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 eight projects that are starting to deliver exciting results in diverse aspects of antibiotic development. The total budget of the programme now stands at around €650 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.
- 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.
- 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.
- 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.
- 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).