ND4BB

New Drugs for Bad Bugs
Ongoing | IMI1 |

Summary

Antimicrobial resistance (AMR) represents a serious and growing threat to human and animal health worldwide. It already kills 700 000 people globally every year, and that figure could rise to 10 million by 2050. The IMI programme New Drugs 4 Bad Bugs (ND4BB) represents an unprecedented partnership between industry, academia and biotech organisations to combat antimicrobial resistance in Europe. The EUR 700 million programme comprises 8 projects that are finding solutions to the scientific, regulatory, and business challenges that are hampering the development of new antibiotics.

In its 2011 action plan on antimicrobial resistance, the European Commission called for ‘unprecedented collaborative research and development efforts to bring new antibiotics to patients’ by, among other things, launching an IMI programme in this vitally important area. The result is New Drugs 4 Bad Bugs (ND4BB). The first projects kicked off in early 2013, and the programme now encompasses seven projects that are starting to deliver exciting results in diverse aspects of antibiotic development. The total budget of the programme now stands at around €700 million. Between them, the projects address some of the biggest challenges in antibiotic development, covering basic science and early stage drug development, clinical trials, and economics.

The science of getting drugs into bugs (and keeping them there)!

The TRANSLOCATION project focuses on identifying new ways of getting potential antibiotics into bacteria and preventing bacteria from destroying or expelling the drugs before they can take effect. It is working primarily on Gram-negative pathogens such as Escherichia coli and Klebsiella pneumoniae; getting antibiotics into these bacteria is particularly challenging.

Key achievements

  • Development of new techniques to analyse the uptake of antibiotics by bacteria.
  • Worked out the structure of 20 proteins found in the membranes of bacteria that cause many infections. These proteins play a vital role transporting substances (including, potentially, antibiotics) into and out of bacterial cells.
  • Greater understanding of the workings of efflux pumps (which bacteria use to expel antibiotics).
  • Creation of a database to gather data from both new antibiotic research projects and abandoned ones.

Building a drug discovery platform for antibiotics

The early stages of antibiotic discovery and development are extremely difficult. Researchers with promising potential antibiotics that are in the early stages of drug discovery can apply to access the antibiotic development platform created by IMI’s ENABLE project. The platform was set up to test and optimise molecules with the potential to become future drug candidates capable of treating infections due to resistant Gram-negative bacteria. Applications are assessed for their scientific potential. Universities and small companies selected to join the project have the opportunity to collaborate with experts in all areas of antibacterial drug discovery, such as microbiology, pharmacology and chemistry, to help advance their molecule through the drug development process, through to clinical testing.

Key achievements

  • Since the project started in February 2014, it has received over 70 applications to join the project from organisations with promising anti-infective research and development programmes.
  • As of the end of 2016, 16 programmes (mainly from academia and small biotech) had been selected to join the project, including one programme that started life in IMI’s European Lead Factory project.
  • Through these programmes, the project has identified two advanced molecules that show particularly promising antibacterial activity and are worthy of further study and optimisation.
  • Project partners have also identified a new way of targeting drug-resistant bacteria.
  • There are more programmes in the pipeline. The project has a rolling open Call for proposals and the ENABLE team is continually reviewing submissions.
  • The project has attracted the interest of SMEs working on antibiotic development both in Europe and beyond; at the end of 2016, there were 15 SMEs in the project.

Establishing a pan-European network of clinical sites

The COMBACTE family of projects (COMBACTE-CARE, COMBACTE-MAGNET, COMBACTE-NET, COMBACTE-CDI) is building a self-sustaining, pan European antibacterial development network and using it to run high-quality clinical studies of new antibiotics for multi-drug resistant bacteria.

COMBACTE-NET is dedicated to building strong clinical, laboratory and research networks across Europe. The hope is that these networks, which bring together vast amounts of expertise from universities, hospitals, the pharmaceutical industry, and more, will become the reference point in Europe for the clinical development of new antibiotics.

COMBACTE-CARE focuses on infections caused by bacteria known as ‘carbapenem-resistant enterobacteriaceae’ (CRE). CRE are resistant to most available antibiotics and are so difficult to treat they are considered to be one of the most dangerous drug-resistant bacteria in the world. COMBACTE-CARE aims to shed new light on the best ways to understand and treat CRE infections. It will also run clinical trials of a novel antibiotic combination product designed to tackle a sub-type of CRE infections for which there are limited or no treatment options. Further funding for the trial comes from the US-based Biomedical Advanced Research and Development Authority (BARDA); this will be used to support additional studies needed to advance the development of this urgently-needed treatment.

COMBACTE-MAGNET addresses the need for new approaches to preventing and treating life-threatening infections among patients in intensive care units. This group is particularly vulnerable to infections, for example in their lungs and airways. Increasingly, these infections are resistant to a range of antibiotics, leaving doctors with few options to treat their patients.

