Fexinidazole Winthrop (fexinidazole) / Sanofi - LARVOL DELTA

Design, synthesis, and antitrypanosomal activity of novel analogs of the hit benzofuranone for the protozoan parasitic disease Human African trypanosomiasis | Poster Board #1757 (ACS-Fall 2026) - "Currently available treatments, including fexinidazole, pentamidine, suramin, melarsoprol, nifurtimox, and eflornithine are limited by drug resistance, toxicity, poor CNS penetration, and the need for parenteral administration. Further derivatization of the hit/analogs was also carried out for biological evaluation. The design, synthesis, and antitrypanosomal activity of the analogs will be presented."

CNS Disorders • Infectious Disease • Narcolepsy • Sleep Disorder

Design, synthesis, and antitrypanosomal activity of novel analogs of the hit benzofuranone for the protozoan parasitic disease Human African trypanosomiasis | Poster Board #1173 (ACS-Fall 2026) - "Currently available treatments, including fexinidazole, pentamidine, suramin, melarsoprol, nifurtimox, and eflornithine are limited by drug resistance, toxicity, poor CNS penetration, and the need for parenteral administration. Further derivatization of the hit/analogs was also carried out for biological evaluation. The design, synthesis, and antitrypanosomal activity of the analogs will be presented."

CNS Disorders • Infectious Disease • Narcolepsy • Sleep Disorder

Pharmacokinetics and Tolerability of Fexinidazole in Subjects with Hepatic Impairment. (PubMed, Clin Drug Investig) - "A single oral dose of 1200 mg of fexinidazole showed a good safety profile and was well-tolerated in participants with mild and moderate HI and matched healthy controls. These slight PK modifications suggest they should not modify the efficacy and safety of fexinidazole in patients with HAT who have mild or moderate HI, compared with those without HI, supporting its use in this population with appropriate clinical recommendations."

Journal • PK/PD data • CNS Disorders • Hepatology • Narcolepsy • Sleep Disorder

Simultaneous Determination of Fexinidazole and Its Major Metabolites in Rat Plasma by UPLC-MS/MS: Method Validation and Application to Pharmacokinetic Study. (PubMed, Drug Des Devel Ther) - "An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of fexinidazole, M1, and M2 in rat plasma, using fluconazole as the internal standard (IS). The developed UPLC-MS/MS method exhibited satisfactory sensitivity, accuracy, and reproducibility for the quantification of fexinidazole and its active metabolites in rat plasma. This method provides reliable analytical support for pharmacokinetic studies and contributes to the preclinical investigation of fexinidazole."

Journal • PK/PD data • Preclinical

RNA Polymerase 1 inhibitors against African trypanosomes in vitro and in mice. (PubMed, Antimicrob Agents Chemother) - "Therapy of human African trypanosomiasis, fatal if not treated, has been greatly improved by orally available and safer fexinidazole, but reliable cure of late-stage central nervous system (CNS) infection remains a challenge...Although Compound 2 accumulates 20-fold in mouse brain tissue vs plasma, efficacy against CNS T. b. brucei in mice was limited. RNA Pol 1 remains an attractive target for developing new and more selectively toxic antitrypanosomal agents."

Journal • Preclinical • Infectious Disease • Oncology

Control of Human African Trypanosomiasis in the Nola-Bilolo Focus, Central African Republic, 2020-2024: Outcome of Capacity Building, Improved Diagnosis and Treatment. (PubMed, J Parasitol Res) - "The introduction of fexinidazole (2021) and mAECT (2022) likely contributed to the rise in reported cases (from 45 in 2021 to 111 in 2024) and improved screening coverage in the study area, reflecting enhanced case detection and access to care. There is a necessity to establish diagnostic quality assurance and to reinforce the other control measures including vector control."

Journal

Effects of CYP3A4 variants and drug-drug interactions on the metabolism of fexinidazole. (PubMed, Biochem Pharmacol) - "Furthermore, continuous administration of EGCG significantly downregulated key hepatic CYP450 (CYP3a1, CYP2d1/2, CYP2b1/2, and CYP2c11) at both the protein and mRNA levels. This study elucidated the major metabolic pathways of fexinidazole and reported the effects of genetic polymorphisms and the drug EGCG on its metabolism for the first time."

Journal • CYP3A4

Unexpected Clinical Drug-Drug Interaction of Fexinidazole on Midazolam Pharmacokinetics: Insights into Underlying Mechanisms from Clinical Phase I Study Results and Supporting In Vivo/Vitro Evidence. (PubMed, Clin Drug Investig) - "While in vitro studies showed weak induction by fexinidazole and its metabolite M1, the clinical pharmacokinetic data provided stronger evidence, supporting the conclusion that fexinidazole is a moderate inducer of CYP3A4/5 in vivo. Thus, it is suggested to update the product information by including the potential for CYP3A4/5 induction in vitro, removing the risk of CYP3A4 inhibition in vivo, and adding clinical interaction data highlighting the risk of induction on drugs predominantly metabolised by CYP3A4/5."

