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N Engl J Med. 2014 Jul 31;371(5):403-10. doi: 10.1056/NEJMoa1315860.

Spiroindolone KAE609 for falciparum and vivax malaria.

Author information

1
From the Mahidol-Oxford Tropical Medicine Research Unit (N.J.W., F.N., A.J.) and the Department of Clinical Tropical Medicine (S.P., P.J.), Faculty of Tropical Medicine, Mahidol University, Bangkok, and the Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University (A.P.P., F.N.), and Mae Sot General Hospital (R.R.), Mae Sot - all in Thailand; the Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom (N.J.W., F.N.); Novartis Healthcare, Hyderabad, India (J.P.J.); Novartis, Basel, Switzerland (G.L., B.M.); Novartis Institute of Biomedical Research, Beijing (R.L.); and Novartis Institute for Tropical Diseases, Singapore (T.T.D., F.J.L.).

Abstract

BACKGROUND:

KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum.

METHODS:

We conducted a phase 2, open-label study at three centers in Thailand to assess the antimalarial efficacy, safety, and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days, in two sequential cohorts of adults with uncomplicated P. vivax malaria (10 patients) or P. falciparum malaria (11). The primary end point was the parasite clearance time.

RESULTS:

The median parasite clearance time was 12 hours in each cohort (interquartile range, 8 to 16 hours in patients with P. vivax malaria and 10 to 16 hours in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 hours (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 hours (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 hour. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 hours (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen.

CONCLUSIONS:

KAE609, at dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01524341.).

Comment in

PMID:
25075833
PMCID:
PMC4143746
DOI:
10.1056/NEJMoa1315860
[Indexed for MEDLINE]
Free PMC Article

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