Efficacy and safety of acoziborole in patients with human African trypanosomiasis caused by Trypanosoma brucei gambiense: a multicentre, open-label, single-arm, phase 2/3 trial

Kumeso, Victor Kande Betu; Kalonji, Wilfried Mutombo; Rembry, Sandra; Mordt, Olaf Valverde; Tete, Digas Ngolo; Prêtre, Adeline; Delhomme, Sophie; Kyhi, Médard Ilunga Wa; Camara, Mamadou; Catusse, Julie; Schneitter, Stefan; Nusbaumer, Morgane; Miaka, Erick Mwamba; Mbembo, Hélène Mahenzi; Mayawula, Joseph Makaya; Camara, Mariame; Massa, Félix Akwaso; Bonama, Augustin Kasongo; Lukula, Papy Kavunga; Kalonji, Sylvain Mutanda; Philemon, Phyll Mariero; Nganyonyi, Ricardo Mokilifi; Mankiara, Hugues Embana; Nguba, André Asuka Akongo; Muanza, Vincent Kobo; Nasandhel, Ernest Mulenge; Bambuwu, Aimée Fifi Nzeza; Scherrer, Bruno; Strub‐Wourgaft, Nathalie; Tarral, Antoine

doi:10.1016/s1473-3099(22)00660-0

Cited by 42 publications

(35 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Infected control mice groups were those that received either no treatment or given vehicle only (vehicle controls). For both sets of controls, parasitemia had increased to between 1 × 10 8 and 1 × 10 9 parasites/ml of blood by day 3 post-infection (Figure 7 and Table S2) and were humanely euthanized as, otherwise, they would have died within 24 h. Pentamidine, at 4 mg/kg, decreased parasitemia to below the detectable limit ( i.e., 2.5 × 10 5 parasites/ml) within 24 h of administration (Figure 7A). TPD 3 , at 5, 7.5 and 10 mg/kg, significantly decreased parasitemia levels relative to the infected untreated control after 24 h, and, for the two higher doses, parasitemia was below the detection limit (Figure 7B).…”

Section: Resultsmentioning

confidence: 99%

“…6, 7 Also, recent encouraging clinical Phase II/III trial data with an investigational oxaborole drug, acoziborole, suggest that this compound may soon be registered as a new chemotherapeutic for combatting T. b. gambiense infection. 8 Nonetheless, given that trypanosomes have developed resistance to approved drugs in the past, 9–12 the search for alternative treatments should remain a priority.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis

Monti

Liu

Varricchio

et al. 2023

Preprint

View full text Add to dashboard Cite

Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT-active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei-infected mice with tolerable doses of TPDs 3 and 4 significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of 4 at 10 mg/kg significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis

Monti

Liu

Varricchio

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, inclusion of participants in the study was not done by expert clinicians but by local health workers from the health centres. However, in particular for important weight loss, severe itching and motor disorders, detailed clinical data collected in therapeutic trials carried out on Guinean HAT patients could be consulted retrospectively [ 41 ]. Many DBS of RDT positives were missing, leading to relatively large confidence intervals in diagnostic test performance estimations.…”

Section: Discussionmentioning

confidence: 99%

“…Performance of both HAT Sero- K -Set and SD Bioline HAT is sufficient for referring RDT positives for microscopic examination. Taking into account the future availability of non-toxic oral drugs to treat both stages of HAT [ 41 ], a target product profile has been established by the World Health Organization for a gambiense HAT test to identify individuals with suspected but microscopically unconfirmed g-HAT infection, eligible for treatment [ 42 ]. In HAT endemic areas in Guinea, both RDTs largely meet the minimum requirements for specificity, while HAT Sero- K -Set meets the desirable and SD Bioline HAT approaches the minimal sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Performance of clinical signs and symptoms, rapid and reference laboratory diagnostic tests for diagnosis of human African trypanosomiasis by passive screening in Guinea: a prospective diagnostic accuracy study

