Tackling a major global health challenge
Antimicrobial resistance (AMR) is a major threat to public health worldwide, with drug-resistant bacteria now killing over a million people globally every year. We urgently need new, effective antibiotics, yet antibiotic development is highly challenging for scientific, regulatory and economic reasons.
ENABLE was set up to create a drug discovery and development platform with the expertise and resources needed to move potential antibiotics through the early stages of drug development. The project focused on antibiotics designed to tackle drug-resistant bacteria classed as ‘critical priority’ by the World Health Organisation (WHO). It set itself the goal of getting a certain number of potential antibiotics to key stages in the drug development process, including getting at least one compound into clinical trials.
The project launched calls for expressions of interest through which organisations could apply to join the project and use its platform to advance the development of their own promising antibiotic development programmes.
Applications were assessed by the project’s Portfolio Management Committee, which was made up of 15 experts in antibiotic development: 5 from the project’s private sector partners; 5 from the project’s public partners; and 5 from outside the project. The group met regularly to review new applications and assess the progress of, and offer recommendations to, ongoing programmes.
In total 23 programmes were accepted into the project, and benefited from the partners’ expertise in fields such as chemistry, microbiology, medicines safety, modelling, and more. The programmes coming into the project were generally ‘hits’, i.e. they had shown the desired level of activity against one of the bacteria that were the focus of ENABLE. In fact, one programme came from another IMI project – the European Lead Factory – whose main goal was to help researchers identify ‘hits’ against their drug targets.
Thanks to the ENABLE platform, these hits were able to move along the drug development pipelines and the project exceeded its initial goals:
- 6 ‘leads’ – in drug development, a ‘hit’ becomes a ‘lead’ when it has been refined and improved to make it more potent against the target.
- 3 candidates – to be selected as a candidate, a compound must meet more demanding requirements that demonstrate its potential to be a safe, effective antibiotic.
- 2 compounds entering preclinical studies – preclinical studies drill down into the safety and efficacy of the compound to verify that it is safe and suitable to be tested in humans.
- 1 compound entering Phase 1 clinical trials – in Phase 1 clinical trials, the compound is tested in healthy volunteers to test it for safety and to get initial indications regarding dosing. The trial carried out in ENABLE showed that the compound was safe and well tolerated, supporting its further development.
Where are they now?
A number of the compounds that reached key drug development milestones in ENABLE have now been picked up by other antibiotic development programmes, including IMI project GNA-NOW, CARB-X, ENABLE-2 and the Ineos Oxford Institute. These investments are testament to the quality of the work carried out by the ENABLE team.
ENABLE-2 – continuing the good work
The success of ENABLE prompted a group of institutes to set up the ENABLE-2 Drug Development Platform with funding from the Swedish government. Like ENABLE, ENABLE-2 aims to move potential antibiotics through the early stages of drug development, with the hope that they will successfully ‘graduate’ to other initiatives that focus more on the later stages. A number of programmes have already been accepted into ENABLE-2, including one which had got to the ‘lead’ stage in the initial ENABLE project.
More broadly, the bonds forged in ENABLE have resulted in other bilateral and multilateral collaborations that have continued beyond the end of the project.
A valuable education for Europe’s antibiotic development experts
ENABLE brought together experts from diverse disciplines in academia, SMEs and larger pharmaceutical companies. This allowed all involved in the project to learn a lot from the other partners. For example, SMEs and academics whose compounds were accepted into the ENABLE pipeline learnt a lot about what is needed to get a compound through the different stages of drug development, and they can now apply this knowledge to other programmes within their organisations. For their part, large pharmaceutical companies gained access to technical expertise in universities and SMEs which they could also use in their own projects.
The project’s legacy also lives on in numerous scientific publications, presentations and posters as well as 9 patents filed by the project. Crucially, the ENABLE team believes that its guidelines, processes, policies and charters could be adapted to other therapeutic areas where there is an unmet medical need.
