Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development

Abstract

The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping review provides an overview of antimalarial drug candidates undergoing phase I and II studies between 1 January 2016 and 28 April 2021. PubMed, Web of Science, Embase, clinical trial registries and reference lists were searched for relevant studies. Information regarding antimalarial compound details, clinical trial characteristics, study population, drug pharmacokinetics and pharmacodynamics (PK-PD) were extracted. A total of 50 studies were included of which 24 had published their results and 26 were unpublished. New antimalarial compounds were evaluated as monotherapy (28 studies, 14 drug candidates) and combination therapy (9 studies, 10 candidates). Fourteen active compounds were identified in the current antimalarial drug development pipeline together with 11 compounds that are inactive; six due to insufficient efficacy. PK-PD data were available from 24 studies published as open-access articles. Four unpublished studies have made their results publicly available on clinical trial registries. The terminal elimination half-life of new antimalarial compounds ranged from 14.7 to 483 hours. The log 10 parasite reduction ratio over 48 hours and parasite clearance half-life for P. falciparum following a single dose monotherapy were 1.55–4.1 and 3.4–9.4 hours, respectively. The antimalarial drug development landscape has seen a number of novel compounds, with promising PK-PD properties, evaluated in phase I and II studies over the past 5 years. Timely public disclosure of PK-PD data is crucial for informative decision-making and drug development strategy.

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity

“…1 Although there are clinically approved antimalarial agents in use, drug resistance has spread quickly and widely, and the limited availability of antimalarials has led many researchers to seek new antimalarials. 2–4…”

“…1 Although there are clinically approved antimalarial agents in use, drug resistance has spread quickly and widely, and the limited availability of antimalarials has led many researchers to seek new antimalarials. [2][3][4] In Plasmodium, thiamine 1 (Fig. 1) is converted into its active form, thiamine pyrophosphate (TPP) 2, by the enzyme thiamine pyrophosphokinase (TPK).…”

Discovery of New Broad-Spectrum Anti-Infectives for Eukaryotic Pathogens Using Bioorganometallic Chemistry

“…8,9 A successful strategy for developing low-cost, alternative therapies to improve the potency and therapeutic scope of an organic anti-infective drug is the use of metal complexes 10,11 or the addition of a ferrocenyl moiety 12 to the parent drug, as exemplified with the antimalarial ferroquine, 13,14 which successfully completed phase II clinical trials. 15,16 Importantly, we demonstrated that the replacement of one of the triazoles of FCZ by an organometallic moiety (e.g., ferrocene and ruthenocene) allowed unveiling of a subset of FCZ analogs (1a−4a, Figure 1A) more effective than the parent FCZ against various fungal strains. 17 In the present study, we expanded on our previous work and assessed the efficacy of eight newly synthesized FCZ analogs (5a−12a; Figure 1B) that are metabolically more stable than the previous series tested on a panel of clinical fungal isolates, including highly drug-resistant strains.…”

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

“…Estimates of the PK-PD model parameters can be derived using different statistical methods. Maximum likelihood methods are widely used in the analysis of data from early phase antimalarial-drug trials [9,16]. However, these methods are limited, often failing to achieve convergence unless 10 many of the parameter values are fixed.…”

“…Drug development is a resource-heavy, expensive and time-consuming process, with only approximately 10% of drugs tested in Phase 1 trials ultimately gaining approval [8]. 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].…”