Product development partnerships have revived antimalarial drug development, and a variety of target candidate and product profiles have been defined to support control and elimination goals |
New agents (arterolane, cipargamin, KAF156) on the horizon show potential to replace failing artemisinin combination therapies as part of novel combinations |
The loss of front-line therapies to resistance has stimulated a reappraisal of the current approach to combination therapy for malaria, with consideration of a switch from dual to triple drug combinations |
1 Introduction
2 Search Strategy
3 Drugs in Clinical Development
3.1 New Drugs in Clinical Development for Treatment
Individual antimalarial drugs | Examples |
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Anti-parasitic activity | |
Stage-specificity, e.g. blood schizonticide (treatment), gametocytocide or sporontocide (transmission-blocking), hypnozoiticide (relapse prevention), hepatic schizonticide (causal prophylaxis) | The artemisinin derivatives have the broadest stage-specificity of action of all registered antimalarials (trophozoites, including young rings, gametocytes, with the exception of Stage V) Only the 8-aminoquinolines (primaquine, tafenoquine) are active against hypnozoites for relapse prevention in vivax or ovale malaria |
Pharmacokinetics | |
Speed of action (including dependence on co-factors, e.g. for absorption) | Lumefantrine AUC is the principal determinant of cure following artemether–lumefantrine treatment (absorption is enhanced by coadministration with fat) |
Speed of elimination | Slowly eliminated drugs (e.g. piperaquine) have the added advantage of a longer post-treatment prophylactic effect and hence fewer episodes of malaria in high-transmission areas [115] |
Pharmacodynamics | |
Parasiticidal effect: relates to asexual stage-specific activity | The most potent antimalarials have the greatest inhibitory effect on parasite multiplication. The average parasite biomass in an adult with uncomplicated falciparum malaria is > 1012. Artesunate reduces the biomass by ~ 104 per asexual life-cycle (48 h) in sensitive infections. Thus, if used alone ≥ 6-day treatment (3 cycles) must be given to have the best chance of cure [5] |
Safety/toxicity | |
Pregnant women and children | ACTs were contraindicated in the first trimester of pregnancy due to concerns of embryotoxicity in animals and a lack of safety data in humans until recently |
Repeated dosing | Patients in high transmission areas may have multiple episodes of malaria per year. Repeated dosing of artesunate-pyronaridine was not recommended initially due to safety concerns (signal of hepatotoxicity). This caution has since been lifted |
Propensity for resistance to develop | Atovaquone–proguanil is extremely vulnerable to resistance development due to rapid selection of cytochrome b mutations |
Cost | Artemether–lumefantrine costs US$0.38–1.3 per treatment [116] |
Antimalarial combinations | |
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Formulation | |
Co-formulations, tablet burden | All leading ACTs now exist as fixed-dose combinations with the exception of AS-SP |
Paediatric formulations | Most leading ACTs have paediatric dosage forms |
Posology | |
Dose number and frequency | Most antimalarials are given as 3-day treatments. Artemether lumefantrine has the highest dose frequency (6 doses) |
Matched pharmacokinetics | |
Elimination half-lives | For the ACTs in use there is a mismatch of the elimination kinetics of artemisinin derivatives and partner drugs, which leaves the slowly eliminated drug unprotected |
Drug–drug interactions | Triple ACTs under evaluation exploit inverse resistance selection properties of different partner drug pairings, e.g. amodiaquine and lumefantrine |
Global recommendations to add a single low dose of primaquine to ACTs in areas targeting elimination necessitate study of potential drug-drug interactions with any new treatment |
Name and development partners | Type/target | Activity spectrum | First in human | In vivo or in vitro efficacy data | Safety | Vision for development |
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Under review by stringent regulatory authorities
