Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria

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Term Occurence Count Dictionary
atovaquone 17 infectiousdiseasesdrugs
malaria 94 infectiousdiseases
primaquine 1 infectiousdiseasesdrugs
proguanil 20 infectiousdiseasesdrugs
sulfadoxine 3 infectiousdiseasesdrugs
tuberculosis 1 infectiousdiseases
Plasmodium falciparum malaria 1 infectiousdiseases
abscess 2 infectiousdiseases
chloroquine 5 infectiousdiseasesdrugs
dapsone 1 infectiousdiseasesdrugs
doxycycline 2 infectiousdiseasesdrugs
pyrimethamine 4 infectiousdiseasesdrugs
yaws 1 infectiousdiseases

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Select Drug Character Offset Drug Term Instance
atovaquone 5011 Currently, the predominant oral prophylactics used by travelers are (rarely) mefloquine, doxycycline and atovaquone –proguanil. These were initially developed as treatments for uncomplicated malaria [[15], [16]]. They
atovaquone 5291 delivered at lower doses on a weekly basis, in the case of mefloquine, and a daily basis in the case of atovaquone –proguanil, respectively [[17], [18]].Protective vaccine strategies have focused on developing an immune
atovaquone 11002 regulatory strategy. As mentioned earlier, previous generations of medicines, such as mefloquine and atovaquone –proguanil, were first approved for case management, and were only subsequently approved for use at
atovaquone 25643 adults, adolescents and children (≥ 11 kg) visiting malaria-endemic regions and receiving once-daily atovaquone /proguanil (250/100 mg in adults and dosage based on body weight in children < 40 kg), had no cases
atovaquone 29089 endpoint based on asexual blood stage infection from the liver [[57]]. Here, the benchmarking with atovaquone shows that a highly efficacious compound should be able to lower the parasite 18S RNA signal in the
atovaquone 30594 mutations are not transmitted. It has been shown that is relatively easy to select for mutations against atovaquone both in vitro and in patients, but that these mutations are difficult to transmit [[59]]. Second, species
atovaquone 37508 This would apply to new formulation or a prodrug of a molecule already used for prophylaxis, such as atovaquone –proguanil. Here the safety and tolerability of the combination is well understood for oral administrations
atovaquone 54276 prophylacticThe Phase II and Phase III clinical strategy is based on the lessons learned from the development of atovaquone –proguanil [[55], [85], [86]] for malaria prophylaxis. Atovaquone–proguanil was first developed as
atovaquone 60446 significant risk of malaria infection. Ethically, these studies need to be active controlled studies; oral atovaquone –proguanil being the most likely comparator. The protective efficacy of both atovaquone–proguanil
atovaquone 60535 studies; oral atovaquone–proguanil being the most likely comparator. The protective efficacy of both atovaquone –proguanil and the NCE (new chemical entity) is expected to be high, therefore a very low rate of malaria
atovaquone 60874 required to demonstrate non-inferiority of the new medicine. For this reason, in the development of atovaquone –proguanil, the primary endpoint in Phase III studies was the overall frequency of any adverse events
atovaquone 61201 comparator studies, confirmed P. falciparum malaria occurred in 0/486 and 0/477 subjects receiving atovaquone –proguanil and mefloquine, respectively [[55]], and in 0/501 and 3/507 subjects receiving atovaquone–proguanil
atovaquone 61303 atovaquone–proguanil and mefloquine, respectively [[55]], and in 0/501 and 3/507 subjects receiving atovaquone –proguanil and chloroquine–proguanil, respectively [[87]], illustrating the difficulty of this approach.