The value of a collaborative spirit
ENABLE not only exceeded its initial goals; it leaves a lasting legacy in the form of the ENABLE-2 platform; the potential antibiotics being carried forward in other programmes; and the collaborations arising from contacts made through ENABLE. According to the project partners, the key to ENABLE’s success can be found in the highly collaborative spirit of the diverse project partners. Throughout the project, the partners devoted significant amounts of energy to ENABLE, maintained a flexible approach, and willingly shared knowledge to keep the project on track.
Achievements & News
Laboratory studies show that a potential antibiotic dubbed NOSO-502 is active against some of the most dangerous drug-resistant bacteria. The...
Research from the IMI projects ENABLE and ELF have discovered a treatment that could reverse antibiotic resistance in some bacteria.
A study in healthy volunteers showed that the antibiotic EBL-1003 is safe and well tolerated. EBL-1003 (a purified form of apramycin) shows promise as a treatment for complex drug-resistant infections. The finding is a great result for the ENABLE project, which set up an antibiotic development platform to provide researchers with the expertise, resources and support needed to advance promising early research stage antibiotics into Phase 1 clinical trials in humans.###
The clinical potential of apramycin was discovered by researchers at the University of Zurich who set up a spin-out company, Juvabis, to develop it further. Juvabis joined ENABLE in 2016. Thanks to the collaboration with ENABLE, Juvabis was able to demonstrate the safety and efficacy of in animal models for various infections, including infections caused by some of the more dangerous drug-resistant bacteria.
The Phase I clinical trial started in 2019; the goal of the trial was to assess the safety and tolerability of the drug as well as how it behaves in the body. Healthy volunteers received single intravenous doses or a placebo.
The results of that trial are now in, and they show that EBL-1003 is both safe and well tolerated. The Juvabis team now plans to run a further Phase I trial in patients with complicated urinary tract infections – one of the disease areas where EBL-1003 shows the most promise.
If further trials confirm EBL-1003’s antibiotic abilities, it would be a valuable weapon for treating infections involving bacteria that are increasingly resistant to many existing antibiotics.
‘We urgently need new antibiotics to tackle the ever-growing threat of antimicrobial resistance. ENABLE’s successes demonstrate that with the right support from a team of experts from academia and industry, potential antibiotics can be identified and supported through the highly challenging early stages of antibiotic development,’ said IMI Executive Director Dr Pierre Meulien. ‘More broadly, this result demonstrates the strength of public-private partnerships in tackling major health challenges.’
Find out more
The IMI project ENABLE was launched in 2014 to speed up the development of new antibiotics for the treatment of Gram-negative systemic infections. The project has achieved and surpassed its initial goals, ###having so far identified 5 antibacterial leads, selected 2 antibacterial development candidates and advanced 1 compound into preclinical and phase one clinical studies.
With several promising compounds in the pipeline, IMI granted the project a one year no-cost extension (i.e. total spend will remain within original budget). Here’s a breakdown of the achievements of the research teams so far:
- ENABLE currently has 10 active programmes: 6 are in Hit to Lead, 2 in Lead to Candidate, 1 in Candidate to Phase I and 1 in Phase I.
- ENABLE selected its first candidate – Juvabis’ apramycin programme – in October 2018. Mutabilis’ candidate MUT485 received candidate status in November 2019.
- Juvabis’ clinical candidate apramycin is currently evaluated in a Phase I randomised, double-blind, placebo-controlled single ascending dose study in healthy volunteers. Apramycin is an aminoglycoside antibiotic which has demonstrated promising efficacy against multidrug-resistant bacteria. First results are expected in 2020.
Anders Karlén, leader of ENABLE Managing Entity and professor at Uppsala University, said: 'This achievement is an immense success given the complexity and number of partners involved. We have brought the leading experts in the antimicrobial resistance field together, set up a unique and effective collaboration and delivered.'
