acoziborole (SCYX-7158) / SCYNEXIS - LARVOL DELTA

Boron-Based Bioisosteres in Medicinal Chemistry: Advances in Heterocycles and Therapeutic. (PubMed, ChemMedChem) - "Benzoxaboroles have reached clinical relevance, including antifungal drugs such as tavaborole and crisaborole, as well as late-stage candidates like epetraborole and acoziborole. Benzoxaborinines and olaparib isosteres exhibit activity against carbonic anhydrases and PARP enzymes, while boronic acid drugs such as bortezomib and ixazomib are established proteasome inhibitors used in cancer therapy...Despite these advances, challenges remain regarding potency, pharmacokinetics, and mechanistic understanding of boron-target interactions. Overall, boron-based bioisosteres represent a versatile platform for developing new therapeutics across diverse disease areas."

Journal • Review • Oncology • PARP1

STROgHAT: Stop Transmission of Gambiense Human African Trypanosomiasis (clinicaltrials.gov) - P3 | N=2500 | Recruiting | Sponsor: Institute of Tropical Medicine, Belgium

New P3 trial

Boron-Containing Drug Candidates in Clinical Trials. (PubMed, Handb Exp Pharmacol) - "The agents reviewed include borofalan, delanzomib, flovagatran, dutogliptin, talabostat, numidargistat, OATD-02, AN0128, epetraborole, ganfeborole, acoziborole, taniborbactam, xeruborbactam, and sodium borocaptate, as well as the five FDA-approved boroncontaining drugs (bortezomib, ixazomib, crisaborole, tavaborole, vaborbactam). The review also highlights how clinical success depends on matching pharmacology with unmet need, feasible administration, competitive differentiation, and durable development partnerships. Ongoing advances in scaffold design, delivery, combination therapy, and indication selection are expected to broaden the therapeutic impact of boron-containing medicines."

Journal • Cardiovascular • Head and Neck Cancer • Hematological Disorders • Infectious Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thrombosis • Tuberculosis

Acoziborole: First Approval. (PubMed, Drugs) - "Acoziborole was assessed via the EU-M4all procedure for medicines intended for use outside of the EU, and the positive opinion will facilitate the registration of acoziborole in sub-Saharan African countries where g-HAT is endemic. This article summarizes the milestones in the development of acoziborole leading to this positive opinion for the treatment of first- and second-stage g-HAT."

Journal

OXA005: Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients (clinicaltrials.gov) - P2/3 | N=35 | Completed | Sponsor: Drugs for Neglected Diseases | Recruiting ➔ Completed

Trial completion • 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 | Recruiting | Sponsor: Drugs for Neglected Diseases | Active, not recruiting ➔ Recruiting

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

Acoziborole resistance associated mutations in Trypanosoma brucei CPSF3. (PubMed, PLoS Pathog) - "Computational modelling revealed how the combinatorial mutations can disrupt acoziborole - CPSF3 interactions by introducing steric clash and by disrupting hydrophobic and water-mediated interactions. We conclude that acoziborole safety and efficacy can be explained by selective affinity for, and rapid turnover of, trypanosome CPSF3."

Journal • Narcolepsy • Sleep Disorder

A CRISPR-based diagnostic tool to survey drug resistance in human African trypanosomiasis. (PubMed, Antimicrob Agents Chemother) - "The CPSF3(SNV) SHERLOCK assay discriminated between wild-type CPSF3 RNA and CPSF3 bearing a single A-C mutation that confers resistance to acoziborole in vitro. These SHERLOCK assays are amenable for use as a high-throughput screening method to monitor for drug-resistant-associated mutations in Trypanosoma brucei, providing a new molecular tool for epidemiological surveillance during the gHAT elimination phase."

Journal

Mass balance, pharmacokinetics, metabolism, and excretion of radiolabeled acoziborole, a potential novel treatment for human African trypanosomiasis, following single microtracer oral dose to humans. (PubMed, Antimicrob Agents Chemother) - "In feces, acoziborole, SCYX-3109, and two other oxidized or deboronated forms of acoziborole represented 33.6%, 12.3%, and 2.3% of the dose, respectively. Acoziborole showed good absorption, limited metabolism, minimal urinary elimination, and predominant but slow biliary-fecal elimination."

Journal • PK/PD data

OXA005: Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients (clinicaltrials.gov) - P2/3 | N=35 | Active, not recruiting | Sponsor: Drugs for Neglected Diseases | Recruiting ➔ Active, not recruiting | Trial primary completion date: Mar 2025 ➔ Mar 2026

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

Towards elimination: Challenges in community participation to a gHAT 'screen and treat' strategy using the new oral drug acoziborole in the Democratic Republic of the Congo. (PubMed, PLoS Negl Trop Dis) - "Those barriers are important to anticipate and include in elimination strategy. Also a monitor perception about acoziborole screen and treat during all the process through other social science based research is to foreseen."

Journal

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