Spiroindolone KAE609 for Falciparum and Vivax Malaria

White, Nicholas J.; Pukrittayakamee, S.; Phyo, Aung Phae; Rueangweerayut, Ronnatrai; Nosten, François; Jittamala, Podjanee; Jeeyapant, Atthanee; Jain, Jay Prakash; Lefèvre, Gilbert; Li, R; Magnusson, Baldur; Diagana, Thierry T.; Leong, F. Joel

doi:10.1056/nejmoa1315860

Cited by 210 publications

(202 citation statements)

References 13 publications

Supporting

Mentioning

195

Contrasting

Order By: Relevance

“…First, the host-mediated mechanism leads to extremely rapid clearance in vivo, thus obviating the need for extended coverage. Indeed, the spiroindolones have proven faster acting in the clinic than expected from preclinical modeling (30). Second, they have exquisite selectivity due to a host-mediated mechanism-only affecting infected and treated erythrocytes.…”

Section: Clearance Ofmentioning

confidence: 99%

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Jiménez-Dı́az

Ebert

Salinas

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

212

291

View full text Add to dashboard Cite

Significance Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.

show abstract

Section: Clearance Ofmentioning

confidence: 99%

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Jiménez-Dı́az

Ebert

Salinas

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

212

291

View full text Add to dashboard Cite

show abstract

“…The importance of identifying multistage active compounds -those that can prevent liver infection and transmission, as well as cure symptomatic blood stage infections -is becoming increasingly appreciated (8). The challenge of developing liver stage active compounds is highlighted by the recently developed spiroindolone class of antimalarial drugs, which -despite having remarkably potent blood stage killing kinetics (median parasite clearance half-life of 0.9 hours) and a potentially novel target (PfATP4) -have failed to demonstrate significant liver stage activity (24,25). One major barrier in the development of liver stage active compounds is the lack of a model system that sufficiently reproduces the complexity of human liver infection with P. falciparum.…”

Section: Discussionmentioning

confidence: 99%

Assessing drug efficacy against Plasmodium falciparum liver stages in vivo

et al. 2018

View full text Add to dashboard Cite

“…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). The median fever clearance time was 8 hours and 12 hours for P. vivax and P. falciparum, respectively.…”

Section: Introductionmentioning

confidence: 99%

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

Huskey¹,

Zhu²,

Fredenhagen³

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

KAE609 [(19R,39S)-5,79-dichloro-69-fluoro-39-methyl-29,39,49,99-tetrahydrospiro[indoline-3,19-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. This study investigated the absorption, distribution, metabolism, and excretion of KAE609 after oral administration of [ 14 C]KAE609 in healthy subjects. After oral administration to human subjects, KAE609 was the major radioactive component (approximately 76% of the total radioactivity in plasma); M23 was the major circulating oxidative metabolite (approximately 12% of the total radioactivity in plasma). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for approximately 3%-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized, such that KAE609 accounted for approximately 32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported semen discoloration after dosing in prior studies; therefore, semen samples were collected once from each subject to further evaluate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the rationale that this yellow-colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biologic matrices albeit at low levels. All 19 recombinant human cytochrome P450 enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was used to generate a sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in humans are summarized herein and M23 is the major metabolite in plasma and excreta.

show abstract

Spiroindolone KAE609 for Falciparum and Vivax Malaria

Abstract: BACKGROUND-KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum.

Cited by 210 publications

References 13 publications

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Assessing drug efficacy against Plasmodium falciparum liver stages in vivo

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

Contact Info

Product

Resources

About