A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers

Abstract

This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–∞) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24 on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (≤0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the Cmax was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.

Imaging-Based High-Throughput Screening Assay To Identify New Molecules with Transmission-Blocking Potential against Plasmodium falciparum Female Gamete Formation

“…These phenotypic screenings have identified new active compounds, and some of them (KAE609 [45], OZ439 [46]) are currently in clinical development. To achieve the goal of malaria eradication proposed by the scientific community, the same approach should be applied to parasite stages, responsible for transmission.…”

KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects

“…1), a spiroindolone, represents a new class of potent, fast-acting, schizonticidal agents Yeung et al, 2010;Meister et al, 2011;Spillman et al, 2013). KAE609 was safe and well tolerated in healthy subjects up to the highest tested single dose of 300 mg and the highest tested multiple dose of 150 mg daily for 3 days (Leong et al, 2014). Evaluation in 21 evaluable adult patients with uncomplicated malaria due to either P. vivax (n = 10) or P. falciparum (n = 11) showed that once-daily dosing of KAE609 at 30 mg for 3 days was well tolerated and resulted in a rapid median parasite clearance time of approximately 12 hours for both P. vivax and P. falciparum (White et al, 2014).…”

Identification of Three Novel Ring Expansion Metabolites of KAE609, a New Spiroindolone Agent for the Treatment of Malaria, in Rats, Dogs, and Humans

“…1; Yeung et al, 2010), a spiroindolone, represents a new class of potent, fast-acting, schizonticidal agents for the treatment of malaria Meister et al, 2011;Spillman et al, 2013). More recently, KAE609 was shown to be safe and well tolerated in healthy subjects up to a single dose of 300 mg and multiple doses of 150 mg daily for 3 days (Leong et al, 2014). Evaluation in 21 adult patients with uncomplicated malaria due to either Plasmodium vivax (n = 10) or Plasmodium falciparum (n = 11) showed that once-daily dosing of KAE609 at 30 mg for 3 days resulted in a rapid median parasite clearance time of approximately 12 hours for both P. vivax and P. falciparum (White et al, 2014).…”