Spiroindolone KAE609 for Falciparum and Vivax Malaria

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

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.).

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antimalarials / adverse effects
  • Antimalarials / pharmacokinetics
  • Antimalarials / therapeutic use*
  • Area Under Curve
  • Female
  • Humans
  • Indoles / adverse effects
  • Indoles / pharmacokinetics
  • Indoles / therapeutic use*
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / metabolism
  • Malaria, Falciparum / parasitology
  • Malaria, Vivax / drug therapy*
  • Malaria, Vivax / metabolism
  • Malaria, Vivax / parasitology
  • Male
  • Middle Aged
  • Nausea / chemically induced
  • Parasite Load
  • Parasitemia / drug therapy
  • Plasmodium falciparum / isolation & purification
  • Plasmodium vivax / isolation & purification
  • Spiro Compounds / adverse effects
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / therapeutic use*
  • Thailand
  • Young Adult

Substances

  • Antimalarials
  • Indoles
  • NITD 609
  • Spiro Compounds

Associated data

  • ClinicalTrials.gov/NCT01524341