Antimicrobial resistance (AMR) is a growing problem worldwide, and with few new drugs making it to the market, there is an urgent need for new medicines to treat resistant infections. Enter the IMI-funded COMBACTE project, which aims to give antibiotic drug development a much-needed boost by pioneering new ways of designing and implementing efficient clinical trials for novel antibiotics. COMBACTE forms part of the New Drugs for Bad Bugs (ND4BB) initiative, IMI’s wider programme to tackle AMR.
The AMR arms race – developing New Drugs for Bad Bugs
AMR represents a serious and growing threat to human and animal health worldwide. According to the World Health Organization (WHO), ‘antibiotic resistance is becoming a public health emergency of yet unknown proportions’. In the EU, AMR is responsible for some 25 000 deaths every year, and the annual treatment and social costs have been estimated at some €1.5 billion. Meanwhile, new forms of resistance continue to arise and spread, leaving clinicians with few weapons to bring infections under control. Yet despite the recognised need for new antibiotics, the reality is that only two new classes of antibiotics have been brought to the market in the last three decades.
The reasons for this are manifold. On the scientific front, there is an urgent need for a greater understanding of how antibiotics work, how bacteria develop resistance to them, and what molecular mechanisms could be exploited to get round bacterial defence mechanisms. Running clinical trials on new antibiotics is also problematic due to regulatory requirements and the large numbers of patients required– put simply, a lot of patients have to be recruited to the major studies of efficacy performed for each clinical indication sought in order to be sure of having enough patients with the resistant bacteria under investigation and to demonstrate that the new antibiotic is not inferior to comparable antibacterial drugs. These issues mean that the costs of carrying out a clinical trial on a new antibiotic are extremely high.
At the same time, because some antibiotics will only be used on a very small number of patients, the costs of development often exceed the potential return on investment. In other words, antibiotic development is simply no longer a financially viable option for pharmaceutical companies, and just a handful of pharmaceutical companies remain in the field.
If no action is taken to address these issues, we risk leaving society in a situation where doctors will have few, if any, options to treat resistant bacterial infections. To avoid a public health emergency, the entire antibiotic research community, including researchers in universities, small and medium-sized enterprises (SMEs), and pharmaceutical companies must work together to reinvigorate research into new antibiotics. As a public-private partnership (PPP), IMI is the ideal platform to launch such an initiative.
In its Action Plan against the rising threats from Antimicrobial Resistance of November 2011, 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 ‘for research on new antibiotics aimed at improving the efficiency of research and development of new antibiotics through unprecedented open sharing of knowledge’.
The result is the New Drugs for Bad Bugs (ND4BB) programme, which includes the COMBACTE project.
COMBACTE – improving clinical trials for antibiotics
The COMBACTE project focuses on addressing the barriers to clinical development. A key outcome of the project will be a high quality, pan-European clinical trial network. Dubbed COMBACTE CLIN-Net, it will be capable of recruiting sufficient patients into multinational trials at all stages of development. Alongside this, the project will also establish a pan-European laboratory network (COMBACTE LAB-Net), which will deliver epidemiological information and data from microbial surveillance work to guide the selection of clinical trial sites. Crucially, the COMBACTE team aims to generate innovative trial designs to facilitate the registration of novel antibacterial agents. It will also design and validate tests to support the diagnosis of patients, identify the most appropriate treatments, and monitor the patient’s response.
A large part of the project will be devoted to the performance of clinical trials of drugs under development in the pharmaceutical companies involved in the project. The first antibiotic to undergo clinical trials under COMBACTE is GSK1322322, which inhibits the action of a bacterial enzyme called peptide deformylase (PDF) and appears to be effective against multi-drug resistant respiratory and skin pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). Most importantly, GSK1322322 represents a new class of antibiotics with a novel mode of action. In COMBACTE, experts will run clinical trials to evaluate GSK1322322’s efficacy at treating acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.
