Acoziborole

Associated long-acting platforms

Oral solid form

Administration route

Oral

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Round-bottom flasks / reaction flasks, 20 mL scintillation vials, Magnetic stirrers / stir bars, Oil bath for heated reactions, Ice bath / cooling setup, Nitrogen / inert atmosphere setup, Sealed reaction vessels with rubber septa / Teflon screw caps, Büchi rotary evaporator for solvent removal under vacuum, Vacuum source / vacuum concentration setup, Drying / concentration setup.

Manufacturing

Acoziborole and related compounds can be manufactured in ISO Class 8 (equivalent to EU GMP Grade D “at rest”) by Sanofi Winthrop Industrie. Manufacturing process includes:- 1) Preparation the aryl-amine precursor 2) Install the boron functionality (boronylation) under Pd catalysis at controlled temperature 3) Aldehyde reduction and cyclize to the oxaborole ring 4) Debenzylate / deprotect to obtain the 6-amino oxaborole intermediate 5) Form the final amide (key finishing step for acoziborole-type molecules)

Specific analytical instrument required for characterization of formulation

1) HPLC, LCMS, NMR, Silica gel chromatography, 2) Flash chromatography using Teledyne ISCO CombiFlash / Companion systems, 3) Reverse-phase chromatography / Biotage C18 cartridges, 4) Prep-HPLC / Waters Prep LC systems, and 5) Crystallization / isolation after solvent remova

OXA002

Identifier

NCT03087955

Link

https://clinicaltrials.gov/study/NCT03087955

Phase

Phase II/III

Status

Completed

Sponsor

Drugs for Neglected Diseases

More details

The goal of this study is to assess efficacy and safety of acoziborole in adult participants with Trypanosoma brucei gambiense (T.b. gambiense) HAT, either early- or intermediate-stage HAT (first arm) or late-stage HAT (second arm). Participants will receive 3 tablets of 320 mg as a single oral dose of acoziborole in the fasting state on Day 1. Participants will stay in the hospital for observation for 15 days. In total, participants will be followed for 18 months.

Purpose

Efficacy and Safety of Acoziborole (SCYX-7158) in Patients With Human African Trypanosomiasis Due to T.b. Gambiense

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2016-10-11

Anticipated Date of Last Follow-up
2025-08-28

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2020-09-08

Actual Completion Date
2020-09-08

Studied populations

Age Cohort

• Children
• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Male or female patient * 15 years of age or older * Signed informed consent form (as well as assent from illiterate and under-age patients, and those unable to give consent) * Karnofsky Performance Status above 50 * Able to ingest oral tablets * Having a permanent address or being traceable by other persons * Able to comply with the schedule of follow-up visits and requirements of the study * Agreement to be hospitalised in order to receive treatment * For patients with late-stage HAT: * Confirmation of g-HAT by detection of the parasite in the blood and/or the lymph and/or the CSF, at the investigational centre * If trypanosomes are found in the blood or lymph, but not in the CSF, the CSF WBC, measured at the investigational centre, must be above 20/μL for the

Health status

Study type

Interventional (clinical trial)

Enrollment

208

Allocation

Not provided

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

OXA005

Identifier

NCT05433350

Link

https://clinicaltrials.gov/study/NCT05433350

Phase

Phase II/III

Status

Not provided

Sponsor

Drugs for Neglected Diseases

More details

Acoziborole has been studied in an open-label pivotal Phase II/III trial (DNDi-OXA-02-HAT) in the DRC and Guinea. As the numbers of reported cases diminish, resources for surveillance and specialised screening will also taper. This decrease, coupled with the loss of diagnostic skills and disease management expertise, will lead to a weak and less specialised HAT technical environment. The history of g-HAT has shown that outbreaks or re-emergence of the disease have already happened under different circumstances when surveillance was relaxed or simply because the populations at risk live in areas of political instability, limiting access to specialised care. Even with a steady decrease of reported incidence, no model can currently predict that HAT could not re-emerge. Although g-HAT is pred

