Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

Abstract

Background The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether–lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. Methods This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether–lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. Results Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether–lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether–lumefantrine. Cipargamin was well tolerated with no safety concerns. Conclusions This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin. Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202

Evaluation of a Bayesian hierarchical pharmacokinetic-pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs

“…The simulated 8-patient PK datasets provided a good visual match to the trial data from McCarthy et al [14] (Figure S1). The PK model was incorporated into a Bayesian hierarchical framework, and fitted to each of the 1000 simulated datasets, restricting data to the cipargamin concentrations which correspond to the sampling times of the original Phase 2 trial (1,2,3,4,6,8,12,16,24,36,48,72,96 and 120 hours post-treatment), and the posterior median estimate of each population PK parameter obtained. To evaluate how accurately this model can estimate PK parameters, we calculated the difference (absolute and relative bias) between the posterior median estimate of the population-level PK parameter, and the value used to simulate the data (i.e., the 'true' value).…”

“…The journey from early phase clinical trials to Phase 3 clinical trials in patients, to then drug registration, can take many years [9]. Cipargamin is a promising candidate antimalarial drug that has transitioned from early phase studies [10] to Phase 2 clinical trials of adult patients with falciparum malaria [11, 12]. In particular, it is a rapidly acting parenteral agent with promise to replace artemisinin [13].…”

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…This is considered a promising agent to combat the artemisinin resistance parasite [ 62 ]. Hepatic safety behavior was achieved through clinical studies (phase II) across wide-range doses [ 63 , 64 ].…”

Advances in malaria pharmacology and the online guide to MALARIA PHARMACOLOGY: IUPHAR review 38

“…NITD609 clears P. berghei from mice very rapidly (faster than artemisinin derivatives), has a favourable safety profile (Rottmann et al, 2010) and is effective in several human clinical trials (e.g. Ndayisaba et al, 2021). Mutations in PfATP4 have been identified in parasites resistant to NITD609 through gradual exposure to increasing concentrations of the compound, and overexpression of the mutated PfATP4 protein in parasites confirmed the resistance phenotype.…”

“…falciparum and P. vivax with low nanomolar range IC 50 , block gametocyte development in vitro and oocyst development in mosquitoes(Rottmann et al, 2010;van Pelt-Koops et al, 2012). NITD609 clears P. berghei from mice very rapidly (faster than artemisinin derivatives), has a favourable safety profile(Rottmann et al, 2010) and is effective in several human clinical trials (e.g Ndayisaba et al, 2021)…”