The second compound to be tested will be MEDI4893, which is designed to prevent S. aureus disease by neutralising a specific toxin produced by the bug which is behind much of the tissue and organ damage associated with S. aureus infections. Considering the importance of S. aureus as a human pathogen and the extensive problems with antibiotic resistance, MEDI489 represents an attractive preventive measure for patients at high risk of S. aureus infections. Early clinical trials will evaluate the efficacy and safety of MEDI4893 at preventing infections in patients at risk of S. aureus surgical site infections and mechanically-ventilated patients at risk for S. aureus pneumonia. Finally, to support more broadly the clinical development of new treatments for S. aureus, the consortium will gather new data on hospital-associated infections by carrying out epidemiological surveillance among surgical and intensive care unit (ICU) patients across Europe. This will help to assess the impact of patient-related and other factors on the incidence of surgical site infections and ICU pneumonia to identify the patient subgroups that are at an increased risk of these infections.
Hope for the future
The challenge of antimicrobial development is so great that no organisation could take it on alone. By bringing together leading experts from universities, hospitals, and pharmaceutical companies who are skilled in microbiology, epidemiology, drug development, and clinical trial design, COMBACTE is set to give antibiotic development in Europe a major boost.
Unique in its scale, ambition, and its potential benefits for patients, public health and pharmaceutical research in Europe, COMBACTE has the potential to become the powerhouse of antimicrobial drug development in Europe that could serve as a standard for other groups. Ultimately, the hope is that COMBACTE will provide a framework for the rapid and efficient development of new treatments as well as diagnostic tests that can be speedily commercialised for use on the patients that so urgently need them.
Achievements & News
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.
- GlaxoSmithKline Research and Development Ltd, UK
- AstraZeneca AB, Sweden
- Janssen Infectious Diseases Diagnostics BVBA, Belgium
Universities, research organisations, public bodies, non-profit groups
- University Medical Center Utrecht, the Netherlands
- Arbeitsgemeinschaft für Osteosynthesefragen Documentation and Publishing Foundation, Clinical Investigation and Documentation, Switzerland
- Centre Hospitalier Régional Pointe-à- Pitre, France
- Centre Hospitalier Universitaire de Limoges, France
- Cliniques Universitaires Saint Luc, Belgium
- Eberhard Karls Universität Tuebingen, Germany
- Erasmus Universitair Medisch Centrum Rotterdam, the Netherlands
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy
- Fundacio Centre de Recerca en Salut International de Barcelona, Spain
- Fundacio Clinic Per a La Recerca Biomedica, Spain
- Helmholtz-Zentrum für Infektionsforschung GmbH, Germany
- Hospices Cantonaux CHUV, Switzerland
- Institut National de la Santé et de la Recherche Médicale, France
- Instituto Nacional de Saúde, Portugal
- Linköping Universitet, Sweden
- North Bristol National Health Service Trust, UK
- Servicio Andaluz de Salud, Spain
- Servicio Madrileño de Salud, Spain
- Stichting Katholieke Universiteit / Radboud University Nijmegen Medical Centre, the Netherlands
- Tel-Aviv Sourasky Medical Center, Israel
- Universitätsklinikum Freiburg, Germany
- Universitätsklinikum Köln, AöR (University Hospital of Cologne), Germany
- Université Claude Bernard Lyon 1, France
- Université de Genève, Switzerland
- Université Joseph Fourier, Centre de Recherche Inserm, France
- University Medicine of the Ernst Moritz Arndt University of Greifswald, Germany
- University of Antwerp, Belgium
- University of Athens Medical School, Greece
Small and medium-sized enterprises (SMEs)
- Julius Clinical Research BV, the Netherlands
Facts & Figures
|IMI funding||109 433 010|
|EFPIA in kind||133 922 382|
|Other||7 200 000|
|Total cost||250 484 591|
GlaxoSmithKline Research and Development Ltd
Tel.: +1 919 483 1882
E-mail: odin.j.naderer [AT] gsk.com
Marc J M Bonten
University Medical Center Utrecht
Tel.: +31 88 7557394
E-mail: mbonten [AT] umcutrecht.nl
Clinical trials lead
Centre Hospitalier Universitaire de Limoges
Tel.: +33 5 55 05 69 84
E-mail: b.francois[AT]unilim.fr and bruno.francois[AT]chu-limoges.fr