atovaquone 61431 chloroquine–proguanil, respectively [[87]], illustrating the difficulty of this approach. Although atovaquone –proguanil is the best comparator, such studies have the additional complication of a lack of marketing
atovaquone 62679 required to test for non-inferiority of efficacy. Indeed, given the reported 98.5–100% efficacy for atovaquone –proguanil, demonstration of non-inferiority would not be expected, but demonstration of high efficacy
atovaquone 62867 demonstration of high efficacy of the NCE would be required. Therefore, similarly to the development of atovaquone –proguanil, for a long-acting injectable prophylactic trial in adults proposed here (Fig. 1), the
atovaquone 63053 proposed here (Fig. 1), the primary endpoint would be non-inferior safety and tolerability compared to atovaquone –proguanil, with prophylactic efficacy as a secondary endpoint. Hence the required sample size of any
chloroquine 4616 parasitaemia before it becomes clinically significant. Inhibitors of beta-haematin formation, such as chloroquine and mefloquine, and (plastid) ribosomal inhibitors, such as doxycycline, are suppressive chemoprophylactics,
chloroquine 26292 be useful when looking at new chemical entities. However, molecules with pure blood stage activity ( chloroquine and mefloquine) have been the mainstay of oral prophylaxis and so whether this would be acceptable for
chloroquine 61330 mefloquine, respectively [[55]], and in 0/501 and 3/507 subjects receiving atovaquone–proguanil and chloroquine –proguanil, respectively [[87]], illustrating the difficulty of this approach. Although atovaquone–proguanil
chloroquine 62017 efficacy of a prophylactic treatment, Høgh et al. [[17]] estimated that assuming a protective efficacy of chloroquine –proguanil of 72%, a study in travellers designed to show that a new anti-malarial drug with 95% efficacy
chloroquine 62151 study in travellers designed to show that a new anti-malarial drug with 95% efficacy is better than chloroquine –proguanil, assuming a 80% power and a 5% significance level, would require more than 16,000 participants
dapsone 8196 the development of 4-4′-diacetylaminosulphone (DADDS), a long-acting prodrug of the DHPS inhibitor dapsone , and cycloguanil pamoate (CI-501; [[33], [34]]). Clinical protection over 3–5 months was achieved
doxycycline 4688 beta-haematin formation, such as chloroquine and mefloquine, and (plastid) ribosomal inhibitors, such as doxycycline , are suppressive chemoprophylactics, and must be given for at least 2 weeks after leaving a malaria-endemic
doxycycline 4995 endemic area. Currently, the predominant oral prophylactics used by travelers are (rarely) mefloquine, doxycycline and atovaquone–proguanil. These were initially developed as treatments for uncomplicated malaria [[15],
primaquine 4268 DHFR), sulfadoxine (an inhibitor of Plasmodium dihydropteroate synthase, DHPS) and the 8-aminoquinolines primaquine and tafenoquine are the only causal prophylactics with proven clinical efficacy. In suppressive chemoprophylaxis,
proguanil 4103 bc1 inhibitor binding to the Q0 site of the complex), pyrimethamine and cycloguanil and its prodrug proguanil (selective inhibitors of dihydrofolate reductase, DHFR), sulfadoxine (an inhibitor of Plasmodium dihydropteroate
proguanil 5024 predominant oral prophylactics used by travelers are (rarely) mefloquine, doxycycline and atovaquone– proguanil . These were initially developed as treatments for uncomplicated malaria [[15], [16]]. They were subsequently
proguanil 5304 lower doses on a weekly basis, in the case of mefloquine, and a daily basis in the case of atovaquone– proguanil , respectively [[17], [18]].Protective vaccine strategies have focused on developing an immune response
proguanil 11015 strategy. As mentioned earlier, previous generations of medicines, such as mefloquine and atovaquone– proguanil , were first approved for case management, and were only subsequently approved for use at lower doses
proguanil 25654 adolescents and children (≥ 11 kg) visiting malaria-endemic regions and receiving once-daily atovaquone/ proguanil (250/100 mg in adults and dosage based on body weight in children < 40 kg), had no cases of falciparum