Journal • P1 data • PK/PD data • Preclinical

Extending Thioflavin T Fluorescence Probe to 2-Ethenyl-benzothiazole Derivatives: Drug-like Quadruplex Ligands with Potent Antitrypanosomatid Activity. (PubMed, ACS Infect Dis) - "In fact, compound 2b demonstrated superior efficacy and selectivity in comparison to the clinically used drugs suramin, fexinidazole, miltefosine, and amphotericin B. Biophysical studies revealed that all tested derivatives exhibited significant G4 stabilization, surpassing ThT. Location of compound 2b inside the nucleus and the kinetoplast, as well as partially in the mitochondria, opens up the possibility of 2b acting against the parasite through binding to G4."

Journal • Infectious Disease

Strengthening community engagement in the delivery of fexinidazole, a new oral drug against Human African Trypanosomaisis (HAT) in the Democratic Republic of Congo (ASTMH 2025) - "By the end of the project, 1118 HAT patients had been treated with fexinidazole in DRC, representing 64% of all patients treated with fexinidazole in Africa. Community involvement may have played an important role in activities raising awareness about fexinidazole and thus is an important component in the elimination of this disease."

Narcolepsy • Sleep Disorder

Diagnosis and treatment of T.b. gambiense HAT patients with fexinidazole and the active search for trypanolysis-positive cases in the DRC from 2020 to 2021 (ASTMH 2025) - "Fixed health facilities made a significant contribution to diagnosis and ensured the treatment of all patients. Given the declining prevalence of HAT and reduced donor funding, passive screening at health facilities may be the best way to achieve the WHO goal of eliminating sleeping sickness by 2030."

Clinical • Narcolepsy • Sleep Disorder

Fexinidazole results in specific effects on DNA synthesis and DNA damage in the African trypanosome. (PubMed, PLoS Negl Trop Dis) - "Fexinidazole recently joined benznidazole and nifurtimox in this family when it was approved as the first oral monotherapy against Human African trypanosomiasis (HAT). These findings highlight the relationship between nitroaromatic drug treatments, DNA damage formation, and ROS activation. Deconvolving the relationship between anti-parasitic drugs and the molecular basis of their cytotoxic outcomes will support future mechanistic understanding and enable improved drug design."

Journal • Infectious Disease

Human African Trypanosomiasis (HAT): Epidemiology, Biological Diagnosis and Treatment: A Review. (PubMed, Acta Parasitol) - "All these difficulties raised raise questions about the need to develop new diagnostic tools that are more specific, more sensitive and better suited to field screening. They also call out the urgency of finding new drugs that are less toxic, easy to administer and more effective."

Journal • Review • Narcolepsy • Sleep Disorder

Fexinidazole and corallopyronin a target Wolbachia-infected sheath cells present in filarial nematodes. (PubMed, PLoS Pathog) - "and clinical studies have yielded promising results, recent animal studies revealed that Wolbachia levels rebound following treatment with the antibiotic rifampicin. We determined that the Wolbachia within the sheath cells are either quiescent or replicating at a very low rate. Screens of 11 known antibiotics and other drugs revealed that Fexinidazole, Corallopyronin A and Rapamycin reduced the number of Wolbachia clusters infecting sheath cells but only Fexinidazole and Corallopyronin A showed a highly significant difference (p < 0.0001) compared to the control group."

Journal

Use of fexinidazole in gambiense human African trypanosomiasis: a retrospective analysis of cases treated in Lui Hospital, South Sudan (2018-2024). (PubMed, Infection) - "Patients treated with fexinidazole and pentamidine/NECT showed similar results in terms of outcome at discharge and ADRs, in line with current data available in literature. However, few real-life studies on efficacy of fexinidazole treatment were published: to our knowledge, this is the first one conducted in South Sudan."

Journal • Retrospective data

Crystallographic and Electroanalytical Analyses of Fexinidazole and Its Major Metabolites. (PubMed, ACS Omega) - "On the other hand, electroanalytical analysis of fexinidazole revealed a pH-dependent, two-step nitro group reduction mechanism, involving an initial concerted transfer of an electron and a proton, followed by the uptake of three electrons and three protons to likely form a hydroxylamine species. These findings characterize the molecular architecture and reduction mechanism of fexinidazole, providing valuable insights into its structural features and activation mechanism required for anti-infective activity."