Since its launch in 2014, the ENABLE project has helped researchers in universities and small and medium-sized enterprise (SMEs) to progress potential antibiotics through the challenging earlier stages of drug development. Now, the project has selected one potential antibiotic it has worked on, apramycin, as a clinical candidate. ###The clinical potential of apramycin was discovered by researchers at the University of Zurich who set up a spin-out company, Juvabis, to develop it further. Juvabis joined ENABLE in 2016. Thanks to the collaboration with ENABLE, the Juvabis team has now been able to demonstrate the safety and efficacy of apramycin in animal models for various infections, including infections caused by some of the more dangerous drug-resistant bacteria. This prompted the project to select apramycin as a clinical candidate; the plan is to prepare for a Phase I clinical trial application by the end of 2018. ‘We are pleased that our collaboration with ENABLE has further highlighted the potential of apramycin in the treatment of complicated systemic infections in humans,’ says Sven Hobbie, who leads the programme. ‘The nomination by ENABLE of apramycin as a drug candidate will accelerate the preclinical and clinical development of our product into a life-saving medicine.’
ENABLE is still accepting Expressions of Interests from organisations with interesting molecules that could benefit from the project’s unique platform. For more information, visit the project website and watch their new video.
Mutabilis, a French company specialised in developing novel treatments for resistant bacterial infections, has joined IMI antimicrobial resistance (AMR) project ENABLE. Mutabilis works on a family of antibiotics called dabocillins, which are effective against bacteria such as carbapenem resistant enterobacteriaceae (CRE) that are resistant to other antibiotics and are notoriously hard to treat. ### By joining ENABLE, Mutabilis gains not only funding from IMI, but access to the ENABLE project’s expertise and technical resources. ‘Securing this grant is a clear recognision of the quality of our innovative research,’ said Mutabilis Chairman Stéphane Huguet. ‘In accessing its platform of services and receiving the advice of specialists in the field, we have a fantastic opportunity to speed up the development of our compounds and secure the company’s future.’
ENABLE has an open Call for proposals for organisations to join the project and benefit from the platform it has created. More information on how to apply can be found on the project website.
- Read the Mutabilis press release
Scientists from IMI’s ENABLE project have found a new mechanism to target drug-resistant bacteria, opening up a promising new pathway for further research. The mechanism involves DNA gyrase, a well-known enzyme that is a target of already existing antibiotics. ENABLE scientists found a new way to inhibit this enzyme and kill drug-resistant bacteria in the laboratory. In the study, published recently in the Proceedings of the National Academy of Sciences, they identified and characterised two new compounds, which have the ability to kill bacteria resistant to quinolones, a family of broad-spectrum antibiotic drugs, in this novel way.### Although the work on these specific compounds will not continue within the ENABLE project because the compounds showed toxicity, the new mechanism which was uncovered holds potential for future research. ‘This study is very significant, but not because these specific compounds are likely to end up as clinical drugs’, said Anthony Maxwell of the John Innes Centre in the UK, one of the ENABLE project partners who played a key role in this study. ‘It is significant because it has revealed a novel way of targeting a well validated anti-bacterial target, DNA gyrase, and that new way of targeting this enzyme is not subject to pre-existing resistance to antibiotics. It is very exciting. Eventually this could lead to the development of the new antibiotics.’
Two IMI flagship projects, the European Lead Factory and ENABLE, have together propelled a promising, new antibiotic programme, which could result in new antibiotics for patients. A researcher from the University of Oxford, Chris Schofield, kick-started the process through his group’s focus on a potential target within gram-negative bacteria that could eliminate resistance### against antibiotics. He applied to the European Lead Factory project, where the target was screened against their library of about 300,000 compounds. Small molecule hits with very promising activity against the target were identified. The Oxford and ELF teams worked further to improve the hits, resulting in highly potent compounds that create a strong base for further development. Schofield then turned to the ENABLE project, which has the mission to develop attractive antibacterial candidates for testing in the clinic. The application was deemed to have high novelty and potential for development and was accepted by the project. Schofield’s group is now collaborating with ENABLE partners in the pharmaceutical industry, SMEs and universities from across Europe to develop these early stage compounds towards clinical trials. ‘Through collaborative efforts across Europe, we have been able to take a potential antibiotic target and identify compounds active against it, improve them and start development towards the holy grail of new antibiotics for patients’, said Schofield. ‘This is transforming an almost impossible task for an individual academic group into a solid scientific and commercially viable pathway.’ And there is more in the pipeline: ELF is currently working on another 5 antibiotic programmes and ENABLE accommodates 8 active programmes.
