Background
Replacement for ACT?
KAE609 | KAF156 | OZ439 | OZ277 | |
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Potential partner drug? | Ferroquine | Solid dispersion formulation-lumefantrine | Piperaquine ferroquine | Piperaquine |
Drug half-life (h) | 21 | 48–60 | 46–62 | 2–4 |
Efficacy | PCt1/2 0.9 h | PCt1/2 3.5 h | PC1/2 = 4.4 (WT K13) PC1/2 = 5.5 (Mutant) | Median PCt = 24 h same as coartem |
PCR-corrected ACPR on day 42 was under 50% with single dose piperaquine | PCR-corrected ACPR on day 42 was >98% in both groups | |||
Transmission blocking | Reduction in stage 5 gametocyte in vitro and inhibit oocyst development in standard membrane feeding assay | Reduction in stage 5 gametocyte in vitro and inhibit oocyst development in standard membrane feeding assay | 7 patients with pre-treatment and 10 patients with post-treatment Pf gametocytes; one had up to day-6 | Day 7 and Day 14 carriage higher than coartem [23] |
Adverse event | Raised transaminase (3/21 patients) | Raised transaminase (30% of patients) | 12/82 patients increased CPK | 6.9% (49) got QTcF > 500 ms compared to 1.7% (6) in coartem |
7/82 patients increased transaminases | ||||
2/82 patients QTcF > 450 ms. 18/82 patients with prolongation of QTcF > 30 ms from baseline | ||||
Resistance | SNP at PfATP4 gene can be selected in vitro after 4-months exposure to incremental increasing conc. of KAE | SNP at PfCARL gene can be selected in vitro after 4-months exposure to incremental increasing conc. of KAF | Slower PCt1/2 in K-13 mutation even though in vitro RSA suggested no difference | Not tested |
MIC | 0.1 ng/ml | 4.1 ng/ml [17] |
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KAE 609, Cipargamin™, (a phase-2 compound), is the most advanced candidate targeting ATPase4. It has the shortest parasite clearance time (PCt ½ < 1 h) observed in any anti-malarial drug [10]. A major concern is single nucleotide polymorphisms (SNP) at the PfATP4 gene which can be selected in vitro after 3–4 months exposure to incrementally increasing sub-lethal concentrations of KAE 609 [11]. If this finding is substantiated, the loss of KAE 609, like atovaquone earlier, seems likely. A second concern about KAE 609 is that administration resulted in abnormal liver function in 3 of 21 [12], alkaline phosphatase increase in 10 of 25, ALT increase in 1 of 25 and hyper-bilirubinaemia in 5 of 25 [13] study participants.
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KAF 156, an imidazolopiperazine (a phase-2 compound), has a slower PCt rate than KAE 609 but presents similar concerns [12, 14, 15]. Single nucleotide polymorphisms (SNP) in PfCARL, the likely drug target of KAF 156, can be selected in vitro after 4 months exposure to incrementally increasing concentrations of KAF [16]. In addition, 30% of study participants had elevated transaminases.
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OZ 439, Artefenomel™, (a phase-2 compound), belongs to the ozonides class of drugs, which share peroxide pharmacophore with artemisinins [17, 18]. Like artemisinins, the PCt 1/2 of OZ439 is slower in parasites with k13 mutation suggesting cross-resistance between ozonides and artemisinins [18]. There are safety concerns, as trial participants receiving the drug candidate had elevated creatine phosphokinase (CPK), transaminases and a QTc interval prolongation [18]. A study of 60 volunteers, given a single dose regimen combining 800 mg OZ439 with 960 or 1440 mg piperaquine, is expected to result in lower peak piperaquine plasma concentrations compared with available 3-day piperaquine-artemisinin combinations and can therefore be expected to cause less QTc prolongation [19].
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OZ 277, Arterolane™, (a phase-4 compound); another synthetic peroxide is the most advanced of the new anti-malarials. Combined with piperaquine, this new drug is already registered and marketed by Ranbaxy in India [20‐22]. There is a concern that OZ277 shares cross-resistance with the artemisinin derivatives. High resistance levels against the partner drug piperaquine have already been documented in Cambodia and Vietnam. A further concern is the QTc prolongation observed in 6.9% of study participants [23].