the vectors
tuberculosis 19626 especially those under consideration for SMCNo interactions with other anti-malarial, anti-retroviral or tuberculosis medicinesSafetySafety margin > tenfold between therapeutic exposure and NOAEL in preclinical studies,

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