Combacte magazine 2016

COMBACTE Magazine 2016

Combatting Bacterial Resistance in Europe

02 GAME-CHANGER Foreword by Pierre Meulien, Executive Director of IMI

16 COLLABORATING EXPERTS Academics and pharmaceuticals sharing knowledge and working together

42 COMBACTE NETWORK The continuous growth of the COMBACTE networks

PIERRE MEULIEN, IMI

GAME-CHANGER

We are building an extensive network to span the continent.

And there is interest elsewhere, too. By creating the perfect environment to develop new medicines we may eventually see new antibiotics get to the patients that need them. The foundation has now been laid. And it’s a game-changer.

Pierre Meulien T

he middle of the 20th century was the golden age for antibiotics. The first antibiotics were mass produced during this period and saved countless lives which otherwise would have been taken by tuberculosis, pneumonia, syphilis and other deadly diseases. For years, doctors relied on antibiotics, a powerful weapon, to treat their patients. However, the success of antibiotics has had consequences and their overuse has now led to a global threat – antimicrobial resistance – at a very worrying scale. In Europe alone, 25,000 people die each year from resistant bacterial infections. Although most deaths occur in European regions with outdated care facilities, multi-resistant bacteria threaten even the most advanced of hospitals. Now, new strains are proving immune – to our current arsenal, at least.

Attempts to do the obvious – develop new antibiotics – have been fraught with challenges. Firstly, bacteria are very good at defending themselves from antibiotics, and devising ways of getting round these bacterial defenses is scientifically difficult.

Secondly, regulatory requirements make running clinical trials of new antibiotics far from trivial. Finally, as new antibiotics are used sparingly, there is a lack of incentives for industry to develop them. The truth is, no institution, company or even country can solve these problems alone.

Photo: Genome Canada

FOREWORD

The Innovative Medicines Initiative program New Drugs for Bad Bugs (ND4BB), of which COMBACTE forms a key part, is addressing these issues.

Through ND4BB, the best and brightest of the pharmaceutical industry and medical science are pooling their knowledge and sharing data, findings and insights with each other. We are building an extensive network to span the continent. And there is interest elsewhere, too. By creating the perfect environment to develop new medicines we may eventually see new antibiotics get to the patients that need them. The foundation has now been laid. And it’s a game-changer.

Pierre Meulien Executive Director Innovative Medicines Initiative (IMI)

‘No institution, company or country can solve these problems alone’

TABLE OF CONTENTS

COMBACTE MAGAZINE

OVERVIEW

06 BRIGHT FUTURE

16 AMONG EXPERTS

20 COMBACTE-NET

30 RESCUING MY COMBACTE COMMUNITY

8 INFOGRAPHIC Overview of all COMBACTE projects

The Issue The Challenge The Projects

Marc Bonten about the current status of COMBACTE and his vision for the future

The unique collaboration of academics and pharmaceuticals, according to Bruno Francois and Hasan Jafri

Building a network to develop new antibiotics faster, more effectively and

Fighting drug-resistant complicated urinary tract infections

more economically

COLOPHON

12 OUR CHOICE

22 FUNDING

32 GCP TRAINING

40 EURECA

Issued by the COMBACTE Consortium, March 2016

What The Medicines Company has to offer

Overview of the funding of the COMBACTE projects

High quality standards for all sites

Getting ready to fight carba-

Chief Editors and Project Management Claire-Marie Martis and Marike Oudshoorn, COMBACTE Communications Office (UMC Utrecht) Concept Today, Utrecht JCM Context, Utrecht Design Today, Utrecht Copywriting JCM Context, Utrecht Photography Jaap Vork Marijn de Wijs Printing Platform P, Utrecht Contact Questions or suggestions are welcome at info@combacte.com.

Please let us know if you would like to acquire additional copies of COMBACTE Magazine.

