Phase 2a, Open-Label, 4-Escalating-Dose, Randomized Multicenter Study Evaluating the Safety and Activity of Ferroquine (SSR97193) Plus Artesunate, versus Amodiaquine Plus Artesunate, in African Adult Men with Uncomplicated Plasmodium falciparum Malaria

Abstract

Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated malaria. Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to = 12 for each ferroquine dose and = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).

Combining Stage Specificity and Metabolomic Profiling to Advance Antimalarial Drug Discovery

“…WLL-vs is of particular interest given its selectivity for the parasite proteasome and the fact that resistance is rare and low-grade (Li et al, 2016;Stokes et al, 2019;Yoo et al, 2018). Ferroquine has shown promising efficacy in phase II trials (Supan et al, 2017) and our assays indicated a unique ring-active profile that underscores its potential. With GNF-Pf-5660, chemical derivatization efforts are underway to improve its partial in vivo efficacy, established in rodent malaria models (Vanaerschot et al, 2017).…”

“…Methylene blue, in contrast to piperaquine, is also potent against mature gametocytes that are not thought to degrade hemoglobin (Adjalley et al, 2011), implying an additional mode of action for methylene blue that might affect additional redox cycling agents such as NADPH levels (Siciliano et al, 2017). Interestingly, ferroquine and naphthoquine, which are both chloroquine derivatives that are currently part of artemisininbased combination therapies under clinical trials (Isba et al, 2015;Supan et al, 2017), shared a unique stage specificity profile showing peak activity during early rings and a gradual increase of IC 50 8h values through to schizonts (Figure 2). Ferroquine has hemozoin inhibitory activity similar to chloroquine and has been shown to induce the formation of hydroxyl radicals via the Fenton reaction, leading to lipid peroxidation and exacerbating oxidative stress in the parasite (Atamna and Ginsburg, 1993;Chavain et al, 2008;Dubar et al, 2008).…”

Recent updates in the discovery and development of novel antimalarial drug candidates

“…Piperaquine (18), another 4-aminoquinoline, is currently part of an ACT treatment regimen with 3 in a fixed-dose combination, which has shown excellent tolerability and high malaria cure rates. [22][23][24] Discovered more recently is ferroquine (19), which has completed phase IIa clinical trials, 25 and has recently shown efficacy in combination with 1. 26…”

Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs

“…Thus, future patients treated with ferroquine must have their hepatic and cardiac profiles monitored. (42,43) Cipargamin (Fig. 5 -NITD609, Novartis ® ) is a spiroindolone in Phase II clinical trials.…”

“…Thus, future patients treated with ferroquine must have their hepatic and cardiac profiles monitored. 42 , 43 …”