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
COMBACTE launches ASPIRE study
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 countries. COMBACTE 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. (June 2015)
COMBACTE launches open call for new clinical trial programmes/studies - deadline 29 April
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 programs or studies to join the COMBACTE project. A webinar on the open call is planned for 17 April - details of how to participate can be found on the COMBACTE website.
-Deadline for submissions: 29 April 2015 at 19:00 Central European Summer Time (CEST).
-Read the open call protocol and guidelines for submitting proposals
-Download the proposal submission template and evaluation criteria
COMBACTE clinical trial of new antibiotic gets underway
The first patient has been enrolled into a clinical trial of a novel antibiotic run by IMI’s COMBACTE project. The patient, who is based in Belgium, is the first participant in a Phase II trial of a medicine called MEDI4893, which is designed to prevent Staphyolococcus aureus pneumonia in intensive care patients who need a machine to help them breathe. S. aureus is a common ###cause of hospital-associated infections and drug-resistant strains of the bacteria have been identified. MEDI4893, which was developed by pharmaceutical company MedImmune, works by targeting a toxin produced by S. aureus. The enrolment of the first patient in the trial is the result of months of hard work on the part of the project partners, who come from academia and industry and worked closely together to set up the study. ‘An increase in emergence of antimicrobial resistance and a steady decline in the number of novel antimicrobials being developed across industry have significantly limited treatment options for diseases like pneumonia caused by Staphylococcus aureus,’ said MedImmune’s Hasan Jafri, EFPIA Lead for the study.’ Novel biologics under investigation such as MEDI4893 may offer a unique opportunity to help prevent these serious infections without inducing antimicrobial resistance. We believe collaboration with world-renowned experts such as those within COMBACTE is one of the best models to advance development in this area, and supports our commitment to bring novel and effective anti-infectives to patients.’
- Read the project’s press release.
COMBACTE clinical trial of new anti-infective gets underway
The first patient has been enrolled into a clinical trial of a novel anti-infective monoclonal antibody run by IMI’s COMBACTE project. The patient, who is based in Belgium, is the first participant in a Phase II trial of a medicine called MEDI4893, which is designed to prevent Staphyolococcus aureus pneumonia in intensive care patients who need a machine to help them breathe. ###S. aureus is a common cause of hospital-associated infections and drug-resistant strains of the bacteria have been identified. MEDI4893, which was developed by pharmaceutical company MedImmune, works by targeting a toxin produced by S. aureus. The enrolment of the first patient in the trial is the result of months of hard work on the part of the project partners, who come from academia and industry and worked closely together to set up the study. ‘An increase in emergence of antimicrobial resistance and a steady decline in the number of novel antimicrobials being developed across industry have significantly limited treatment options for diseases like pneumonia caused by Staphylococcus aureus,’ said MedImmune’s Hasan Jafri, EFPIA Lead for the study.’ Novel biologics under investigation such as MEDI4893 may offer a unique opportunity to help prevent these serious infections without inducing antimicrobial resistance. We believe collaboration with world-renowned experts such as those within COMBACTE is one of the best models to advance development in this area, and supports our commitment to bring novel and effective anti-infectives to patients.’
- Read the project’s press release.
COMBACTE’s new video on AMR released
COMBACTE has released a short video on antibiotic resistance (AMR) and how the project is working to fight AMR.
The video explains why COMBACTE is in a unique position to ###tackle AMR and how it is pioneering new ways of designing and implementing efficient clinical trials for new antibiotics. COMBACTE is creating a new environment for the clinical development of new antibiotics to fight AMR. By 2020 COMBACTE aims to show that high quality, cost-effective clinical trials characterised by a shorter recruitment period can be a reality.
COMBACTE is the first public-private partnership with pharmaceutical companies in drug development for infectious diseases. With this initiative, Europe takes the lead in tackling the global threat of AMR.
Bacterial infections are becoming more and more resistant to antibiotics. However, only two new classes of antibiotics have been brought to the market in the last three decades. According to the World Health Organization (WHO), AMR is becoming a public health emergency of yet unknown proportions. In the European Union, AMR is responsible for some 25 000 deaths every year.
COMBACTE at the European Congress of Clinical Microbiology and Infectious Diseases
IMI’s antimicrobial resistance project COMBACTE was present at the 24th European Congress of Clinical Microbiology and Infectious Diseases which took place in Barcelona, Spain from 10 to 13 May 2014. ###In addition to a COMBACTE exhibition stand where project leaders were available to answer questions, COMBACTE representatives presented the project and its latest progress during a lunchtime meeting on 11 May. During the meeting a video that was made to make the project better known and accessible to a wider audience was launched.
The 24th European Congress of Clinical Microbiology and Infectious Diseases featured exhibition stands, series of keynote lectures, symposium, educational workshops and meet-the-expert sessions on parallel tracks, covering the entire field of infectious diseases and clinical microbiology.
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.’
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||133 912 392|
|Other||7 131 466|
|Total cost||250 476 868|
GlaxoSmithKline Research and Development Ltd
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