Table 4 New products under development

Azithromycin 250 mg, chloroquine 155 mg

Pfizer, MMV, London School of Hygiene and Tropical Medicine

AZCQ

Phase III

Azithromycin is a macrolide requiring 2000 mg/day to be effective as monotherapy but shows clinical synergy with chloroquine even where chloroquine resistance is as high as 50%. Entered Phase III for intermittent preventive treatment of Plasmodium falciparum malaria in pregnancy (IPTp) in Oct 2010. The primary outcome is a reduction in the number of subjects with suboptimal pregnancy outcome, and results should be available in 2014.

[72–76]

Trimethoprim/sulphamethoxazole

Studies by Institute of Tropical Medicine, Antwerp in Zambia and UCSF in Uganda

Co-trimoxazole

Phase III for malaria

An antibacterial with activity against malaria. Early data in children showed similar efficacy to amodiaquine artesunate. A Phase III study comparing against SP and DHA-piperaquine is expected to be completed in Jul 2014. A Phase III study with 1,714 subjects in Zambia is testing its effectiveness as prophylaxis to prevent malaria in pregnancy, expected to be completed in Nov 2011

[77–80] NCT01053325 NCT00948896

Rbx11160/OZ277 150 mg, piperaquine phosphate 750 mg

MMV, Ranbaxy

Arterolane maleate + piperaquine phosphate

Phase III

First generation synthetic peroxide (trioxalane), given as one tablet per day for three days. Arterolane as a monotheraphy drug showed lower efficacy than artesunate with seven days of dosing. A Phase III trial in India, Bangladesh and Thailand is now underway. The medicine was approved in India in early 2012.

[81–86] NCT00362050

OZ439

MMV, (University of Nebraska, Monash University and Swiss TPHI)

Phase IIa (monotherapy)

Next-generation synthetic peroxide. Phase I showed OZ439 was safe at doses up to 1,600 mg as a single dose, and gives plasma concentrations with anti-parasite activity up to 72 hours. A Phase IIa study in P. falciparum and P. vivax patients was completed in mid-2012.

[84] NCT01383096 NCT00928083

SSR97193, artesunate

Sanofi

Ferroquine

Phase IIa

4-aminoquinoline active in vitro against multidrug resistant P. falciparum. Phase II studies showed that it is active in combination with artesunate in African adults and children. Project was put on hold, presumably because of insufficient product differentiation.

[87–91]

Fosmidomycin, clindamycin

Jomaa Pharma Ltd

Fosclin

Phase IIa

Fosmidomycin is a DOXP inhibitor, used in combination with the antibiotic clindamycin. A study in children showed good tolerability and 94% efficacy. A further Phase II was completed in Sept 2011.

[92–96]

Methylene blue, chloroquine

Ruprecht-Karls-Universität, Heidelberg, DSM

Phase II

Methylene blue was originally suggested by Paul Ehrlich. The combination MB-CQ is safe in adults and children with or without G6PD deficiency. Local acceptability studies imply discolouration of urine is not seen as a major issue.

[97–99]

NITD609

Novartis, MMV

Phase IIa (monotherapy)

Spiroindolone suppresses protein synthesis in the parasite, working through PfATP4. NITD609 has the pharmacokinetic properties compatible with once-daily oral dosing for the potential treatment of falciparum and vivax malaria. A Phase IIa trial started in December 2011.

[100, 101]

Actelion antimalarial

Actelion

Phase I

A compound of undisclosed structure with similar parasite reduction rates as chloroquine. Completed Phase I in summer 2012

GNF156

Genome Foundation of Novartis, MMV

Preclinical

An imidazolopiperazine active against blood, liver and gametocytes, with stages of Plasmodium, and active in murine models. Preclinical safety studies started in the first quarter of 2011, and Phase I early in 2012.

Oxaboroles

Anacor, MMV

Preclinical

A new class of oxaboroles. Highly potent against P. falciparum parasites, and curative in animal models. Has a good safety profile and excellent drug-like properties, and low cost-of-goods.

DSM265

University of Texas Southwestern, MMV, University of Washington, Monash University

Preclinical

A dihydroorotate dehydrogenase (DHODH) inhibitor. In June 2010, a compound was chosen from the inhibitor series for full preclinical development. First in human studies are planned for early 2013.

[102–105]

MK4815

Merck, MMV

Preclinical

A cell-based inhibitor that has demonstrated potency against P. falciparum malaria when tested in vivo. Its mechanism of action appears to involve the mitochondrial electron transport chain of the parasite, and when administered, concentrates in infected erythrocytes. Due to safety issues, the molecule is still in preclinical evaluation.

P218

BIOTEC, Monash University, LSHTM, MMV

Preclinical

A dihydrofolate reductase inhibitor binds with high affinity to the wild-type and resistant DHFR enzymes and has an excellent ADME-PK profile. Currently in preclinical development, although there are concerns about the impact of pre-existing DHFR mutant stains of parasite.

Genz668764

Genzyme Corp (Sanofi), MMV

Preclinical

An aminoindole, with activity against both P. falciparum and P. knowlesi. This family has the advantage that it has been impossible so far to produce resistant mutant strains of parasite. Preclinical evaluation started in early 2011.

[106]

RKA 182

Liverpool School of Tropical Medicine, Liverpool University

Preclinical

Lead compound from a series of tetraoxanes with rapid anti-parasitic activity. Has shown anti-malarial activity against a range of multi-drug resistant isolates. Its half-life is intermediate between OZ277 and OZ439. Next-generation compounds are currently being tested.

[107, 108]

BCX4945

Albert Einstein College of Medicine, Biocryst Pharmaceuticals,

On Hold

Parasites cultured in human erythrocytes can be killed rapidly by this purine nucleoside phosphorylase (PNP) (immucillin-H). Purine salvage pathways in the mouse suggest a mechanism for lack of in vivo activity, and that these compounds will have to be tested directly in human challenge models.

[109, 110]

CDRI 99/411

Ipca, CDRI

On Hold

A trioxane anti-malarial candidate, shown initially to be safe in pre-clinical studies. An IND was approved in March 2010 in India, but no further progress has been reported.

[111]

AQ-13

Immtech

On hold

AQ-13 is another 4-aminoquinoline, active against chloroquine-resistant P. falciparum infection. A Phase I study with 126 individuals was successfully completed in 2005, but no further development was reported. The compound has no significant advantages over other 4-aminoquinolines.

[112, 113] NCT00323375

N-tertiary-butyl isoquine

Liverpool School of Tropical Medicine, GSK, MMV

On hold

N-tert-butyl isoquine was developed as a safer alternative to amodiaquine. In May 2008, a single-blinded, placebo-controlled, randomized Phase I trial was initiated in healthy volunteers. The trial was stopped later in 2008 as a result of adverse events, at the highest dose. Experiments are ongoing to recalculate the estimated human effective dose.

[114–117]

SAR116242/PA1103

Palumed, MMV

On hold

A fusion compound containing a trioxane ring and a 4-aminoquinoline group. It entered preclinical development in 2007, but has not progressed into human studies.

[118]

Artemisone

Hong Kong University of Science and Technology, (MMV, Bayer)

Artemefone (semisynthetic artemisinin derivative)

On hold

In preclinical studies, artemisone, a new artemisinin derivative proposed to have enhanced safety over artesunate. Currently being discussed as an option for treating artemisinin-resistant malaria, although clinical trials have not started, and a commercial partner is still being sought.

[119–122] NCT00936767