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 .).

Figure 1. Parasite Counts in the Multiple-Dose and Single-Dose Cohorts.

Shown are individual parasite counts from screening until parasite clearance in patients with Plasmodium vivax malaria (cohort 1) or P. falciparum malaria (cohort 2) who received KAF156 at a dose of 400 mg daily for 3 days (Panel A) and patients with P. falciparum malaria who received a single 800-mg dose (cohort 3) (Panel B). Each line represents an individual patient. In each cohort, the solid vertical line indicates the median parasite clearance time.

Figure 2. Mean Plasma Concentration–Time Profiles of KAF156.

The data for patients in the multiple-dose cohorts on day 1 and day 3 after oral administration of 400 mg once daily (day 1 to day 3) are shown in patients with P. vivax infection (Panel A) and in those with P. falciparum infection (Panel B). Panel C shows the data for patients with P. falciparum infection in the single-dose cohort. I bars indicate standard deviation.