First-in-Humans Study of the Safety, Tolerability, and Pharmacokinetics of ACT-451840, a New Chemical Entity with Antimalarial Activity

Abstract

Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant Plasmodium falciparum strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects. In the 200-and 500-mg dose groups, the effect of food was investigated, and antimalarial activity was assessed using an ex vivo bioassay with P. falciparum. No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (C max ) and the area under the plasma concentration-time curve from zero to infinity of ACT-451840 under fasted conditions reached 11.9 ng/ml and 100.6 ng · h/ml, respectively, and these were approximately 13-fold higher under fed conditions. Food did not affect the half-life (approximately 34 h) of the drug, while the C max was attained 2.0 and 3.5 h postdose under fasted and fed conditions, respectively. The plasma concentrations estimated by the bioassay were approximately 4-fold higher than those measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Several potentially active metabolites were also identified. ACT-451840 was well tolerated across all doses. Exposure to ACT-451840 significantly increased with food. The bioassay indicated the presence of circulating active metabolites. (This study has been registered at ClinicalTrials.gov under registration no. NCT02186002.)

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

“…ACT‐451840, a preclinical drug molecule, is another example of a compound with potent activity against sensitive and resistant P. falciparum strains (Fig. ) . Preclinical studies of CT‐451840 have been carried out by several groups in partnership with academic and industrial researchers .…”

“…6). [70][71][72] Preclinical studies of CT-451840 have been carried out by several groups in partnership with academic and industrial researchers. 73 This compound exhibited a range of activities against multiple life cycle stages of the human malaria parasite P. falciparum (asexual and sexual) and P. vivax (asexual).…”

CRISPR‐Cas9‐modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine‐containing compounds but potentiates artemisinin‐based combination therapy partner drugs

“…ACT-451840 is a potent piperazine-containing compound that targets all three stages (rings, trophozoites, and schizonts) of P. falciparum asexual blood stage development. Phase I clinical trials with this compound, developed by Actelion Pharmaceuticals with support from the Medicines for Malaria Venture, documented a good safety and tolerability profile with no serious adverse events (Bruderer et al, 2015). Heterologous expression studies found that ACT-213615, a previous analog in this chemical series, bound to the P. falciparum transporter PfMDR1 (multidrug resistance-1), which is a parasite ortholog of the mammalian dug efflux transporter P-glycoprotein 1.…”

Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action

“…ACT-451840( 132)i sacandidate for preclinical and clinical development. [21] Further resultswill be reported in due course.…”

“…The compounds act through a novel and unknown mechanism of action. ACT‐451840 ( 132 ) is a candidate for preclinical and clinical development . Further results will be reported in due course.…”