proguanil 37521 apply to new formulation or a prodrug of a molecule already used for prophylaxis, such as atovaquone– proguanil . Here the safety and tolerability of the combination is well understood for oral administrations of
proguanil 54289 and Phase III clinical strategy is based on the lessons learned from the development of atovaquone– proguanil [[55], [85], [86]] for malaria prophylaxis. Atovaquone–proguanil was first developed as a malaria
proguanil 54356 the development of atovaquone–proguanil [[55], [85], [86]] for malaria prophylaxis. Atovaquone– proguanil was first developed as a malaria treatment, and was subsequently shown to be efficacious in prophylaxis,
proguanil 60459 malaria infection. Ethically, these studies need to be active controlled studies; oral atovaquone– proguanil being the most likely comparator. The protective efficacy of both atovaquone–proguanil and the NCE
proguanil 60548 atovaquone–proguanil being the most likely comparator. The protective efficacy of both atovaquone– proguanil and the NCE (new chemical entity) is expected to be high, therefore a very low rate of malaria infection
proguanil 60887 demonstrate non-inferiority of the new medicine. For this reason, in the development of atovaquone– proguanil , the primary endpoint in Phase III studies was the overall frequency of any adverse events assessed
proguanil 61214 studies, confirmed P. falciparum malaria occurred in 0/486 and 0/477 subjects receiving atovaquone– proguanil and mefloquine, respectively [[55]], and in 0/501 and 3/507 subjects receiving atovaquone–proguanil
proguanil 61316 atovaquone–proguanil and mefloquine, respectively [[55]], and in 0/501 and 3/507 subjects receiving atovaquone– proguanil and chloroquine–proguanil, respectively [[87]], illustrating the difficulty of this approach. Although
proguanil 61344 respectively [[55]], and in 0/501 and 3/507 subjects receiving atovaquone–proguanil and chloroquine– proguanil , respectively [[87]], illustrating the difficulty of this approach. Although atovaquone–proguanil
proguanil 61444 chloroquine–proguanil, respectively [[87]], illustrating the difficulty of this approach. Although atovaquone– proguanil is the best comparator, such studies have the additional complication of a lack of marketing authorization
proguanil 62031 prophylactic treatment, Høgh et al. [[17]] estimated that assuming a protective efficacy of chloroquine– proguanil of 72%, a study in travellers designed to show that a new anti-malarial drug with 95% efficacy is better
proguanil 62165 travellers designed to show that a new anti-malarial drug with 95% efficacy is better than chloroquine– proguanil , assuming a 80% power and a 5% significance level, would require more than 16,000 participants While
proguanil 62692 test for non-inferiority of efficacy. Indeed, given the reported 98.5–100% efficacy for atovaquone– proguanil , demonstration of non-inferiority would not be expected, but demonstration of high efficacy of the NCE
proguanil 62880 high efficacy of the NCE would be required. Therefore, similarly to the development of atovaquone– proguanil , for a long-acting injectable prophylactic trial in adults proposed here (Fig. 1), the primary endpoint
proguanil 63066 (Fig. 1), the primary endpoint would be non-inferior safety and tolerability compared to atovaquone– proguanil , with prophylactic efficacy as a secondary endpoint. Hence the required sample size of any future Phase
pyrimethamine 4057 malaria. Atovaquone (a Plasmodium mitochondrial bc1 inhibitor binding to the Q0 site of the complex), pyrimethamine and cycloguanil and its prodrug proguanil (selective inhibitors of dihydrofolate reductase, DHFR), sulfadoxine
pyrimethamine 8544 discomfort and abscesses [[35]]. Failure to protect was assumed to be due to cross resistance with pyrimethamine , which was emerging at the time. Interest in long-lasting anti-malarials was renewed in 1976, supported
pyrimethamine 14060 Here, administration of full treatment courses of 3 days of amodiaquine and one dose of sulfadoxine– pyrimethamine were delivered to 15 million children in 12 countries in 2016 [[44]]. This raises the question as to
pyrimethamine 19668 distinct from the other uses. Over recent years, there has been a massive deployment of sulfadoxine– pyrimethamine plus amodiaquine (SP–AQ) for SMC. Chemoprevention is defined as giving a full curative course of treatment.