Purpose

Pharmacokinetic, Efficacy, Safety and Tolerability Study of a Single Dose of Acoziborole in g-HAT Paediatric Patients

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2022-07-09

Anticipated Date of Last Follow-up
2025-07-04

Estimated Primary Completion Date
2026-03-31

Estimated Completion Date
2026-03-31

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Signed informed consent from one parent or from the legal representative * Assent from the paediatric patient (for paediatric patients \>6 years of age) to participate in the study, collected in the presence of an impartial witness * Between 1 and 14 years of age and between 10 and ≤40 kg (as per the requirements of step 1 and step 2) * Male or female * Evidence of trypanosomes in any body fluid (blood or lymph or CSF) * Having a permanent address and able to comply with the schedule of follow-up visits * Agreement to not take part in any other clinical trials during the participation in this study * For pubescent girls of childbearing potential must agree to have avoid getting pregnant during the screening period and up to 3 months after acoziborole dosing by using

Health status

Study type

Interventional (clinical trial)

Enrollment

35

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

STROgHAT

Identifier

NCT06356974

Link

https://clinicaltrials.gov/study/NCT06356974

Phase

Phase III

Status

Not yet recruiting

Sponsor

Drugs for Neglected Diseases

More details

This protocol describes both the epidemiological study which aims at assessing whether over a three-year period a zero prevalence can be achieved when implementing a screen \& treat approach with acoziborole, as well as a nested clinical study aimed at generating further evidence on safety of acoziborole in gambiense human African trypanosomiasis (gHAT) seropositives individuals. The overall coordinator will be ITM. ITM will be fully responsible for the epidemiological study (study Part A), including cost effectiveness and evaluation of diagnostic tests. DNDi will be the legal sponsor of the nested safety clinical study (study Part B) and will ensure compliance with regulatory requirements and good clinical practices (GCP) for this part of the study. The investigators hypothesize that by

Purpose

Stop Transmission of Gambiense Human African Trypanosomiasis (STROgHAT)

Interventions

Intervention 1

Countries

Not provided

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
2024-04-08

Actual Start Date
Not provided

Anticipated Date of Last Follow-up
2024-04-04

Estimated Primary Completion Date
2026-12-30

Estimated Completion Date
2027-12-30

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children
• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * • Participants able to give signed informed consent and assent form for adolescents, which includes willingness to comply with the schedule of follow-up visits and other requirements and restrictions listed in the informed consent form (ICF) and in this protocol * All sexes * 11 years of age or older at the start of the study and weight ≥30 kg at the screening of Part B * Participants who are CATT test or HAT RDT positive (information provided by the mobile team and included into TrypElim (see Part A) * Participants who are able to ingest oral tablets * Participants with known address and/or contact details provided * Participants who are able to comply with the schedule of follow-up visits and other requirements of the study * Participants must agree

Health status

Study type

Interventional (clinical trial)

Enrollment

2500

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

DNDi-OXA-03-HAT

Identifier

NCT04270981

Link

https://clinicaltrials.gov/study/NCT04270981

Phase

Phase I

Status

Completed

Sponsor

Drugs for Neglected Diseases

More details

This is a single centre, open-label, single group, non-randomised, single oral dose study in healthy male subjects designed to assess the mass balance recovery, PK, metabolite profile and metabolite identification, and exploratory pharmacodynamics of acoziborole. It is planned to enrol 6 subjects. All subjects will receive an oral dose of 960 mg \[14C\] acoziborole on a single occasion as 4 capsules containing a small amount of radioactivity (not more than \[NMT\] 1000 nCi \[37 KBq\] 14C).

