Institut für Medizinische Biometrie
und Statistik (IMBI)

Zusammenfassung

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 collaborate 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, the first two topics of which were launched as IMI’s 6th Call for proposals in May 2012. COMBACTE is the result of one of those topics. A third topic under ND4BB was launched as part of IMI’s 8th Call for proposals in December 2012.

Since the launch of ND4BB, the European Parliament has also weighed in on the issue. In December 2012 it adopted a resolution on the rising threat of AMR that highlights the important role of PPPs in reinvigorating antimicrobial R&D.

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. Looking to the future, trials of other drugs are planned. For example, IMI’s 8th Call for proposals included a subtopic on the conduct of early clinical studies on MEDI4893, a new human immunoglobulin monoclocal antibody which targets S. aureus alpha toxin, which is behind much of the tissue and organ damage associated with S. aureus infection. The outcome of the 8th Call for proposals will be made public in the second half of 2013.

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.

Participants

EFPIA companies
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
Centre Hospitalier Régional Universitaire de Besançon, France
Centre Hospitalier Universitaire de Limoges, France
Cliniques Universitaires Saint Luc, Belgium
Fundacio Centre de Recerca en Salut International de Barcelona, Spain
Helmholtz-Zentrum für Infektionsforschung GmbH, Germany
Hospices Cantonaux CHUV, Switzerland
Institut National de la Santé et de la Recherche Médicale, France
North Bristol National Health Service Trust, UK
Servicio Andaluz de Salud, Spain
Stichting Katholieke Universiteit / Radboud University Nijmegen Medical Centre, The Netherlands
Universitätsklinikum Freiburg, Germany
Universitätsklinikum Köln, AöR (University Hospital of Cologne), Germany
Université de Genève, Switzerland
Université Joseph Fourier, Centre de Recherche Inserm, France
University of Antwerp, Belgium

Small and medium-sized enterprises (SMEs)

Julius Clinical Research BV, The Netherlands

This research project receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115523, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.