Evaluating the safety, pharmacokinetics, and antiparasitic activity of DSM265, a novel antimalarial plasmodium dihydroorotate dehydrogenase inhibitor: a systematic review and meta-analysis of early clinical trials

Background The growing resistance to current antimalarial drugs has stalled the eradication of malaria in endemic countries. DSM265 has recently been studied in phase I and II clinical trials. Aim This meta-analysis aims to evaluate the safety, pharmacokinetics (PK), and antiparasitic activity of DSM265 based on available early-phase clinical trials. Methods This systematic review (PROSPERO: CRD42024499167) was conducted to identify any relevant clinical trials reporting DSM265 safety and PK data. Five databases were searched, i.e., PubMed, Cochrane CENTRAL, EBSCOhost, Clinicaltrials.gov, and ScienceDirect. Eligible clinical trials on DSM265 that reported safety outcomes and PK parameters were included. The risk of bias was assessed by Cochrane’s Collaboration tool. Meta-analysis was conducted to present the pooled adverse events (AEs) and summary estimates for PK parameters, including maximum drug concentration (Cmax [μg/mL]), time to maximum drug concentration (Tmax [hours (h)]), elimination half-lives (T1/2 [h]), and area under the concentration–time curves (AUCs [h·μg/mL]). Subgroup analysis and meta-regression analyses were conducted among various doses and drug formulations. Results Seven trials were eligible for systematic review. Overall, DSM265 was associated with increased risks of AEs (relative risk [RR] [95% CI] = 1.46 [1.15, 1.84]); subgroup analysis showed significant risks only among the low-dose (25–250 mg) (RR [95% CI] = 1.86 CI [1.36, 2.54]) and high-dose (600–1200 mg) (RR [95% CI] = 1.67 CI [1.03, 2.72]) subgroups. When given as oral suspension at 400 mg dose, DSM265 achieved Cmax: 9.3 μg/mL (95% CI = 7.5, 11.2), Tmax: 5.4 h (95% CI = 2.7, 8.2), T1/2: 112.1 h (95% CI = 91.3, 132.9), and AUC0-∞h: 1,601.9 h·μg/mL (95% CI = 1,233.5, 1970.3). A substantial heterogeneity in PK parameters was evident and justified in meta-regression, which showed linear dose-PK parameter relationships. DSM265 has been shown to target Plasmodium falciparum DHODH with greater selectivity compared to Plasmodium vivax. Furthermore, the drug did not exhibit anti-gametocyte activity which was consistent with preclinical studies. Conclusion In this meta-analysis, DSM265 demonstrated a favorable safety profile after a single 400 mg dose. While preclinical signals of teratogenicity and testicular toxicity have halted further development, these effects were not reported in the included clinical trials. Substantial variability in PK parameters was noted, driven primarily by administered doses.