Results of a 3-part trial found that the novel compound triaminopyrimidine ZY-19489 was safe and well-tolerated among healthy adults and should be developed further as an antimalarial therapy. These findings were published in The Lancet Infectious Diseases.
This 3-part trial was conducted in Australia between 2019 and 2020. The first part of this study was a double-blind, randomized, placebo-controlled, single ascending dose trial. Participants (n=48) were randomly assigned in a 3:1 fashion to receive either oral ZY-19489 at a dose of 25, 75, 150, 450, 900, or 1500 mg or placebo. The second part was an open-label, randomized, 2-period cross-over, food-effect trial. Participants (n=8) were randomly assigned in a 1:1 fashion to receive ZY-19489 300 mg in a fasted-fed or fed-fasted sequence. The third part of this study was an open-label, randomized, volunteer infection trial. Participants (n=15) were infected with Plasmodium falciparum and received ZY-19489 at a dose of either 200, 300, or 900 mg. The primary outcomes for all 3 parts were the incidence and severity of adverse events related to treatment with ZY-19489. The safety, pharmacokinetics, and parasite clearance associated with ZY-19489 were also assessed.
Among all participants included in the analysis, the mean age ranged between 23.8 and 31.0 years and men comprised between 0% and 83% of those included in each group.
In part 1, 72% of participants who received ZY-19489 and 50% of those who received placebo reported 1 or more adverse events. Events considered to be related to treatment with ZY-19489 were reported by 50% of participants, with headache as the most common adverse event. Drug-related events were more common among participants who received ZY-19489 1500 mg, all of whom experienced mild gastrointestinal symptoms.
In part 2, all participants allocated to receive ZY-19489 reported 1 or more adverse events, with headache as the most common event. One participant withdrew from the study due to the development of a grade 3 increase in the concentration of aspartate aminotransferase on day 27, which was likely unrelated with the study procedures.
In part 3, all participants allocated to receive ZY-19489 reported 1 or more adverse events, of which the majority were associated with complications of malaria. Drug-related events included headache, diarrhea, nausea, and myalgia. On day 8, prior to receipt of ZY-19489 300 mg, 1 participant developed severe neutropenia after P falciparum inoculation. This participant also developed a temperature of 38.1°C and was subsequently admitted to the hospital and administered intravenous piperacillin-tazobactam.
Among participants who received oral ZY-19489 at any dose, the researchers found that the median time to reach the maximum serum concentration (tmax) ranged between 5.0 and 8.8 hours, with an elimination half-life (t1/2) that ranged between 49.9 and 97.0 hours. Among participants who received a 300-mg dose of ZY-19489, delayed absorption was observed among those who received treatment after a meal compared with those who received treatment before a meal, with a median tmax of 12.0 vs 6.0 hours, respectively.
Among participants included in the infection study, the parasite clearance rate was similar for those who received ZY-19489 at either the 200 mg (parasite clearance rate [log10 PRR48], 2.21; 95% CI, 2.09-2.33), 300 mg (log10 PRR48, 2.13; 95% CI, 2.03-2.23), and 900 mg (log10 PRR48, 2.04; 95% CI, 1.91-2.18) doses. Recrudescence up to day 23 was observed among 80% of participants who received ZY-19489 200 mg, 63% of those who received 300 mg, and none of those who received ZY-19489 900 mg.
The researchers performed whole-genome sequencing and found that recrudescent parasites from 7 participants showed no coding or copy-number variations compared with the parental strain.
This study was limited by its population, as participants were younger (age range, 18-55 years) and healthy, and the majority were White (range, 75%-100%).
According to the researchers, “combination treatments are the focus of new antimalarial therapies to [decrease] the risk [for] drug resistance development and ensure clearance of different parasite lifecycle stages. They concluded that, “consideration of partner drugs will be important for ZY-19489 given the apparent absence of activity against the liver stage and transmissible sexual stage of the parasite lifecycle observed in preclinical studies.”
Disclosure: Multiple authors declared affiliations with industry. Please see the original reference for a full list of disclosures.
Barber BE, Fernandez M, Patel HB, et al. Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study. Lancet Infect Dis. Published online March 2, 2022. doi:10.1016/S1473-3099(21)00679-4