- Read the press release
IMI antimicrobial resistance project ENABLE is looking for partners to join its consortium. Specifically, the team is looking for organisations with expertise in bacterial potentiation or small molecule uptake. Details of the expertise required, the types of organisations that are eligible for funding, and information on how to apply, can be found on the project website.### The project will also hold a webinar on the process on 31 August. The deadline for submitting expressions of interest is 9 September 2016.
Meanwhile, ENABLE’s open Call for innovative anti-infective programmes remains open. The Call provides early stage anti-infective programmes with an exciting opportunity to progress through the challenging, earlier stages of drug development and draw on the extensive expertise of the ENABLE consortium.
French SME Nosopharm has joined IMI’s antimicrobial resistance project ENABLE. Thanks to this move, Nosopharm will be able to advance the development of a novel antibiotic it has created called NOSO-95179, which is designed to treat multidrug-resistant hospital-acquired infections. ###Specifically, Nosopharm will be able to access significant technical expertise and financial support to complete further studies. Nosopharm will also participate in collaborative research with ENABLE’s expert partners across Europe. Finally, the project will strengthen the company’s intellectual property as all NOSO-95179 results will be owned by Nosopharm. ‘Being selected for ENABLE strengthens Nosopharm’s position among the most innovative companies in the antibacterial R&D community,’ said Philippe Villain-Guillot, president of Nosopharm. ‘This is a major milestone in the development of our NOSO-95179 candidate. We would like to warmly thank the IMI and the ENABLE team for their trust and support.’ Meanwhile IMI Executive Director Pierre Meulien said: ‘IMI is delighted that projects such as ENABLE can support SMEs to advance programs through the most challenging phases of development. This is an example of how public-private partnerships such as IMI can address critical scientific and commercial challenges for the benefit of patients.’
IMI’s antimicrobial resistance project ENABLE has a rolling programme of Open Calls for promising Gram-negative antibiotic programmes, and the next deadline for submissions is on 27 March 2015.### If you have an interesting Gram-negative programme that targets Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and/or Acinetobacter baumannii and that meets the minimum activity thresholds specified within the call text, this is an opportunity to join the ENABLE project. Selected programmes can join the ENABLE consortium and gain access to the ENABLE discovery pipeline, which can develop a programme through to phase I clinical trials and significantly accelerate your work. Following earlier Calls, the project has started three programmes, with a further two due to start soon.
Details of how to apply can be found on the Open Calls page of the ENABLE website.
Questions? Contact opencall[AT]nd4bb-enable.eu.
IMI antimicrobial resistance project ENABLE is seeking promising early stage Gram-negative programmes to join the €85 million project which has the mission to bring at least one candidate to phase 1 clinical trial.### Small and medium-sized enterprises (SMEs) and research groups from Europe working on direct acting systemic Gram-negative programmes are invited submit a three-page Expression of Interest to the project. Successful applicants will be invited to join the ENABLE consortium - retaining full ownership of their programme and having a skilled international consortium working on accelerating their programme to clinic. Details of how to submit applications can be found on the Open Calls page of the project website. The project is also organising webinars on its procedures on 3 and 24 November and 8 December. Registration for the webinars is via the project website.
