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.)

New developments in anti-malarial target candidate and product profiles

“…But more recent studies in patients, such as those with a single dose of KAF156 [10], OZ439 [26], DSM265 [27, 28] or three doses of ferroquine [29] have allowed a 28-day follow-up. The best molecules are now giving clinical efficacy of 70–90% when used as monotherapy.…”

“…The last 4 years has seen a new generation of compounds with novel mechanisms of action entering clinical development [6]. These have resulted from a combination of phenotypic screening and rational design, with four new compounds currently shown to be active in patients: OZ439 [7], KAE609 [8], KAF156 [9, 10], and DSM265 [11]. However, in the same 4 years there have been increasing reports of multi-drug resistant malaria in the Greater Mekong Sub-region (GMS).…”

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

“…This compound recently showed encouraging clinical efficacy, with 14 of 21 patients cured of acute uncomplicated P. falciparum malaria following treatment with a single dose 113 . Resistance to KAF156 and related imidazolopiperazines in ABS can be mediated by point mutations in the P. falciparum cyclic amine resistance locus ( pfcarl ), which encodes a conserved protein that localizes in the cis -Golgi apparatus, where it might contribute to protein sorting or membrane trafficking 111,114 .…”

Malaria Parasites: The Great Escape

“…With the advent of decreased efficacy of artemisinin (15, 16), it is now clear that new drugs and other interventions should be developed (9, 17, 18). New drug families, such as spiroindolones (19, 20) and imidalopiperazines (21, 22) compounds, have shown promising results in phase II clinical trials in the recent years and have a great future ahead. However, a vaccine would be the most important tool in the armamentarium against malaria.…”