Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - anTBiotic (AnTBiotic – progressing TB drug candidates to clinical proof of concept)

Teaser

The anTBiotic consortium aims to fuel the long-term Tuberculosis (TB) clinical pipeline while immediately offering new options to clinicians when confronted with multidrug-resistant (MDR)-TB.More specifically, the proposed studies aim to:1. Establish the proof of concept of...

Summary

The anTBiotic consortium aims to fuel the long-term Tuberculosis (TB) clinical pipeline while immediately offering new options to clinicians when confronted with multidrug-resistant (MDR)-TB.

More specifically, the proposed studies aim to:
1. Establish the proof of concept of anti-TB efficacy in humans of a pioneering, first-in class, low-dose oxaborole clinical drug candidate.
2. Identify a combination of β-lactam antibiotics suitable for the treatment of MDR TB orally or as a once daily intravenous or intramuscular application.
3. Incorporate the best β-lactam combination into an explorative salvage regimen for untreatable patients with extensively drug-resistant (XDR)-TB.

TB today rivals HIV/AIDS as the leading cause of death from infectious diseases. The number of TB patients has never been higher than today and the growing proportion of drug-resistant TB is threatening control strategies.

MDR TB, defined as resistant to at least rifampicin and isoniazid (two out of the four components of the gold standard treatment), is of special concern with approximately 480000 new cases globally in 2014. If this was not enough, the incidence of XDR-TB, defined as MDR-TB plus resistance to at least one of the currently used second-line injectable drug and fluoroquinolones, is presently at around 10% of MDR-TB patients and has already been reported in 105 countries.

Given the increasing incidence of MDR- and XDR-cases worldwide, new effective drugs are urgently needed to be incorporated into new combination therapies that can shorten treatment and improve outcomes.

To accelerate and foster the development of new antitubercular drugs, this project will study new compounds in the clinic as well as test drug combinations using repurposed drugs that were not previously used against TB or that were discarded due to previous resistances.

The consortium will undertake novel Early Bactericidal Activity Phase IIa studies with the objectives of:

• Renewing the pipeline: GSK´656 is an exciting, clinic-ready new asset for the treatment of TB, with a new mechanism of action that has no pre-existent resistance in the field and the potential to be developed into an oral drug for the treatment of both drug sensitive and MDR/XDR-TB as part of future drug combination regimens.

• Repurposing an optimized combination of meropenem or ertapenem and amoxicillin-clavulanate for MDR/XDR TB chemotherapy. The repurposing strategy of β-lactam combinations is based on a positive proof concept generated within FP7 and EDCTP-funded projects for the combination of meropenem with amoxicillin-clavulanate. This evidence is further supported by a growing body of clinical reports where this combination appears to effectively contribute to sputum conversion in MDR/XDR therapeutically destitute TB patients. Likewise, ertapenem has been successfully incorporated into regimens to treat MDR-TB.

• Re-establishing the efficacy of rifampicin for the treatment of MDR/XDR-TB. Despite its well-established status as the cornerstone of TB chemotherapy, resistance to rifampicin is becoming progressively more common. The β-lactam class has been shown to act with synergy when combined with rifampicin in vitro and we hypothesize that this effect will translate into the clinic.

• Exploring the predictive potential of Positron Emission Tomography (PET) integrated with computed tomography (CT) as a non-invasive approach to evaluate drug action.
The acquisition of PET/CT data at 0 and 2 weeks will complement the more traditional CFU (colony forming units) and TTP (time to culture positivity) EBA sputum markers and further substantiate the correlation between early PET/CT signals and the sterilizing potential of individual drugs or drug regimens. Should this correlation be confirmed, this would impact future clinical trial design, shortening clinical development timelines and lowering the associated uncertainties.

• Validating new EBA biomarkers as surrogates for tre

Work performed

During the first reporting period the consortium has started the work towards the identification of a suitable combination of β-lactam antibiotics. The protocol and the informed consent forms for the 2-week EBA studies were prepared and submitted to the relevant South African regulatory body and ethics committee. The recruitment started after the approval and the study set up, with 17 patients enrolled so far.

The group has also conducted the preliminary work to start the EBA study towards the proof of concept of the new clinical drug candidate, which is foreseen before the end of the year. Mainly, those activities were dedicated to ensuring site readiness, establishing monitoring and data collection plans and writing and submitting the protocol and the informed consent documents for regulatory and ethics approval.

Within the workstream to establish novel clinical parameters as surrogates for treatment outcome, the partners have established the platforms and elaborated the protocol to collect, transport and analyze the samples for the biomarker studies.
Finally, the project team has developed a preliminary mathematical model to predict optimal dosing of meropenem in TB patients based on novel models that incorporate chemical reaction kinetics of the antibiotic with its target with bacterial population biology.

Final results

EXPECTED RESULTS

• A novel anti-TB chemical entity to be further progressed to Phase IIb clinical trials, towards becoming a new approved TB drug.
• New drug regimen options for the treatment of MDR/XDR-TB with agents that are presently out of patent protection and available in the market.


EXPECTED IMPACTS

This project will contribute to address major challenges and needs identified for TB treatment, namely:

• Addressing drug resistance that compromises the effectiveness of first-line and second-line antitubercular drugs, typically less effective, more toxic, costly, and requiring painful injections, which causes failures in adherence, fueling the emergence of XDR-TB.
• Contributing to treatment shortening to facilitate compliance, which is one of the main goals pursued by major TB stakeholders (WHO, TB Alliance, Stop TB Partnership, etc).
• Providing new drugs for new combination therapies
• Developing innovative tools that improve TB clinical practice.
• Contributing to ending the TB epidemic by 2030, which is one of the targets of the Sustainable Development Goals (SDGs) of the United Nations.
• Making best use of the limited funding, which is one the main obstacles for TB drug development.

Website & more info

More info: http://www.antbiotic.eu.