sulfadoxine 4170 and cycloguanil and its prodrug proguanil (selective inhibitors of dihydrofolate reductase, DHFR), sulfadoxine (an inhibitor of Plasmodium dihydropteroate synthase, DHPS) and the 8-aminoquinolines primaquine and
sulfadoxine 14046 2012 [[43]]. Here, administration of full treatment courses of 3 days of amodiaquine and one dose of sulfadoxine –pyrimethamine were delivered to 15 million children in 12 countries in 2016 [[44]]. This raises the
sulfadoxine 19654 is somewhat distinct from the other uses. Over recent years, there has been a massive deployment of sulfadoxine –pyrimethamine plus amodiaquine (SP–AQ) for SMC. Chemoprevention is defined as giving a full curative
Select Disease Character Offset Disease Term Instance
Plasmodium falciparum malaria 23160 HarmonizationThe regulatory strategy in each case would be to file for an indication of ‘Prophylaxis against Plasmodium falciparum malaria ’. This would be defined as prevention of malaria infection in subjects travelling from geographical
abscess 8460 delivered deep into the gluteal muscle tissues (350 mg in adults) and caused local discomfort and abscess es [[35]]. Failure to protect was assumed to be due to cross resistance with pyrimethamine, which was
abscess 22014 exclusion. No unacceptable pain, irritability of inflammation at injection site, especially injection abscess esIdemUse in patients with reduced G6PD activityTesting not required as no enhanced risk in mild-moderate
malaria 38 Title: Malaria JournalInjectable anti- malaria ls revisited: discovery and development of new agents to protect against malariaFiona MacintyreHanu RamachandruniJeremy
malaria 118 JournalInjectable anti-malarials revisited: discovery and development of new agents to protect against malaria Fiona MacintyreHanu RamachandruniJeremy N. BurrowsRené HolmAnna ThomasJörg J. MöhrleStephan DuparcRob
malaria 479 (pmc-release): 11/2018Publication date (collection): /2018AbstractOver the last 15 years, the majority of malaria drug discovery and development efforts have focused on new molecules and regimens to treat patients
malaria 1003 requires less frequent administration than this would be a key tool for the control and elimination of malaria . Recent progress in HIV drug discovery has shown that small molecules can be formulated for injections
malaria 1401 potentially provide protection for several months. Building on earlier profiles for uncomplicated and severe malaria , a target product profile is proposed here for an injectable medicine providing long-term protection
malaria 1875 medicines. An overall framework for these approaches is suggested here.IntroductionOne of the challenges of malaria control is to be able to provide protection for vulnerable populations. In recent years, there has been
malaria 2290 injectable formulations. Although there are currently no long-acting injectable medicines in development for malaria , new formulation technologies, similar to those developed for prophylaxis against HIV, might point the
malaria 2549 addition, recent developments in monoclonal antibody technology may be applicable to protect against malaria , especially in vulnerable populations. This paper discusses how such treatments would fit the target
malaria 2679 vulnerable populations. This paper discusses how such treatments would fit the target product profiles for malaria , and a regulatory pathway for their development. Since they pose similar challenges and possibilities
malaria 3026 considerable increase in the portfolio of new molecules which are being developed for the treatment of malaria [[1], [2]]. New paradigms of screening [[3]–[8]] have led to another generation of molecules progressing
malaria 3259 development, aimed at producing new medicines which overcome the current problems of multi-drug resistant malaria [[9]–[11]] and which also simplify therapy from the current 3-day therapy, to single exposure cures.
malaria 3467 cures. Protecting vulnerable populations from clinically significant infections is also a key aspect of malaria control and elimination [[12]]. Although a highly effective vaccine is the ultimate goal of much basic
malaria 3578 control and elimination [[12]]. Although a highly effective vaccine is the ultimate goal of much basic malaria research, the absence of a sterilizing immune response to naturally acquired disease shows how difficult
malaria 3955 achieved by a variety of different mechanisms. Causal prophylactics target the asexual hepatic stages of malaria . Atovaquone (a Plasmodium mitochondrial bc1 inhibitor binding to the Q0 site of the complex), pyrimethamine
malaria 4793 doxycycline, are suppressive chemoprophylactics, and must be given for at least 2 weeks after leaving a malaria -endemic area to clear any parasites that emerge from the liver after a person has left the endemic area.