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Tafenoquine GSK, MMV, US Army | 3-phenoxy-substituted 8-aminoquinoline, i.e. synthetic analogue of primaquine | PV blood and tissue schizonticide, gametocytocidal | FIH study in HAVs reported in 1998 defined long half-life (14 days) and good tolerability [117] | Relapse-free efficacy at 6 months of chloroquine (CQ) + 300 mg tafenoquine 89.2% (77–95%) compared to 37.5% (23–52) for CQ alone [118] | Acute haemolytic anaemia in G6PD deficiency, elevated creatinine, methaemoglobinaemia | Single-dose relapse prevention for PV (given in combination with blood schizonticide) |
Phase 2
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Artefenomel (formerly OZ439) MMV (+ ferroquine) | Synthetic endoperoxide; several theories on mechanism of action [119] | Blood schizonticide for falciparum and vivax | Study of artefenomel in HAVs demonstrated a terminal half-life of 25–30 h; exposure increased by co-administration with food [120]. Evaluation in human induced blood-stage malaria model predicted an MIC of 4.1 ng/mL [121] FQ FIH data in HAVs were not published in a primary report [122] | Artefenomel-piperaquine, PCt1/2 (min–max) in Vietnam was 6.1 (1.1–12.7) vs 3.5 (1.2–7.7) h in Africa and D-28 ACPR were 66.2% (95% CI 54.6–76.6) vs 74.5% (95% CI 7.81–79.7) [49] | Single dose combination treatment [49] (NCT02497612) | |
KAF156 MMV, Novartis (+ lumefantrine solid dispersion formulation) | Imidazolopiperazine; unknown mechanism of action | KAF 156 FIH study in male HAVs published in 2014 with PK [126] | Median (IQR) PCt1/2 3.5 h (3.4–3.8) multiple-dose and 3.4 (3.2–4.1) single dose. Single-dose D-28 ACPR 67% [50] | Post-treatment mild transaminitis. Asymptomatic bradycardia [50] | Single dose multi-stage treatment (with lumefantrine) | |
Cipargamin (formerly) KAE609 MMV, Novartis | Spiroindolone | Blood schizonticide for falciparum and vivax | Single- and multiple-dose cohorts studied. Dose-related gastrointestinal and genitourinary adverse events reported [128] | Hepatotoxicity concerns-dose-escalation safety study ongoing (NCT03334747) | To combine with longer-acting partner drug not prone to PfATP4 mutation | |
Fosmidomycin (+ piperaquine) JOMAA | Inhibitor of 1-deoxy-d-xylulose 5-phosphate reductoisomerase in isoprenoid biosynthesis pathway | Uncomplicated PF blood schizonticide | PK study of parenteral and oral fosmidomycin reported in 1982 [62] | Mild post-treatment transaminitis [130] | Combination therapy in areas with no piperaquine resistance | |
DSM265 Takeda, MMV, UT Southwestern | Dihydroorotate dehydrogenase inhibitor | Uncomplicated PF schizonticide, liver stage activity; no gametocytocidal activity; no data in PV | Favourable early safety, tolerability, pharmacokinetic, and activity data published in HAVs and human challenge study in 2017 [66] | Parasite reduction ratio at 48 h in the human challenge study measured 1.55 (95% CI 1.42–1.67), which was lower than that following a 10 mg/kg dose of mefloquine (2.34) | Mild, e.g. headache [66] | Prevention (travellers’ market) and partner drug in combination therapy |
AQ-13 Immtech and Tulane University | Modified 4-aminoquinoline | Blood schizonticide for falciparum and vivax | HAV study published in 2007 showed a similar tolerability and PK profile to chloroquine [70] | Mean PCT 47.3 h (43.5–51.1) vs 32.5 (28.0–37.0) for artemether–lumefantrine (AL): by day 42, 0/28 vs 2/33 recrudescences in AL arm [69] | No grade 2–4 adverse events [69] | Partner drug in combination therapy |
Methylene Blue University of Heidelberg | Phenothiazine derivative. Prevents haem polymerisation by inhibiting P. falciparum glutathione reductase | PF schizonticide and potent gametocytocidal agent (male and female Stage V gametocytes) | First description of methylene blue to treat malaria was in 1891 [131] | Increased vomiting when combined with artesunate–amodiaquine [82] | Part of a triple combination with ACTs + transmission blocking | |
Sevuparin (DF02) Dilaforette-Karolinska Institute | Anti-adhesive polysaccharide derived from heparin with eliminated antithrombin binding site [87] | Blocks merozoite invasion and sequestration [87] | Well tolerated in HAVs [87] | No adverse event leading to study withdrawal. No bleeding AEs [87] | Adjunctive treatment for severe malaria | |
