acoziborole (SCYX-7158) / SCYNEXIS - LARVOL DELTA

The STROGHAT study protocol: An intervention study to evaluate safety, effectiveness and feasibility of treating gambiense HAT seropositive subjects with acoziborole. (PubMed, Open Res Eur) - P3 | "NCT06356974. Date of registration: April 4, 2024."

Journal

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

OXA005: Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in G-HAT Paediatric Patients (clinicaltrials.gov) - P2/3 | N=35 | Recruiting | Sponsor: Drugs for Neglected Diseases | Trial completion date: Jun 2024 ➔ Mar 2026 | Trial primary completion date: Jun 2024 ➔ Mar 2025

Trial completion date • Trial primary completion date • Infectious Disease • Narcolepsy • Pediatrics • Sleep Disorder

Exploring intervention strategies to maximise the impacts of a new single-dose oral drug on reducing disease burden and achieving elimination in at-risk settings of sleeping sickness in the DRC (ASTMH 2024) - "Acoziborole, a new single-dose oral drug, could revolutionise this approach if its safety and high efficacy are confirmed in clinical trials...In passive screening, onsite availability of treatment could drastically reduce transmission, whereas S&T with centralised stocks is predicted to have a marginal impact due to treatment delays and loss to follow-up. In active screening, recruiting high-risk individuals who typically do not participate (systematic non-participants) is predicted to substantially increase the S&T impact."

Late-breaking abstract • Infectious Disease • Narcolepsy • Sleep Disorder

Acoziborole: The development of a single-dose oral treatment for sleeping sickness (ASTMH 2024) - No abstract available

Narcolepsy • Sleep Disorder

186 - Will HAT be the Next NTD to Achieve Global Elimination? (ASTMH 2024) - "Bringing together experts, researchers and policymakers we will discuss themes including what makes gHAT unique and a target for EoT, reasons to be optimistic, the challenges that lie ahead, the diverse toolkit for gHAT control and transmission interruption, current challenges for control and surveillance and ways to strengthen them, the potential impact of a new single-dose oral drug, acoziborole, current diagnostics and the necessity for new tools to reach EoT, the extent to which tsetse control is needed to reach EoT, the challenges with current deployment methodologies and alternative approaches, the importance of sustained vigilance after achieving EoT and transmission and health economic modelling as a tool to support the operationalisation and application of interventions. We will also highlight uncertainties and old vs. new strategies as we approach elimination including (i) recommendations for scale-up, where and why (ii) where current strategies should be..."

Clinical

New human African trypanosomiasis treatments for children: DNDi research on NECT, Fexinidazole and Acoziborole (ASTMH 2024) - No abstract available

Clinical

88 - Advancing Research to Improve Treatment of Neglected Tropical Diseases in Children (ASTMH 2024) - "Peter Steinmann of the Swiss TPH will discuss the experience of ADOPT (Adoption of Levo-Praziquantel 150mg for schistosomiasis by endemic countries), an initiative of the Pediatric Praziquantel Consortium, which aims to facilitate large-scale delivery of this new treatment to preschool age children in Africa. Olaf Valverde of the Drugs for Neglected Diseases initiative will discuss recent clinical trials in pediatric populations to treat human African trypanosomiasis, including an ongoing trial (ACOZI-Kids), to evaluate acoziborole for treatment of Stage 1 and Stage 2 sleeping sickness caused by T.b.gambiense...About 25% of people affected by mycetoma in Sudan are children, and the disease has long lacked a viable treatment, but there are recent therapeutic advances to share. Saschveen Singh of Medecins sans Frontieres will discuss treatment and access challenges for children with cutaneous and visceral forms of leishmaniasis, as well as efforts to confront the burden of..."

Clinical • Infectious Disease • Narcolepsy • Pediatrics • Sleep Disorder

Pass the boron: benzoxaboroles as antiparasite drugs. (PubMed, Trends Parasitol) - "Most notable is the recent demonstration of a single oral dose cure using acoziborole against African trypanosomiasis. Common and species-/structure-specific interactions between benzoxaboroles and parasite species have emerged and provide vital insights into the mechanisms of cidality, as well as potential challenges in terms of resistance and/or side effects. Here, we discuss the literature specific to benzoxaborole studies in parasitic protists and consider unanswered questions concerning this important new drug class."

Journal • Review • Infectious Disease

To Explore Potential Inhibitors Against Various Enzymatic Targets of Human African Trypanosomiasis. (PubMed, Comb Chem High Throughput Screen) - "Extracting these compounds and studying their efficacy, toxicity, and target mechanism extensively, this review has proposed a list of different compounds, including some synthetic and natural compounds along with multi-target inhibitors such as acoziborole, fexinidazole, etc. Potential inhibitors against these enzymatic targets of the T. brucei are important candidates for designing novel therapeutics against HAT. Multi-target inhibitors have also been identified as crucial molecules because of their potential advantage against the development of drug resistance."

Journal • Infectious Disease • HSP90AA1

Stop Transmission of Gambiense Human African Trypanosomiasis (STROgHAT) (clinicaltrials.gov) - P3 | N=2500 | Not yet recruiting | Sponsor: Drugs for Neglected Diseases

New P3 trial

Elemental exchange: Bioisosteric replacement of phosphorus by boron in drug design. (PubMed, Eur J Med Chem) - "Although boron phosphate-mimetic molecules - FDA-approved Crisaborole and phase II/III clinical candidate Acoziborole are products of the boron-phosphorus bioisosteric elemental exchange strategy, this technique is still in its infancy. The review aims to promote the use of this strategy in future medicinal chemistry projects."