malaria 5098 doxycycline and atovaquone–proguanil. These were initially developed as treatments for uncomplicated malaria [[15], [16]]. They were subsequently shown to have good protective efficacy when delivered at lower
malaria 5886 Efficacious vaccines would hold tremendous promise for prophylaxis, but unlike many viral infections, malaria is not a disease where natural infection results in sterilizing immunity, indicating that the bar to
malaria 6060 immunity, indicating that the bar to the identification of a highly effective vaccination regimen for malaria remains very high.Identifying new classes of anti-malarial chemoprotective molecules targeting either
malaria 6118 highly effective vaccination regimen for malaria remains very high.Identifying new classes of anti- malaria l chemoprotective molecules targeting either blood- or liver-stage has historically been limited by the
malaria 7961 confirm activity of compounds without asexual blood stage activity, and to avoid a focus on murine- malaria specific prophylaxis.Work on injectable depot anti-malarials was a key part of the previous malaria
malaria 8020 activity, and to avoid a focus on murine-malaria specific prophylaxis.Work on injectable depot anti- malaria ls was a key part of the previous malaria eradication campaign with the development of 4-4′-diacetylaminosulphone
malaria 8061 murine-malaria specific prophylaxis.Work on injectable depot anti-malarials was a key part of the previous malaria eradication campaign with the development of 4-4′-diacetylaminosulphone (DADDS), a long-acting prodrug
malaria 8621 cross resistance with pyrimethamine, which was emerging at the time. Interest in long-lasting anti- malaria ls was renewed in 1976, supported by the UNDP/World Bank/WHO special program for Research and Training
malaria 15398 Product Profiles (TPPs) presented here will need to be refined and updated in discussions within the malaria community, as and when new data become available.The different modalities for deploying malaria prophylaxisThere
malaria 15494 the malaria community, as and when new data become available.The different modalities for deploying malaria prophylaxisThere are multiple uses for an injectable anti-malarial prophylaxis (Table 1). The first
malaria 15560 different modalities for deploying malaria prophylaxisThere are multiple uses for an injectable anti- malaria l prophylaxis (Table 1). The first is to protect populations such as migrant workers, soldiers, tourists
malaria 15735 as migrant workers, soldiers, tourists and university or boarding school students originating from a malaria -free area from becoming infected when they travel to areas with endemic malaria. Historically prophylaxis
malaria 15815 originating from a malaria-free area from becoming infected when they travel to areas with endemic malaria . Historically prophylaxis has been considered as a premium priced market, largely targeting western
malaria 16021 western tourists and the military, who can afford to pay $5/day for protection. However, as the impact of malaria elimination has progressed, there are now many areas, especially in Africa, where it is relatively easy
malaria 16291 such as from Southern to Northern Zambia. This latter group is an important and expanding group in the malaria agenda. With the progress of the elimination agenda there will be a need for affordably-priced protection
malaria 16635 Europe or the USA, whose families come from an endemic area and who return to visit their families in a malaria endemic area. This group is responsible for the highest proportion of cases of imported malaria in Europe.Table 1Summary
malaria 16731 in a malaria endemic area. This group is responsible for the highest proportion of cases of imported malaria in Europe.Table 1Summary of potential uses for injectable prophylactic medicinesUse caseDescriptionTarget
malaria 16917 medicinesUse caseDescriptionTarget populationComments(1) TravellersResidents of regions of very low or no malaria incidence travelling to malaria endemic areasInitially, all adults and children > 5 yearsIncreasing
malaria 16949 populationComments(1) TravellersResidents of regions of very low or no malaria incidence travelling to malaria endemic areasInitially, all adults and children > 5 yearsIncreasing numbers of travellers within
malaria 17184 GDP; increasing numbers of Africans in areas of low transmission(2a) Malaria epidemicRe-emergence of malaria in zones which had been previously declared malaria freeEntire populationNeed demonstration of safety
malaria 17236 transmission(2a) Malaria epidemicRe-emergence of malaria in zones which had been previously declared malaria freeEntire populationNeed demonstration of safety in first trimester of pregnancy; deployment during
malaria 17420 pregnancy; deployment during ‘maintaining zero’(2b) Febrile epidemicProtection of a population from malaria during epidemics such as EbolaEntire populationNeed demonstration of safety in first trimester of pregnancy.
