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.

F Joel Leong,Ruobing Li,Gilbert Lefèvre,Baldur Magnusson,Thierry T Diagana,Peter Pertel,Jay Prakash Jain

doi:10.1128/aac.03393-14

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.

Highlights

Novartis Institute for Tropical Diseases, Singaporea; Novartis Institutes for BioMedical Research, Beijing, People’s Republic of Chinab; Novartis Healthcare Private Limited, Hyderabad, Indiac; Novartis Pharma AG, Basel, Switzerlandd; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USAe
Gastrointestinal and genitourinary adverse events increased with rising doses
KAE609 was well tolerated in this group of healthy adults, with essentially transient gastrointestinal and genitourinary adverse events of mild to moderate intensity

Summary

Introduction

In an experimental malaria mouse model, KAE609 was more active than artemether, and single-dose cure has been demonstrated in a Plasmodium berghei rodent model of blood-stage malaria [9] This potent antimalarial activity observed in a preclinical rodent model was borne out in a human malaria patient trial, which followed this first-in-human study but was published in advance [16], that showed that KAE609 clears parasitemia rapidly in falciparum and vivax malaria patients. The objectives of this first-in-human study were to assess the safety and tolerability of KAE609 in healthy adult volunteers after single and multiple oral dosing and to assess the pharmacokinetics after single (including food effect) and multiple dosing

Methods

Results

Conclusion