Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria.

Abstract

BACKGROUND:

KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites.

METHODS:

We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg).

RESULTS:

Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts.

CONCLUSIONS:

KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01753323 .).

• Authors: Nicholas J White, Tran T Duong, Chirapong Uthaisin, François Nosten, Aung P Phyo, Borimas Hanboonkunupakarn, Sasithon Pukrittayakamee, Podjanee Jittamala, Kittiphum Chuthasmit, Ming S Cheung, Yiyan Feng, Ruobing Li, Baldur Magnusson, Marc Sultan, Daniela Wieser, Xiaolei Xun, Rong Zhao, Thierry T Diagana, Peter Pertel, F Joel Leong
• Journal: The New England journal of medicine (N Engl J Med) Vol. 375 Issue 12 Pg. 1152-60 (09 22 2016) ISSN: 1533-4406 [Electronic] United States
• PMID: 27653565 (Publication Type: Clinical Trial, Phase II, Journal Article)

Chemical References

• Antimalarials
• Imidazoles
• Piperazines
• ganaplacide

Topics

• Administration, Oral
• Adult
• Antimalarials (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Fever
• Humans
• Imidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Malaria, Falciparum (drug therapy)
• Malaria, Vivax (drug therapy)
• Male
• Middle Aged
• Parasite Load
• Piperazines (administration & dosage, adverse effects, pharmacokinetics)
• Plasmodium falciparum (isolation & purification)
• Plasmodium vivax (isolation & purification)
• Young Adult