Journal • Infectious Disease

Treatment options applied to the preclinical studies using animal models for Chagas Disease: a systematic review and meta-analysis. (PubMed, F1000Res) - "However, of these emerging therapies, only posaconazole and fexinidazole have progressed to clinical trials, yielding unsatisfactory outcomes as CD monotherapies. Collaborative efforts among the academic community, pharmaceutical industries, funding agencies, and government agencies are urgently needed to accelerate the development of more effective medications against CD. INPLASY202430101 (25/03/2024)."

Clinical • Journal • Preclinical • Retrospective data • Review

Antitrypanosomal secondary metabolites from medicinal plants: a review. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "There are currently six drugs available for the treatment of African sleeping sickness, namely, pentamidine, suramin, melarsoprol, nifurtimox, eflornithine, and fexinidazole. The literature search was carried out in various databases including ScienceDirect, Google Scholar, tandfonline.com, Journal of Natural Products, MDPI, WILEY Online Library, tandfonline.com, and The Lancet. In this article, the secondary metabolites organized in different classes including alkaloids, terpenoids, and flavonoids that have potency against trypanosomes are discussed."

Journal • Review • Narcolepsy • Sleep Disorder

Fexinidazole for human African trypanosomiasis: the challenge of accessibility. (PubMed, Lancet Glob Health) - No abstract available

Journal

Effectiveness and safety of fexinidazole for gambiense human African trypanosomiasis and exploration of adherence in outpatients: a phase 3b, prospective, open-label, non-randomised, cohort study. (PubMed, Lancet Glob Health) - P3 | "The effectiveness and safety of fexinidazole in this wider population was similar to that described in previous clinical trials, and treatment at home seems feasible in selected patients who had the support of their caregiver."

Journal • P3 data • Pediatrics

Fexinidazole as a new oral treatment for human African trypanosomiasis due to Trypanosoma brucei rhodesiense: a prospective, open-label, single-arm, phase 2-3, non-randomised study. (PubMed, Lancet Glob Health) - P2/3 | "Fexinidazole is a safe and easy-to-use treatment, and is a better-accepted alternative to existing treatments for rhodesiense human African trypanosomiasis, such as melarsoprol or suramin."

Journal • P2/3 data

Human African trypanosomiasis. (PubMed, Lancet) - "A new oral drug, fexinidazole, became the first-line treatment for gambiense human African trypanosomiasis without severe meningo-encephalitic disease, as well as for rhodesiense human African trypanosomiasis...The elimination of human African trypanosomiasis as a public health problem has been achieved, and elimination of gambiense human African trypanosomiasis transmission is now targeted for 2030. Improved diagnostics and drugs, continued involvement of populations at risk of disease, health staff, national authorities, and partners and donors all contribute to achieve this goal."

Journal • Review • CNS Disorders • Infectious Disease • Narcolepsy • Sleep Disorder

Transforming the chemotherapy of human African trypanosomiasis. (PubMed, Clin Microbiol Rev) - "SUMMARYPrior to 2019, when the orally available drug fexinidazole began its clinical use, the treatment of human African trypanosomiasis (HAT) was complex and unsatisfactory for many reasons...Gambiense disease required pentamidine or nifurtimox-eflornithine combination therapy, while for rhodesiense disease, suramin or melarsoprol was given for stages 1 and 2, respectively...Another compound, acoziborole, effective in both stages 1 and 2 gambiense disease with a single dosing is anticipated to become available within a few years. Moreover, the recent engagement of multilateral organizations in seeking other compounds that could be used in HAT therapy has also been successful, and a rich vein of new trypanocides has been discovered. Here, the clinical use, modes of action, and resistance risks for drugs used against HAT are discussed."

Biomarker • Clinical • Journal • Observational data • Retrospective data • Review

Fexinidazole and Corallopyronin A target Wolbachia -infected sheath cells present in filarial nematodes. (PubMed, bioRxiv) - "While lab and clinical studies have yielded promising results, recent animal studies reveal that Wolbachia levels may rebound following treatment with suboptimal doses of the antibiotic rifampicin. We also determined that the Wolbachia within the sheath cells are either quiescent or replicating at a very low rate. Screens of known antibiotics and other drugs revealed that two drugs, Fexinidazole and Corallopyronin A, significantly reduced the number of clustered Wolbachia located within the sheath cells."

Journal

Fexinidazole in Patients with Human African Trypanosomiasis Due to Trypanosoma brucei rhodesiense, towards an arsenic free first line therapy (ASTMH 2024) - "Full results will be communicated during the presentation, including all secondary endpoints and safety data. Conclusion After its addition to the treatment arsenal for gambiense HAT, fexinidazole has now been shown to be a good first-line treatment alternative to replace melarsoprol and suramin for the oral treatment of both stages of r-HAT."

Clinical • CNS Disorders • Narcolepsy • Sleep Disorder