MMV 390048 MMV and University of Cape Town | Aminopyridine PfPI (4) K inhibitor [71] | Blood schizonticide inhibits gametocytogenesis and oocyst formation (preclinical) [71] | FIH (NCT02230579; NCT02554799), PK (NCT02783820) and human challenge studies (NCT02281344) are complete (data not published) | Phase 2a study (NCT02880241) recruitment suspended for interim data analysis | Not published | Part of single-dose treatment, transmission- blocking, chemoprevention |
Phase 1
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P218 MMV, Janssen (Biotec Thailand) | PF-dihydrofolate reductase (DHFR) inhibitor | Blood schizonticide but inactive across all gametocyte stages [135] | Safety, tolerability and PK study in HAVs completed; not published (NCT02885506) | In vitro IC50 (SD) for quadruple DHFR mutant is 56 nM (20) compared to > 100,000 for pyrimethamine [136] | – | Chemoprevention |
CDRI 97/78 Ipca | Trioxane | Blood schizonticide | Well-tolerated in HAVs with half-life of 11.85 ± 1.94 h [137] | – | AEs were few and not severe [137] | Part of a combination therapy |
M5717 (formerly) DDD107498 MMV, Merck, University of Dundee | Quinoline-4-carboxamide inhibits P. falciparum translation elongation factor-2 required for protein synthesis [72] | Multi-stage (liver, blood and transmission blocking) | FIH study of single ascending dose, multiple ascending dose and malaria challenge model in healthy subjects is recruiting (NCT03261401) | More potent than artesunate in ex vivo study: median EC50 0.81 nM (range 0.29–3.29 nM) [72] | – | Single-dose treatment costing US$1 |
SJ733 MMV, University of Kentucky, Eisai | Dihydroisoquinoline inhibiting PfATP4 | Dose-escalation study in HAVs (NCT02661373) is due to complete recruitment in July 2018. A human challenge (early induced blood stage malaria infection) study is complete (NCT02867059) | EC50 range 10–60 nM. Effective dose and exposure (AUCED90) superior to artesunate in animal models [139] | No toxicity in mouse model with a dose ~ 43-fold higher than effective dose [139] | Part of single dose treatment | |
ACT-451840 Actelion Pharmaceuticals [140] | Phenylalanine-based compound; unknown mechanism of action | Blood schizonticide | Single ascending-dose study in HAVs. Exposure increased with food. Half-life ~ 34 h [141] | Minimal parasiticidal concentration was 1.5 ng/mL [141] | No adverse event leading to withdrawal [141] | Combination therapy, e.g. with lumefantrine or mefloquine [140] |
3.2 New Drugs in Clinical Development for Prevention
3.3 New Drugs in Clinical Development for Relapse Prevention (Plasmodium vivax and Plasmodium ovale)
3.4 New Drugs in Clinical Development for Transmission-Blocking
3.5 Re-purposing of Antimicrobial Drugs for Malaria Prevention or Treatment
3.6 New Adjunctive Therapies in Development for the Treatment of Severe Malaria
4 Drugs in Pre-clinical Development
Name/ development partners | Type/target | Activity spectrum | Other characteristics | Vision for development |
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MMV 253 (previously AZ13721412)/MMV and Zydus Cadila [142] | Triaminopyrimidine, Plasmodium ATPase inhibitor | Blood schizonticide | Long acting | Part of a single-dose radical cure |
AN 13762/MMV, University of California, San Francisco [143] | Benzoxaborole, mechanism of action unknown | Blood schizonticide | Reassuring pre-clinical toxicology | Part of a single-dose radical cure, prevention |
JPC-3210/MMV and Zydus Cadila [90] | Aminomethylphenol | Blood schizonticide | Long acting | Treatment and prevention |
UCT 943 (previously MMV 642943)/MMV, H3D, University of Cape Town | PfPI(4)K inhibitor [144] | Multi-stage, falciparum and vivax | – | Back-up for MMV048 [71] (part of a single-dose radical cure, transmission blocking, prevention) |
8-Aminoquinoline (single enantiomer) | Multi-stage | Superior radical curative activity to primaquine in animal models [146] | Vivax malaria relapse prevention | |
SC83288/University of Heidelberg [92] | Amicarbalide derivative | Blood schizonticide | Rapid action (log parasite reduction ratio ~ 3 in a mouse model) | Severe malaria treatment |
SAR121 (previously MMV688533)/Sanofi, MMV | Unknown mechanism of action | Blood schizonticide | Long acting | Part of a single-dose radical cure |
DM1157(PL 69)/DesignMedix | “Reversed chloroquine”, similar mechanism of action | Blood schizonticide | No published data (similar to chloroquine) | Part of a single-dose radical cure [147] |