IMI’s antimicrobial resistance project ENABLE has launched its second open call for promising Gram-negative programmes. If you have an interesting Gram-negative programme that targets Escherichia coli,### Klebsiella pneumoniae, Pseudomonas aeruginosa and/or Acinetobacter baumannii and that meets the minimum activity thresholds specified within the call text, this is an opportunity to join the ENABLE project. Selected programmes will gain access to the ENABLE discovery pipeline, which can develop a programme through to phase I clinical trials and significantly accelerate your work. If you are interested in applying, please visit the open calls page of the project website for full details and a template for completing the short expression of interest. The application forms and guidance material have been revised following the project’s first Call, meaning that applying to be part of the programme is easier than ever.
- Deadline for applications: 27 June 2014
- Questions? Contact opencall[AT]nd4bb-enable.eu.
IMI’s new antimicrobial resistance project ENABLE has launched its first open call for promising Gram-negative programmes.
If you have an interesting Gram-negative programme that targets Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and/or Acinetobacter baumannii### and that meets the minimum activity thresholds specified within the call text, this is an opportunity to join the ENABLE project. Selected programmes will gain access to the ENABLE discovery pipeline, which can develop a programme through to phase I clinical trials and significantly accelerate your work.
The first deadline is 31 March 2014, and regular six-month deadlines will be scheduled following this, with the next deadline planned for mid-September.
If you are interested in applying, please visit the open calls page of the project website for full details and a template for completing the three-page expression of interest.
- Questions? Contact opencall[AT]nd4bb-enable.eu.
ND4BB – the story so far, in Nature Reviews Microbiology
IMI’s antimicrobial resistance (AMR) programme New Drugs for Bad Bugs (ND4BB) is the focus of a recent comment piece in Nature Reviews Microbiology by John Rex of AstraZeneca, who is involved in ND4BB. The article explains how ###IMI and other projects around the world are tackling the biggest challenges in antibiotic research and development. For example, TRANSLOCATION is investigating how to transport antibiotics into bacteria, while COMBACTE focuses on the design and implementation of more efficient clinical trials. ENABLE, IMI’s newest AMR project, is creating a drug discovery platform to fast-track the development of promising molecules. The article also highlights IMI project RAPP-ID, which is working on point-of-care tests, as well as a number of US-based initiatives. Looking to the future, the article notes that IMI has a project in development which will investigate new business models and economic strategies to incentivise the development of new antibiotics.
The article concludes: ‘Although the [AMR] crisis is far from resolved, the leadership of the European Commission are to be commended for their far-sighted approach to creating ND4BB and its projects, all of which provide hope that the global community will have access to an adequate pipeline of novel antimicrobial agents with which to address the challenge of AMR.’
ParticipantsShow participants on map
- Astrazeneca AB, Södertälje, Sweden
- Basilea Pharmaceutica International AG, Basel, Switzerland
- Evotec International GMBH, Hamburg, Germany
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
Universities, research organisations, public bodies, non-profit groups
- Agencia Estatal Consejo Superior De Investigaciones Cientificas, Madrid, Spain
- Aston University, Birmingham, United Kingdom
- Cardiff University, Cardiff, United Kingdom