Journal • Review

OXA004: Safety and Tolerability Study of Acoziborole in g-HAT Seropositive Subjects (clinicaltrials.gov) - P2/3 | N=1208 | Completed | Sponsor: Drugs for Neglected Diseases | Recruiting ➔ Completed | Trial completion date: May 2023 ➔ Aug 2023 | Trial primary completion date: May 2023 ➔ Aug 2023

Trial completion • Trial completion date • Trial primary completion date • Infectious Disease • Narcolepsy • Sleep Disorder

OXA-07: DDI Study of Single Oral Dose of Acoziborole With Sequential Co-administration of Midazolam and Dextromethorphan (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Drugs for Neglected Diseases

New P1 trial • CYP3A4

Antiprotozoal drugs: challenges and opportunities. (PubMed, Expert Opin Ther Pat) - No abstract available

Journal

The pipeline for drugs for control and elimination of neglected tropical diseases: 1. Anti-infective drugs for regulatory registration. (PubMed, Parasit Vectors) - "Considering drugs approved for an NTD by at least one stringent regulatory authority: fexinidazole, included in WHO guidelines for Trypanosoma brucei gambiense African trypanosomiasis, is in development for Chagas disease. Moxidectin, registered in 2018 for treatment of individuals ≥ 12 years old with onchocerciasis, is undergoing studies to extend the indication to 4-11-year-old children and obtain additional data to inform WHO and endemic countries' decisions on moxidectin inclusion in guidelines and policies...Considering drugs in at least Phase 2 clinical development, a submission is being prepared for registration of acoziborole as an oral treatment for first and second stage T.b. gambiense African trypanosomiasis. Bedaquiline, registered for tuberculosis, is being evaluated for multibacillary leprosy. Phase 2 studies of emodepside and flubentylosin in O. volvulus-infected individuals are ongoing; studies for Trichuris trichuria and hookworm are planned. A..."

Journal • Review • Dengue Fever • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Determination of the Optimal Single Dose Treatment for Acoziborole, a Novel Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Study. (PubMed, Clin Pharmacokinet) - P1 | "This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of gambiense HAT."

Journal • P1 data

Clinically relevant benzoxaboroles inhibit mRNA processing in Trypanosoma brucei. (PubMed, BMC Res Notes) - "The cleavage and polyadenylation endonuclease CPSF73 is thought to be the target of the anti-trypanosomal benzoxaboroles AN7973, acoziborole and AN11736...Treating the cells with AN7973 for 30 min. did not significantly affect the proteins that copurified with CPSF73."

Journal • Narcolepsy • Sleep Disorder

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. (PubMed, Lancet Infect Dis) - P2/3 | "Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030."

Journal • P2/3 data • Infectious Disease

Trypanosome spliced leader RNA for diagnosis of acoziborole treatment outcome in gambiense human African trypanosomiasis: A longitudinal follow-up study. (PubMed, EBioMedicine) - P=N/A | "SL-RNA detection for HAT treatment outcome assessment shows ≥98.9% specificity in blood and 100% in CSF, and may detect relapses without lumbar puncture."

Journal

Can acoziborole in a "screen and treat" approach change the end-game trajectory of sleeping sickness in the presence of asymptomatic infections? (ASTMH 2022) - "Furthermore, combining screening methods to improve coverage of high-risk groups (e.g. door-to-door screening) with a S&T algorithm appears to be a more effective, medical-only approach to tackle infections, especially if asymptomatic infections are contributing to onward transmission. Using Bayesian statistical approaches we also assessed whether asymptomatic transmission is likely based on the available human case data and provide projections for different strategies, including S&T, for an ensemble model which captures our uncertainty in epidemiology and model parameterisation."

Infectious Disease • Narcolepsy • Sleep Disorder

Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome. (PubMed, iScience) - "In case of polypharmacology, the cell-perturbome workflow elucidates modes of action because it is target-agnostic. Finally, the workflow can be used in any cell that is amenable to proteomic and molecular biology experiments."

Journal • HP

OXA005: Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients (clinicaltrials.gov) - P2/3 | N=35 | Recruiting | Sponsor: Drugs for Neglected Diseases | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Narcolepsy • Pediatrics • Sleep Disorder

OXA005: Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients (clinicaltrials.gov) - P2/3 | N=35 | Not yet recruiting | Sponsor: Drugs for Neglected Diseases

New P2/3 trial • Infectious Disease • Narcolepsy • Pediatrics • Sleep Disorder

An Update on African Trypanocide Pharmaceutics and Resistance. (PubMed, Front Vet Sci) - "Suramin sodium suppresses ATP generation during the glycolytic pathway and is ineffective against T. vivax and T. congolense infections. In humans, the development of resistance and adverse side effects against monotherapies has led to the adoption of nifurtimox-eflornithine combination therapy. Current efforts to develop new prodrug combinations of nifurtimox and eflornithine and nitroimidazole fexinidazole as well as benzoxaborole SCYX-7158 (AN5568) for HAT are in progress while little comparable progress has been done for the development of novel therapies to address trypanocide resistance in AAT."

Journal • Review • Infectious Disease