Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study

Abstract

SummaryBackgroundDSM265 is a novel, long-duration inhibitor of plasmodium dihydroorotate dehydrogenase (DHODH) with excellent selectivity over human DHODH and activity against blood and liver stages of Plasmodium falciparum. This study aimed to assess the efficacy of DSM265 in patients with P falciparum or Plasmodium vivax malaria infection.MethodsThis proof-of-concept, open-label, phase 2a study was conducted at the Asociación Civil Selva Amazónica in Iquitos, Peru. Patients aged 18–70 years, weighing 45–90 kg, who had clinical malaria (P falciparum or P vivax monoinfection) and fever within the previous 24 h were eligible. Exclusion criteria were clinical or laboratory signs of severe malaria, inability to take oral medicine, and use of other antimalarial treatment in the preceding 14 days. Patients were divided into cohorts of those with P falciparum (cohort a) or P vivax (cohort b) infection. Two initial cohorts received single oral doses of 400 mg DSM265. Patients were followed up for efficacy for 28 days and safety for 35 days. Further cohorts received escalated or de-escalated doses of DSM265, after safety and efficacy assessment of the initial dose. The primary endpoints were the proportion of patients achieving PCR-adjusted adequate clinical and parasitological response (ACPR) by day 14 for patients infected with P falciparum and the proportion of patients achieving a crude cure by day 14 for those infected with P vivax. Cohort success, the criteria for dose escalation, was defined as ACPR (P falciparum) or crude cure (P vivax) in at least 80% of patients in the cohort. The primary analysis was done in the intention-to-treat population (ITT) and the per-protocol population, and safety analyses were done in all patients who received the study drug. This study is registered at ClinicalTrials.gov (NCT02123290).FindingsBetween Jan 12, 2015, and Dec 2, 2015, 45 Peruvian patients (24 with P falciparum [cohort a] and 21 with P vivax [cohort b] infection) were sequentially enrolled. For patients with P falciparum malaria in the per-protocol population, all 11 (100%) in the 400 mg group and eight (80%) of ten in the 250 mg group achieved ACPR on day 14. In the ITT analysis, 11 (85%) of 13 in the 400 mg group and eight (73%) of 11 in the 250 mg group achieved ACPR at day 14. For the patients with P vivax malaria, the primary endpoint was not met. In the per-protocol analysis, none of four patients who had 400 mg, three (50%) of six who had 600 mg, and one (25%) of four who had 800 mg DSM265 achieved crude cure at day 14. In the ITT analysis, none of five in the 400 mg group, three (33%) of nine in the 600 mg group, and one (14%) of seven in the 800 mg group achieved crude cure at day 14. During the 28-day extended observation of P falciparum patients, a resistance-associated mutation in the gene encoding the DSM265 target DHODH was observed in two of four recurring patients. DSM265 was well tolerated. The most common adverse events were pyrexia (20 [44%] of 45) and headache (18 [40%] of 45), which are both common ...

Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study

“…The estimated log 10 PRR 48 in this study is similar to the reported values of chloroquine-sensitive isolates (range 2.6-3.6), 38,39 mefloquine (2.6), 38 and halofantrine (2.3). 38 However, the log 10 PRR 48 estimated for chloroquine is lower than artesunate (3.2), 38 artemether (3.2), 38 artefenomel (range 4.6-6.3), 40 and ganaplacide (range 3.1-3.8), 41 but higher than primaquine (1.0), 38 quinine (2.0), 38 DSM265 (range 0.8-1.5), 42 and sulfadoxine-pyrimethamine (range 1.2-1.5) 38 in patients with P. vivax malaria. Simulations showed that chloroquine efficacy was sensitive to changes in E max CQ.…”

Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum

“…Resistance continues to be problematic however, with a number of antimalarials in development yielding resistance readily in culture (Blasco et al, 2017). A recent clinical trial showed that mutations affording moderate resistance to the plasmodial DHODH inhibitor DSM265 were identified in P. falciparum-infected patients who recrudesced following a single dose (Llanos-Cuentas et al, 2018). Resistance also arises readily to another mitochondrial inhibitor, atovaquone, which targets cytochrome b and inhibits electron transport.…”

A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers

“…Parasitemia was measured each morning from day 4 until qPCR results became positive and thereafter at 12-h intervals until treatment initiation. Monitoring then occurred pretreatment and at the following time points posttreatment: 2,4,8,12,16,20,24,30,36,48,60,72,84,96,120, and 144 h. Subsequent measurements were approximately three times per week until the end of the study.…”

“…Preclinical studies indicated that DSM265 is highly selective toward Plasmodium DHODH and is active against both blood and liver stages of P. falciparum (13). Clinical studies have also been performed which have demonstrated the good tolerability profile of DSM265 in humans and its activity in clearing P. falciparum parasitemia (4,(14)(15)(16).…”