Purpose

ADME Study of Acoziborole in Healthy Subjects

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2020-02-05

Anticipated Date of Last Follow-up
2021-04-26

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2020-07-08

Actual Completion Date
2020-07-08

Studied populations

Age Cohort

• Adults

Genders

• Male

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: * Healthy Caucasian males. * Age 18 to 55 years of age at the time of signing informed consent. * Body mass index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening. * Must be willing and able to communicate and participate in the whole study. * Must have regular bowel movements (i.e., average stool production of ≥1 and ≤3 stools per day). * Normal blood pressure (BP): Systolic BP between 90 and 140 (160 if \>45 years old) mmHg (inclusive), diastolic BP 45 to 90 mmHg (inclusive), measured after 10 min rest in supine position at screening and pre-dose. * A resting heart rate (HR) between 45 and 100 bpm (inclusive), measured after 10 min rest in supine position at screening and pre-dose. * ECG recording without clinically significant abnormality, including QTcF measure

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

6

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

OXA004

Identifier

NCT05256017

Link

https://clinicaltrials.gov/study/NCT05256017

Phase

Phase II/III

Status

Completed

Sponsor

Drugs for Neglected Diseases

More details

Human African trypanosomiasis (HAT) or sleeping sickness is a tropical disease which is endemic in sub-Saharan Africa. Most cases of HAT are due to the parasite Trypanosoma brucei gambiense (T.b. gambiense), which is transmitted by the bite of the tsetse fly. HAT can be fatal without diagnosis and treatment. Several treatment options are currently available to treat HAT caused by the T.b. gambiense parasite (g-HAT), but these treatments can be administered only after demonstrating via microscopy the presence of the parasite in a body fluid. However, there are factors such as low parasitaemia and the complexity and low sensitivity of parasitological methods that make such demonstration difficult. It has been demonstrated that a variable proportion (mainly depending on the prevalence) of suc

Purpose

Safety and Tolerability Study of Acoziborole in g-HAT Seropositive Subjects

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-12-30

Anticipated Date of Last Follow-up
2025-02-27

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2023-08-03

Actual Completion Date
2023-08-03

Studied populations

Age Cohort

• Children
• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Signed the informed consent form (ICF) * Male or female * 15 years of age or older * Card agglutination test for trypanosomiasis (CATT) test or HAT sero-K-set rapid diagnostic test (RDT) positive * Parasitology negative (in blood and/or lymph node aspirate \[if lymphadenopathy is present\]) * Karnofsky performance status above 70 * Able to ingest oral tablets * Known address and/or contact details provided * Able to comply with the schedule of follow-up visits and other requirements of the study * Agreement to be hospitalized upon enrolment for at least 5 days (in order to receive in-ward post-treatment observational follow-up through the first 5 days after treatment) * Agreement to not take part in any other clinical trials during the participation in this study * F

Health status

Study type

Interventional (clinical trial)

Enrollment

1208

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Quadruple-blind masking

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

OXA-07

Identifier

NCT05947604

Link

https://clinicaltrials.gov/study/NCT05947604

Phase

Phase I

Status

Completed

Sponsor

Drugs for Neglected Diseases

More details

To assess Drug drug interactions between Acoziborole and Dextromethorphan and Midazolam in healthy male volunteers.

Purpose

DDI Study of Single Oral Dose of Acoziborole With Sequential Co-administration of Midazolam and Dextromethorphan

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-02-09

Anticipated Date of Last Follow-up
2023-07-07

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2023-05-03

Actual Completion Date
2023-05-03

Studied populations

Age Cohort

• Adults

Genders

• Male

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: * Healthy males. * Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.. * Age 18 to 55 (inclusive) years of age at the time of signing informed consent. * Body mass index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening. * Body weight not less than 50 kg. * Non-smokers (defined as has not used nicotine-containing products including e-cigarette for at least 3 months prior to the first dose as confirmed by cotinine test). * Must be willing and able to communicate and participate in the whole study. * Normal blood pressure (BP): Systolic BP (SBP) between 90 and 140 mmHg (inclusive), diastolic BP (DBP) between 45 and 90 mmHg (inclusive), measured after 10 min rest in supine position at

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

20

Allocation

Not provided

Intervention model

Cross-over assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

Not provided

Residual solvents used

No residual solvent used

Description

Boron-containing small molecules as anti-protozoal agents

Brief description

This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.