- Centre National De La Recherche Scientifique Cnrs, Paris, France
- European Biotechnology Network aisbl, Brussels, Belgium
- Forschungszentrum Borstel Leibniz Lungenzentrum, Borstel, Germany
- Fundacion Centro De Excelencia En Investigacion De Medicamentos Innovadores En Andalucia, Granada, Spain
- Helmholtz-Zentrum Fur Infektionsforschung GMBH, Braunschweig, Germany
- John Innes Centre, Norwich, United Kingdom
- Kobenhavns Universitet, Copenhagen, Denmark
- Latvijas Organiskas Sintezes Instituts, Riga, Latvia
- Narodowy Instytut Lekow, Warsaw , Poland
- Region Hovedstaden, Hilleroed, Denmark
- Rise Research Institutes Of Sweden AB, Stockholm, Sweden
- Servicio Madrileno De Salud, Madrid, Spain
- St George'S Hospital Medical School, London, United Kingdom
- Stichting Vu, Amsterdam, Netherlands
- Universitat De Barcelona, Barcelona, Spain
- Universitat Zurich, Zürich, Switzerland
- Universite De Liege, Liège, Belgium
- University of Helsinki, University of Helsinki, Helsinki, Finland
- University of Oxford, Oxford, United Kingdom
- Univerza V Ljubljani, Ljubljana, Slovenia
- Uppsala Universitet, Uppsala, Sweden
Small and medium-sized enterprises (SMEs)
- Abac Therapeutics, SL, Esplugues De Llobregat, Spain
- Asclepia Outsourcing Solutions, Destelbergen, Belgium
- Beactica Therapeutics AB, Uppsala, Sweden
- Bioresources Technology & Engineering GmbH, Giessen, Germany
- Helperby Therapeutics Limited, London, United Kingdom
- Inspiralis Ltd, Norwich, United Kingdom
- Juvabis AG, Furigen, Switzerland
- Molecular Discovery LTD, London, United Kingdom
- Mutabilis, Paris, France
- Northern Antibiotics Oy, Helsinki, Finland
- Nosopharm, Nimes, France
- Ot Chemistry AB, Uppsala, Sweden
- Redx Pharma Ltd, Liverpool, United Kingdom
- Spero Europe Limited, Godalming, Surrey, United Kingdom
- The Research Network Ltd., Sandwch, United Kingdom
- Redx Anti-Infectives LTD, Manchester, United Kingdom
Non EFPIA companies
- Statens Serum Institut, Copenhagen S, Denmark
|Name||EU funding in €|
|Abac Therapeutics, SL||313 622|
|Agencia Estatal Consejo Superior De Investigaciones Cientificas||33 396|
|Asclepia Outsourcing Solutions||676 310|
|Aston University||240 646|
|Beactica Therapeutics AB||169 699|
|Bioresources Technology & Engineering GmbH||61 800|
|Cardiff University||1 042 977|
|Centre National De La Recherche Scientifique Cnrs||175 500|
|European Biotechnology Network aisbl||351 780|
|Forschungszentrum Borstel Leibniz Lungenzentrum||135 794|
|Fundacion Centro De Excelencia En Investigacion De Medicamentos Innovadores En Andalucia||334 305|
|Helmholtz-Zentrum Fur Infektionsforschung GMBH||512 192|
|Helperby Therapeutics Limited||104 120|
|Inspiralis Ltd||229 666|
|John Innes Centre||440 127|
|Juvabis AG||4 754 115|
|Karolinska Institutet (left the project)||151 800|
|KeytoLead AB (left the project)||3 721|
|Kobenhavns Universitet||2 284 778|
|Latvijas Organiskas Sintezes Instituts||7 653 860|
|Molecular Discovery LTD||220 276|
|Mutabilis||6 075 990|
|Narodowy Instytut Lekow||288 003|
|Northern Antibiotics Oy||68 670|
|Nosopharm||1 066 854|
|Ot Chemistry AB||1 152 570|
|Redx Pharma Ltd||26 970|
|Region Hovedstaden||476 100|
|Rise Research Institutes Of Sweden AB||5 408 251|
|Servicio Madrileno De Salud||586 800|
|Spero Europe Limited||41 460|
|St George'S Hospital Medical School||92 200|
|Statens Serum Institut||1 429 896|
|Stichting Vu||2 092 530|
|The Research Network Ltd.||277 085|
|The University Court Of The University Of St Andrews (left the project)||15 764|
|Universitat De Barcelona||326 283|
|Universitat Zurich||2 364 930|
|Universite De Liege||16 150|
|University of Helsinki||761 130|
|University of Oxford||4 107 350|
|Univerza V Ljubljani||476 420|
|Uppsala Universitet||10 760 831|
|Name||Funding in €|
|Redx Anti-Infectives LTD||451 425|
|Statens Serum Institut (left the project)||645 854|
|Total Cost||58 900 000|