Camara¹,

Camara²,

Falzon

et al. 2023

Infect Dis Poverty

Self Cite

View full text Add to dashboard Cite

Background Passive diagnosis of human African trypanosomiasis (HAT) at the health facility level is a major component of HAT control in Guinea. We examined which clinical signs and symptoms are associated with HAT, and assessed the performance of selected clinical presentations, of rapid diagnostic tests (RDT), and of reference laboratory tests on dried blood spots (DBS) for diagnosing HAT in Guinea. Method The study took place in 14 health facilities in Guinea, where 2345 clinical suspects were tested with RDTs (HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT). Seropositives underwent parasitological examination (reference test) to confirm HAT and their DBS were tested in indirect enzyme-linked immunoassay (ELISA)/Trypanosoma brucei gambiense, trypanolysis, Loopamp Trypanosoma brucei Detection kit (LAMP) and m18S quantitative PCR (qPCR). Multivariable regression analysis assessed association of clinical presentation with HAT. Sensitivity, specificity, positive and negative predictive values of key clinical presentations, of the RDTs and of the DBS tests for HAT diagnosis were determined. Results The HAT prevalence, as confirmed parasitologically, was 2.0% (48/2345, 95% CI: 1.5–2.7%). Odds ratios (OR) for HAT were increased for participants with swollen lymph nodes (OR = 96.7, 95% CI: 20.7–452.0), important weight loss (OR = 20.4, 95% CI: 7.05–58.9), severe itching (OR = 45.9, 95% CI: 7.3–288.7) or motor disorders (OR = 4.5, 95% CI: 0.89–22.5). Presence of at least one of these clinical presentations was 75.6% (95% CI: 73.8–77.4%) specific and 97.9% (95% CI: 88.9–99.9%) sensitive for HAT. HAT Sero-K-Set, rHAT Sero-Strip, and SD Bioline HAT were respectively 97.5% (95% CI: 96.8–98.1%), 99.4% (95% CI: 99.0–99.7%) and 97.9% (95% CI: 97.2–98.4%) specific, and 100% (95% CI: 92.5–100.0%), 59.6% (95% CI: 44.3–73.3%) and 93.8% (95% CI: 82.8–98.7%) sensitive for HAT. The RDT’s positive and negative predictive values ranged from 45.2–66.7% and 99.2–100% respectively. All DBS tests had specificities ≥ 92.9%. While LAMP and m18S qPCR sensitivities were below 50%, trypanolysis and ELISA/T.b. gambiense had sensitivities of 85.3% (95% CI: 68.9–95.0%) and 67.6% (95% CI: 49.5–82.6%). Conclusions Presence of swollen lymph nodes, important weight loss, severe itching or motor disorders are simple but accurate clinical criteria for HAT referral in HAT endemic areas in Guinea. Diagnostic performances of HAT Sero-K-Set and SD Bioline HAT are sufficient for referring positives to microscopy. Trypanolysis on DBS may discriminate HAT patients from false RDT positives. Trial registration The trial was registered under NCT03356665 in clinicaltrials.gov (November 29, 2017, retrospectively registered https://clinicaltrials.gov/ct2/show/NCT03356665) Graphical Abstract

show abstract

“…In this context, acoziborole was selected in 2009 by the Drugs for Neglected Diseases initiative (DNDi) as a preclinical candidate to treat sleeping sickness caused by T. b. gambiense [31]. In 2012, acoziborole entered clinical development, and recently, the drug showed high efficacy and favorable safety profile, supporting its use in the fight against human African trypanosomiasis [32]. This is an efficient illustration of how effective the establishment of thematic initiatives to fight neglected diseases can be.…”

Section: Innovation To Prevent Control and Diagnose Fungal Diseasesmentioning

confidence: 99%

Recognition of fungal priority pathogens: What next?

Rodrigues

Nosanchuk

2023

PLoS Negl Trop Dis

View full text Add to dashboard Cite

Fungal diseases kill more than 1.5 million people per year, mostly in regions where neglected populations live [1]. This alarming number of deaths is part of a highly complex problem, since mortality alone does not give a complete picture of the fungal burden in different populations [2]. Indeed, several fungal diseases are associated with low mortality but directly linked to social exclusion and hospitalization. For instance, patients suffering from chromoblastomycosis manifest chronic and progressive cutaneous and subcutaneous lesions that can persist for decades [3]. Affected individuals may have significant mental health issues associated with this rare and chronic condition [4]. Fungal infections are the most diagnosed skin disease in Africa, especially in 1-to 5-years-old children [5], and these cutaneous mycoses are associated with social disapproval and psychological trauma, negatively affecting their performance in class [6]. These and other examples demonstrate that the burden of fungal infections is not restricted to mortality. Another way of measuring the impact of fungi on public health is to determine their overall burden of disease using the disability-adjusted life year (DALY). One DALY represents the loss of the equivalent of 1 year of full health [2]. However, with a few exceptions [5,7-10], DALY estimates are not available for most of the fungal diseases.Although fungal diseases are directly associated with neglected populations, they clearly also cause important public health problems in developed countries. For example, in the United States, individuals with diseases such as coccidioidomycosis experience 3 or more months of diminished mental and emotional health [11]. The economic impact of fungal diseases is remarkable. For example, in 2019, the US spent approximately USD 11.5 billion on serious fungal diseases, distributed into direct medical costs, productivity loss due to absenteeism, and premature deaths [12]. To give this number tangible dimensions, USD 11.5 billion represent 25% of the annual budget of the US National Institutes of Health (NIH) [13]. Even diseases such as onychomycosis cost over USD 2,000 per person affected in antifungal drug expenses alone [14]. In large part due to the complexity of fungi, including that they are eukaryotic organisms, the pace of generation of knowledge in the area of fighting fungal diseases is clearly slower than other areas [15]. There are no human licensed antifungal vaccines, and much has been discussed about the problems of antifungal therapies, which include high costs, emergence of antifungal resistance, significant toxicity, and limited number of antifungal drug classes [16]. It is likely that this complex scenario is the consequence of reduced funding for research and insufficient recognition of the impact of fungal diseases on public health by science policymakers and health authorities [17]. This scenario contrasts with the ever-changing epidemiology of fungal infections, which includes the emergence of highly lethal and drugresistant pa...

show abstract

Efficacy and safety of acoziborole in patients with human African trypanosomiasis caused by Trypanosoma brucei gambiense: a multicentre, open-label, single-arm, phase 2/3 trial

Cited by 42 publications

References 17 publications

Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis

Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis

Performance of clinical signs and symptoms, rapid and reference laboratory diagnostic tests for diagnosis of human African trypanosomiasis by passive screening in Guinea: a prospective diagnostic accuracy study

Recognition of fungal priority pathogens: What next?

Contact Info

Product

Resources

About