malaria 18133 is to protect a non-immune population within their area of residence, who are suddenly exposed to a malaria outbreak or epidemic. This is one of the major concerns late in any eradication effort, in places where
malaria 18323 effort, in places where ‘maintaining zero’ is the priority [[45]]. In a situation where areas are malaria -free, but the mosquito population is still abundant, there may be a need to rapidly protect populations.
malaria 18764 being safe in the first trimester of pregnancy. A variant on this is the protection of populations from malaria during a pandemic outbreak of febrile disease, such as Ebola. During the 2013–2016 outbreak of Ebola
malaria 18924 as Ebola. During the 2013–2016 outbreak of Ebola in West Africa, many patients who presented with malaria l fevers were triaged into the Ebola facilities, where they became infected with Ebola [[46]–[48]],
malaria 19067 facilities, where they became infected with Ebola [[46]–[48]], resulting in patients not seeking malaria treatment and an increase in deaths due to malaria [[49]]. Monthly presumptive treatment with artemisinin-based
malaria 19118 [[46]–[48]], resulting in patients not seeking malaria treatment and an increase in deaths due to malaria [[49]]. Monthly presumptive treatment with artemisinin-based combination therapy (ACT) was used in at-risk
malaria 19441 situation, if it gave a longer period of protection than oral medication.The third potential use for an anti- malaria l chemoprotective agent is to protect vulnerable populations in areas of high malaria incidence, and
malaria 19526 use for an anti-malarial chemoprotective agent is to protect vulnerable populations in areas of high malaria incidence, and this is somewhat distinct from the other uses. Over recent years, there has been a massive
malaria 19976 rainy season in the Sahel (to 13 million children in 2016), to reduce the incidence of symptomatic malaria in this vulnerable population. Since a large part of the cost of deployment of SMC is the delivery,
malaria 20651 better titrated to the needs of protection.Table 2TPP for an injectable prophylactic medicine for malaria Parameter to be clinically evaluated for the combinationMinimum essentialIdealAntimalarial effectsBlood
malaria 20740 medicine for malariaParameter to be clinically evaluated for the combinationMinimum essentialIdealAnti malaria l effectsBlood schizonticides with at least one molecule also having causal prophylactic activity (killing
malaria 21510 efficacy≥ 80% protective efficacy≥ 95% protective efficacy: reduction in incidence of symptomatic malaria No drug-resistant parasites identified in volunteer infection studies still capable of transmissionDrug–drug
malaria 23182 strategy in each case would be to file for an indication of ‘Prophylaxis against Plasmodium falciparum malaria ’. This would be defined as prevention of malaria infection in subjects travelling from geographical
malaria 23233 of ‘Prophylaxis against Plasmodium falciparum malaria’. This would be defined as prevention of malaria infection in subjects travelling from geographical areas with no, or very low risk of malaria infection,
malaria 23327 prevention of malaria infection in subjects travelling from geographical areas with no, or very low risk of malaria infection, to geographical areas with significant risk of malaria infection. The clinical development
malaria 23393 areas with no, or very low risk of malaria infection, to geographical areas with significant risk of malaria infection. The clinical development strategy supports the filing by collecting data to demonstrating
malaria 24013 size, and injection volume should be driven by a favourable comparison to vaccines. The most advanced malaria vaccine, Mosquirix® (RTS,S–AS202) has been approved by the European Commission after having been
malaria 24890 infections, such as mass treatment against yaws [[51]], a new medicine for children protecting against malaria would need to be more child-friendly to be acceptable for repeat use. Intravenous injection of the PfSPZ
malaria 25594 comparative, randomized clinical trials, nonimmune adults, adolescents and children (≥ 11 kg) visiting malaria -endemic regions and receiving once-daily atovaquone/proguanil (250/100 mg in adults and dosage based