COMBACTE-CDI focuses on adding to our understanding of the epidemiology and clinical impact of Clostridium difficile infection (CDI) in Europe.  CDI is one of the most common healthcare-associated infections.

Key achievements

  • The CLIN-Net hospital network includes over 800 hospitals in 42 countries in Europe. The project is now cataloguing these and, where necessary providing training to ensure all are qualified to run high quality clinical studies.
  • The LAB-Net network counts over 600 laboratories in 42 countries.

The projects are already using the networks to run a number of clinical trials and studies, including:

  • RESCUING assessed the clinical management and treatment outcomes of hospitalised patients with complicated urinary tract infections. It is the first study within the COMBACTE family to be completed, and the team is now analysing the data gathered.
  • SAATELLITE is investigating a drug called MEDI4893. MEDI4893 targets a toxin produced by Staphylococcus aureus, a bacteria often associated with hospital‐associated infections and linked to resistance issues.
  • ASPIRE aims to add to our understanding of the incidence and causes of health-care associated infections (HAIs) caused by two bugs: S. aureus and Pseudomonas aeruginosa.
  • ANTICIPATE aims to determine the incidence of Clostridium difficile infections in hospitalised patients on antibiotic treatment.
  • EVADE is assessing the effectiveness of a drug called MEDI3902 in the prevention of Pseudomonas aeruginosa infections, especially in intensive care patients who are on artificial ventilation.
  • REJUVENATE is testing aztreonam-avibactam for the treatment of complicated intra-abdominal infections (cIAI).
  • EURECA focuses on patients with serious carbapanem-resistant infections, and aims to learn how patients across Europe are currently treated and which patients respond well to which treatments.
  • Further clinical studies are ongoing or in the pipeline.

New treatments to help cystic fibrosis patients

Another ND4BB project in the clinical development field is iABC. Respiratory infections, frequently caused by drug-resistant bacteria, are the main cause of disease and death in people with cystic fibrosis (CF) and bronchiectasis (BE). Thanks to inhaled antibiotics, patients now live longer than ever before and enjoy a better quality of life. However, infections are increasingly becoming resistant to the few drugs available, putting patients’ lives at risk. The iABC project is advancing the development of inhaled antibiotics for patients with CF and BE. It is also working to identify ways of improving clinical trials of treatments for these serious diseases.

New economic models for antibiotic development

The DRIVE-AB project focuses on the urgent need to develop a new business model for antibiotic development that will reinvigorate investments in this vital area while also addressing the sustainable use of, and equitable access to, antibiotics. The project is tackling a contradiction at the heart of antibiotic development: on the one hand, pharmaceutical companies make money by selling large volumes of the drugs they develop. On the other hand, the use of new antibiotics should be restricted, so as to minimise the risk of bacteria developing resistance to them. As a result of this situation, sales are low and the costs of development often exceed the potential return on investment. DRIVE-AB is researching and developing the basis for new commercial models that provide industry and other stakeholders with an incentive to invest in this area, while ensuring that new antibiotics are used sustainably.

Key achievements

  • DRIVE-AB achieved international and multidisciplinary consensus on a global definition of responsible antibiotic use comprising 22 domains. Consensus was also achieved on quality indicators and quantity metrics for both inpatient and outpatient settings.
  • The project identified the most promising reward models and presented them to high-level decision-makers, policy experts and economists, as well as regulatory and public health experts and representatives of pharmaceutical companies and research institutions at a specially-organised conference in June 2016.
  • The project has also presented policy briefs to decision-makers at high-level fora such as the United Nations General Assembly and the World Health Assembly.
  • DRIVE-AB scientists discovered that a 30% drop in the efficacy of antibiotics could result in 120 000 additional infections and 6 300 deaths per year in the US alone among people who undergo common surgeries and chemotherapy treatments. The findings were published in the Lancet Infectious Diseases.
  • The project has been recognised by the United Nations (UN) Secretary-General’s high-level panel on access to medicines and by EU health ministers.
  • DRIVE-AB is cited in EU guidelines on prudent use of antimicrobials in human medicine as proposed by the European Centre for Disease Prevention and Control (ECDC).