Representative patent

WO2010045503A1

Category

Not provided

Patent holder

Anacor Pharmaceuticals LLC

Exclusivity

Not provided

Expiration date

April 15, 2011

Status

Ceased

Publications

Betu Kumeso, V. K., Kalonji, W. M., Rembry, S., Valverde Mordt, O., Ngolo Tete, D., Prêtre, A., Delhomme, S., Ilunga Wa Kyhi, M., Camara, M., Catusse, J., Schneitter, S., Nusbaumer, M., Mwamba Miaka, E., Mahenzi Mbembo, H., Makaya Mayawula, J., Layba Camara, M., Akwaso Massa, F., Kaninda Badibabi, L., Kasongo Bonama, A., Kavunga Lukula, P., … Tarral, A. (2023). 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. The Lancet. Infectious diseases, 23(4), 463–470. https://doi.org/10.1016/S1473-3099(22)00660-0

Background

Human African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox–eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT.

Methods

This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955.

Findings

Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2–97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1–99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%.

Interpretation

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.

Funding

Bill & Melinda Gates Foundation, UK Aid, Federal Minis

Tarral, A., Hovsepian, L., Duvauchelle, T., Donazzolo, Y., Latreille, M., Felices, M., Gualano, V., Delhomme, S., Valverde Mordt, O., Blesson, S., Voiriot, P., & Strub-Wourgaft, N. (2023). Determination of the Optimal Single Dose Treatment for Acoziborole, a Novel Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Study. Clinical pharmacokinetics, 62(3), 481–491. https://doi.org/10.1007/s40262-023-01216-8

Background and Objectives

Acoziborole is a novel boron-containing candidate developed as an oral drug for the treatment of human African trypanosomiasis (HAT). Results from preclinical studies allowed progression to Phase 1 trials. We aimed to determine the best dose regimen for all stages of HAT.

Methods

Acoziborole was assessed in 128 healthy adult males of sub-Saharan African origin living in France. The study included a single oral administration of a 20- to 1200-mg dose in a randomised double-blind study in cohorts of 8 (6 active, 2 placebo) to assess safety, tolerability, and pharmacokinetics. In three additional open cohorts of 6 participants, the effect of activated charcoal was evaluated, bioequivalence of capsules versus tablets was assessed, and safety in the 960-mg tablet cohorts was monitored.

Results

Acoziborole was well tolerated at all doses tested; no dose-related adverse events were observed. The drug appeared rapidly in plasma (at 1 h), reached tmax between 24 and 72 h, and remained stable for up to 96 h, after which a slow decrease was quantifiable until 14 weeks after dosing. Charcoal had little impact on the enterohepatic recirculation effect, except for the 20-mg dose. Bioequivalence between capsule and tablet formulations was demonstrated. The therapeutic single dose for administration under fasted conditions was fixed to 960 mg. The maximum administered dose was 1200 mg.

Conclusions

This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of gambiense HAT.

Trial Registration

The study was registered with ClinicalTrials.gov: NCT01533961

Additional documents

No documents were uploaded

Useful links

• EMA Positive Opinion of Acoziborole

	Collaborate for development Consider on a case by case basis, collaborating on developing long acting products with potential significant public health impact, especially for low- and middle-income countries (LMICs), utilising the referred to long-acting technology Not provided
	Share technical information for match-making assessment Provide necessary technical information to a potential partner, under confidentiality agreement, to enable preliminary assessment of whether specific medicines of public health importance in LMICs might be compatible with the referred to long-acting technology to achieve a public health benefit Not provided
	Work with MPP to expand access in LMICs In the event that a product using the referred to long-acting technology is successfully developed, the technology IP holder(s) will work with the Medicines Patent Pool towards putting in place the most appropriate strategy for timely and affordable access in low and middle-income countries, including through licensing Not provided

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