malaria 25773 (250/100 mg in adults and dosage based on body weight in children < 40 kg), had no cases of falciparum malaria for 28 days [[53]], comparable efficacy was also seen in other studies [[54], [55]]. Doxycycline provides
malaria 27818 target product profile (TPP) including other parameters for an injectable prophylactic medicine for malaria is proposed in Table 2.Approaches to finding and developing new small molecule TCP-4 candidatesCompounds
malaria 30938 would be an advantage, since many patients have mixed infections that include P. vivax, Plasmodium malaria e and Plasmodium ovale.Selection of a formulation, which may also involve the use of pro-drugs, is critical
malaria 32826 local tolerability [[60]].The second option for a long-acting injectable for prophylactic treatment of malaria would probably be an aqueous suspension of either micro- or nanoparticles. The advantage of an aqueous
malaria 39122 between cohorts extremely conservative.In some of the uses described above, the population at risk from malaria will include a considerable number of women of childbearing potential, whose pregnancy status may not
malaria 40096 selection of resistance is much lower than when a molecule is used for the treatment of uncomplicated malaria , since the molecule encounters far fewer parasites [[66]]. However, asymptomatic infections with quite
malaria 42590 molecule suitable for development as part of a new injectable, combination regimen for prophylaxis against malaria is detailed in Table 3.Table 3TCP-4 as part of a prophylactic combinationGeneral considerationsMinimum
malaria 43858 volunteer infection studiesDrug–drug interactionsNo unmanageable risksNo interactions with other anti malaria l, anti-retroviral or tuberculosis medicines or oral contraceptionSafety and tolerabilityTherapeutic
malaria 45766 embryo fetal development, NOAEL no-observed-adverse-effect-levelMonoclonal antibodies for long-acting malaria prophylaxisAn alternative approach to protecting vulnerable populations with an injectable small molecule
malaria 45942 populations with an injectable small molecule would be the use of a monoclonal antibody [[68]]. Even though malaria infection in humans does not lead to a sterilizing immune response, it is still possible that monoclonal
malaria 47362 antibody therapies, it is often assumed that the cost of antibody therapy would be prohibitive in most malaria -endemic countries. Provided antibodies are expressed at high levels (4 g/L), and are stable, hence
malaria 48469 estimations are on the borderline of what might be acceptable, in comparison with the pricing for a malaria vaccine. Any decrease in dose, frequency of administration or cost of manufacturing would further bring
malaria 52529 very important to have clear parameters for the TCP.Clinical and regulatory strategy of long-acting malaria prophylaxisFor new chemical entities and antibodies the Phase I single ascending dose study in healthy
malaria 52829 FRG-mice [[84]]. At this concentration, prophylactic activity could be assessed in human volunteer malaria infection studies [[26], [27]]. For new chemical entities, the safety and efficacy in human volunteers
malaria 54155 shown in Fig. 1.Fig. 1Proposed high level clinical development plan for evaluation of a long acting malaria prophylacticThe Phase II and Phase III clinical strategy is based on the lessons learned from the development
malaria 54322 based on the lessons learned from the development of atovaquone–proguanil [[55], [85], [86]] for malaria prophylaxis. Atovaquone–proguanil was first developed as a malaria treatment, and was subsequently
malaria 54391 atovaquone–proguanil [[55], [85], [86]] for malaria prophylaxis. Atovaquone–proguanil was first developed as a malaria treatment, and was subsequently shown to be efficacious in prophylaxis, using a daily dosing regimen.
malaria 55474 is thought that relatively few children less than 5 years of age are likely to be travelling from malaria -free to malaria endemic areas, recruitment into clinical trials of this younger population may be problematic.