Achievements & News

DRIVE-AB recommends ecosystem approach to drive antibiotic development
January 2018

A mix of economic drivers and incentives is needed to stimulate antibiotic development, according to the final report of IMI’s DRIVE-AB project. The report, based on input from diverse stakeholders, highlights four incentives that would be the most effective in stimulating the antibiotic pipeline while also ensuring that critical antibiotics are used sustainably and are accessible to all who need them. ###The incentives picked out by the report are:

  • Grants: non-repayable funds for R&D given to academic institutions, companies and others;
  • Pipeline coordinators: governmental or non-profit organizations that closely track the antibiotic pipeline (or subsets thereof), identify gaps, and actively support R&D projects both financially and technically to fill these gaps;
  • Market entry rewards: a series of financial payments to an antibiotic developer for successfully achieving regulatory approval for an antibiotic that meets specific predefined criteria to address a defined public health need, with obligations for sustainable use, equitable availability and supply;
  • Long-term supply continuity model: a delinked payment to create a predictable supply of important generic antibiotics.

All of the recommended incentives would include mandatory provisions for equitable access and sustainable use in order to ensure these critical medicines are available to patients who need them globally, and remain effective over time. ‘The models are meant to be complementary and don’t operate in isolation. Instead, they’re designed to form an ecosystem that maximizes R&D while ensuring access and sustainable use of new antibiotics over time,’ said Christine Årdal, DRIVE-AB partner and Senior Advisor at the Norwegian Institute of Public Health.

Read the project’s press release

DRIVE-AB recommendations to stimulate the development of new antibiotics
December 2017

New antibiotics will have to be used sparingly to preserve their efficacy. IMI’s DRIVE-AB focuses on ways to stimulate their development. A combination of incentives is required, the researchers note. In particular, they highlight the need to ‘delink’ the revenue generated by new drugs from the quantities sold. To do so, they propose a combination of push and pull mechanisms. ### Priority grants could, for example, be used to get the innovation process moving. A system of rewards for market entry could be set up to encourage its completion. This type of approach would contrast with the business model traditionally applied to drugs, where income depends on the volume of sales.

DRIVE-AB ends in December 2017, and the partners are preparing to publish their final report along with detailed recommendations. ‘We have aimed to encourage a balance between innovation and responsible use,’ says Nicole Mahoney of Merck Sharp & Dohme (MSD), one of the project partners. Policymakers and other stakeholders could find ample inspiration in DRIVE-AB’s conclusions. As a first step, the project’s findings might, for instance, feed into pilot studies at national levels, says Mahoney. ‘We may well see individual countries trialling some of these ideas and setting up reward mechanisms that work within their local context,’ she concludes.

Could molecular vacuum cleaner be key to antibiotic effectiveness?
November 2017

Scientists from IMI’s Translocation project have uncovered the workings of a ‘molecular vacuum cleaner’ in the outer membrane of certain bacteria. The mechanism, described in a paper in Nature Microbiology, helps to keep the outside of the membrane free of clusters of molecules that could weaken it and the system could prove useful as a target for new antibiotics. ### Gram-negative bacteria like Escherichia coli are enclosed by two membranes which form a significant barrier for many antibiotics, limiting their effectiveness. The outer membrane is asymmentric; while the outside is coated in sugars that ward off many molecules that could be harmful to the bacteria, the inside is lined with phospholipids. Sometimes, phospholipids from the inside of the membrane accumulate on the outside. These clumps of phospholipids represent weak spots in the membrane, rendering it more vulnerable to toxic compounds like antibiotics. In this study, the scientists proposed a functional model of the ‘maintenance of lipid asymmetry’ (Mla) system, which removes phospholipids that have strayed into the outside of the membrane, sucking them back into the inside of the membrane where they belong. ‘Our three-dimensional structures and functional data show that MlaA forms a donut in the inner leaflet of the outer membrane. This binds phospholipids from the outer leaflet and removes these via the central channel, somewhat similar to a vacuum cleaner,’ explains Bert van den Berg of Newcastle University in the UK. ‘Our study illuminates a fundamental and important process in Gram-negative bacteria and is a starting point to determine whether the Mla system of Gram-negative pathogens could be targeted by drugs to decrease bacterial virulence, and to make various antibiotics more effective.’

Read more in the press releases from the University of Newcastle and Jacobs University

Mutabilis joins antimicrobial resistance project ENABLE
November 2017

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.

COMBACTE launches ASPIRE study
June 2015

IMI’s COMBACTE project has started work on the ASPIRE-ICU study at a site in the Netherlands. ASPIRE is an epidemiological study of healthcare-associated infections caused by Staphylococcus aureus  and Pseudomonas aeruginosa to determine the incidence of infection in different patient populations and the association between factors such as co-morbidities, colonisation status, relevant biomarkers and infection risk.### Getting the study off the ground required intense collaboration between the COMBACTE partners to obtain ethical approval and to ensure the research team had the necessary training in protocols, procedures and particularly importantly, in specimen sample management. The study has two stages. In stage 1, information from existing intensive care unit (ICU) and surgical surveillance databases will be collected and analysed. In stage 2, ICU and surgical epidemiologic data will be collected from ongoing surveillance which includes collecting bacterial isolates and serum samples for in-depth microbiological and immunological studies. There are plans to launch the study in Spain next and the ASPIRE-ICU study team is working closely together with the regional coordinator there to obtain the required approvals in order to start in late summer 2015. Overall, the ASPIRE-ICU will be initiated in about 30 sites across between 10 to 12 countriesCOMBACTE is working to improve clinical trials for antibiotics and is one of the seven projects included in IMI’s New Drugs for Bad Bugs (ND4BB) platform