malaria 55490 relatively few children less than 5 years of age are likely to be travelling from malaria-free to malaria endemic areas, recruitment into clinical trials of this younger population may be problematic. For this
malaria 56364 efficacy, safety and tolerability in non-naïve subjects in regions of Africa with a high incidence of malaria . The primary endpoint would be protective efficacy (PE). A key aspect of this design is that a sterilizing
malaria 59001 Life Year (DALY).The use of a placebo in adults and children in the Phase II studies in areas of high malaria incidence was strongly recommended in initial discussions with regulatory authorities because this is
malaria 59311 can be measured. The population enrolled in this study would ordinarily be exposed to sub-clinical malaria infection which would otherwise remain untreated. All subjects would receive an initial sterilizing
malaria 59446 otherwise remain untreated. All subjects would receive an initial sterilizing cure for this sub-clinical malaria , and benefit from close clinical safety monitoring during the study, as well as standard-of-care treatment
malaria 60295 and children older than 5 years travelling from geographical areas with no, or a very low risk of malaria infection, to geographical areas of significant risk of malaria infection. Ethically, these studies
malaria 60359 areas with no, or a very low risk of malaria infection, to geographical areas of significant risk of malaria infection. Ethically, these studies need to be active controlled studies; oral atovaquone–proguanil
malaria 60645 atovaquone–proguanil and the NCE (new chemical entity) is expected to be high, therefore a very low rate of malaria infection (‘attack rate’) would be expected in this population, meaning that very large numbers
malaria 61146 with protective efficacy as a secondary endpoint. In these comparator studies, confirmed P. falciparum malaria occurred in 0/486 and 0/477 subjects receiving atovaquone–proguanil and mefloquine, respectively [[55]],
malaria 61767 mentioned above require very large trials. Making a number of assumptions about the risk of developing malaria for travellers from Europe, Canada and South Africa to East Africa who do not take prophylaxis, the
malaria 62104 efficacy of chloroquine–proguanil of 72%, a study in travellers designed to show that a new anti- malaria l drug with 95% efficacy is better than chloroquine–proguanil, assuming a 80% power and a 5% significance
malaria 64192 study.ConclusionsSeveral factors have driven a renewed evaluation of the role of prophylaxis in the malaria elimination agenda over the last few years:First, the general acceptance that countries that are undergoing
malaria 64803 migratory populations in low- and middle-income countries.Second, in countries that have eliminated malaria and are ‘maintaining zero’ [[12]], there is the risk of re-introduction and epidemics, and in the
malaria 65077 protection is needed for populations at risk of an epidemic. A special subcategory is the need for malaria l prophylaxis during fever outbreaks such as the Ebola crisis in West Africa, to reduce the risk of malaria
malaria 65184 malarial prophylaxis during fever outbreaks such as the Ebola crisis in West Africa, to reduce the risk of malaria at the height of the epidemic and to protect health care workers.Third, there have been tremendous successes
malaria 65387 tremendous successes in the last 5 years using SMC, which involves giving a full treatment course of anti- malaria ls every month. A regimen which was truly optimized for prophylaxis, and available as an injection would
malaria 65624 benefit. This latter point has come into focus recently because of the stagnation in the reduction of malaria incidence globally [[44]]. One of the strategic responses here is to ask what else can now be done in
malaria 66117 some optimism for the future:First is the availability of new chemotypes with activity against the malaria parasite, which opens up the possibility of focusing on new medicines specifically designed for prophylaxis.
malaria 66363 situation since, ideally, the same medicine should not be used for both the protection and the treatment of malaria within the same geographic locale. To date, none of the new molecules has a half-life equivalent to
malaria 68908 the next generation of profiles. More discussion is needed with experts in the field and the bigger malaria community e.g. on the clinically relevant level of efficacy to be targeted. Furthermore, MMV is preparing
tuberculosis 43887 studiesDrug–drug interactionsNo unmanageable risksNo interactions with other antimalarial, anti-retroviral or tuberculosis medicines or oral contraceptionSafety and tolerabilityTherapeutic ratio > tenfold between therapeutic
yaws 24830 injection of penicillin-G benzoate crystals for bacterial infections, such as mass treatment against yaws [[51]], a new medicine for children protecting against malaria would need to be more child-friendly

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