COMBACTE open call for clinical trial programmes/studies - deadline 29 April
March 2015

COMBACTE has launched an open call for clinical trial programmes or studies to join the project. The open call aims to identify potential replacement antimicrobial agents or approaches developed by EFPIA companies that could fulfil the overall objectives### of the project i.e. to conduct prospective clinical trials with novel trial designs to deliver safety, pharmacology, and proof of efficacy data for novel agents directed towards treatment, prevention or sequelae of infections due to priority pathogens. COMBACTE is one of the first IMI projects to be launched under the ND4BB programme with the aim of developing a broad European network of fully capable and Good Clinical Practice (GCP) compliant clinical investigation sites associated to microbiological labs to execute clinical trials enabling the registration of novel agents to be used in the treatment of patients with bacterial infections. Following the early termination of development of GSK1322322, the first novel agent to be developed within COMBACTE, there is now opportunity for other clinical trial programmes or studies to join the COMBACTE project. A webinar on the open call is planned - details will be published on the COMBACTE website.

ND4BB – the story so far, in Nature Reviews Microbiology
April 2014

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.’

IMI cited in White House paper on antimicrobial resistance
IMI’s New Drugs for Bad Bugs (ND4BB) programme has been specifically highlighted as a potential collaborator in the recent US National Action Plan for Combating Antibiotic-Resistant Bacteria report issued by the White House in March 2015. The plan outlines steps for implementing and addressing the policy recommendations of the President’s Council of Advisors on Science and Technology (PCAST). ###In setting five goals for collaborative action, the US Government is exploring ways to work with international partners, including the ND4BB programme, in order to incentivise the development of new therapeutics to counter antibiotic resistance which includes finding new, next-generation and alternatives to antibiotics, vaccines, and affordable, rapidly-deployable ‘point-of-need’ diagnostics. IMI projects included in the ND4BB programme are COMBACTE who are creating a pan-European network of clinical sites; TRANSLOCATION who are getting drugs into bugs (and keeping them there); ENABLE which is a drug-discovery platform for antibiotics; DRIVE-AB which is developing new economic models for antibiotic development.
(April 2015)

IMI antimicrobial resistance programme expands with new project
IMI’s antimicrobial resistance programme New Drugs for Bad Bugs has acquired a new project with the launch of COMBACTE-CARE. With 18 academic partners and 3 pharmaceutical companies, the project will bring highly innovative studies and activities related to the treatment of patients with infections caused by Carbapenem-Resistant Enterobacteriaceae (CRE). ###Tough to treat and sometimes deadly, CRE are considered to be one of the most dangerous resistant bacteria in the world. Specifically, the €83 million project aims to understand how patients with CRE infections are managed, with a focus on best available treatment and clinical outcomes. The project will develop new tools to detect CRE and conduct clinical trials with AstraZeneca’s antibiotic combination product Aztreonam-Avibactam (ATM-AVI), in development for the treatment of serious infections due to a difficulty to treat sub-type of CRE infections called metallo‐β‐lactamase producing Gram‐negative pathogens. All clinical and microbiological studies will be conducted in South-Eastern Europe, where infection rates with MDR-GNB are expected to be high. The phase III study is intended to include investigation sites outside Europe to ensure the global assessment of the ATI-AVI combination product.
- Read the project’s press release
(March 2015)

Antimicrobial resistance projects sign memorandum of understanding
IMI’s first antimicrobial resistance projects, COMBACTE and TRANSLOCATION, have signed a Memorandum of Understanding (MoU) to facilitate their collaboration. ### The projects are part of the New Drugs for Bad Bugs (ND4BB) programme. As such, there was always an understanding that the projects would work together – this MoU simply formalises and sets out the framework for collaboration. Specifically, the MoU covers issues such as data sharing (and confidentiality), communication and coordination, as well as the creation of a shared Ethics Committee. One of the tasks of the TRANSLOCATION project is the creation of an Info Centre that would gather data from all ND4BB projects. With this in mind, the MoU also contains a section devoted to data standards and analysis. Looking to the future, the new ND4BB projects that will be set up in the coming months will also be invited to join the MoU.
(December 2013)

Participants

Details of all project participants can be found on the individual project factsheets.

CONTACT

Contact details for the projects can be found in the individual project factsheets.