14 SAATELLITE Testing a new approach: Antibodies against hospitalassociated pneumonia

19 NMS BACKBONE The Network Management System behind COMBACTE

24 TRIAL OVERVIEW

34 COMBACTE-CARE

A clear overview of the fifteen current and planned trials

Meeting the challenge of carbapenem-resistant Enterobacteriaceae

28 COMBACTE-MAGNET

36 QUOTES

Intensive-care units: front line in the war against antibiotic resistance

38 MICROBIOLOGIST & MICROBIOLOGIST Two microbiologists, two personal drives, one project

13 NIENKE CUPERUS Meet my COMBACTE colleagues

penem resistant bacteria

42 COMBACTE NETWORK Overview of participating hospitals and laboratories

44 NATIONAL COORDINATORS Their essential role

27 DRIEKE VANDAMME Meet my COMBACTE colleagues

COMBACTE NOW

MARC BONTEN

7

START

For Marc Bonten, there’s nothing better than doing research with PhDs. But you won’t find him pipetting samples in the lab anymore.

It’s better that way, says the managing researcher, grinning mischievously. Marc Bonten has kept a close eye on antibiotic resistance for over 25 years. Along with Bruno Francois, and the EFPIA partners, he helped create COMBACTE-NET in 2013. We asked Marc Bonten about his experiences and vision for the future.

After initial skepticism, the future looks bright Interview with Marc Bonten, Academic Coordinator of all three COMBACTE projects

Some three years on, COMBACTENET appears to be well on track.

“Absolutely. While the early years were mainly spent setting up and expanding our partner, hospital and laboratory networks, in 2015, they began bearing fruit with the launch of COMBACTE-CARE and COMBACTE-MAGNET, when we embarked on a phase of conducting an increasing number of concrete trials. We will continue along those lines in 2016: more trials are planned in the near future.”

One of the COMBACTE projects defining features is collaboration between the academic world and the pharmaceutical industry.

How did you feel about that?

“Like the other academics, I, too was skeptical when the call came from IMI on behalf of ND4BB. Why help the pharmaceutical industry develop new antibiotics with European tax money? But I immediately got involved, anyway – partly because I instantly saw opportunities for scientific research – my primary motivation. Fortunately, because I think we collaborate really well, in spite of our inherently different perspectives.”

At its core, the COMBACTE-NET project is about setting up a research network. What makes that network so crucial?

“Setting up our network makes it possible for our EFPIA partners, the pharmaceutical companies, to develop new antibiotics faster, more effectively and more economically, lowering the threshold to again invest more in new drugs.

There wasn’t even a clinical trial network specializing in antibiotic resistance research, which is more complex than research into many other conditions.

The number of infections is relatively small, so assembling a large enough research population is more difficult. On top of that, doctors must treat infections quickly, so we have just a few hours to start our research. That means the network has to act very quickly and must be extremely flexible.”

Is that network getting off the ground?

“I’m really pleased. The network is really starting to take shape. We bring together Europe’s best academic partners, partly by linking up existing local networks. Partners in regions with less experience in advanced research, which often are areas where resistant bacteria are more frequently found, such as Eastern Europe, also receive our assistance. In the process, we raise antibiotic resistance research in Europe to a higher level – across the board.”

The network continues to expand. How are you able to recruit new partners?

“That’s a matter of persuasion. No academic partner is a philanthropist. For academics participation must generate funding to realize their own effective clinical research. The financial incentive is important, because more money potentially means better research.

However, the three COMBACTE projects are also involved in addressing an urgent problem. And participants make a direct contribution to those efforts.”

That’s what’s in it for academics. What about the pharmaceutical companies?

“They are also financially motivated: half of the funding comes from the EU. But

"By 2020, the network will need to be selfsustaining"

even without EU funding, pharmaceutical companies would be able to develop new antibiotics faster, more effectively and more economically via our network rather than individually, in part because we have better knowledge about how to select the right sites, and thanks to our academic background, garner a greater commitment from hospitals and laboratories.”

Does the network get the respect it deserves?

“First, just having a network obviously won’t get you anywhere. That’s why the 2015 launch of COMBACTE-CARE and COMBACTE-MAGNET was such a boon - now we can conduct more and more trials. It activates the network and makes us stronger. But we are definitely recognized for building something amazing.

By the Food and Drug Administration in the USA (USFDA), for instance. In many cases, pharmaceutical companies are already actively approaching us. That’s in line with our vision to also intensify collaboration with those companies, separate from the Innovative Medicines Initiative (IMI) program.”

Which brings us to a glimpse of the future. How will the COMBACTE projects evolve?

“IMI funding will not continue indefinitely. By 2020, the network will need to be self-sustaining and attract companies without a financial incentive. In other words, we want to be competitive

enough that pharmaceutical companies will want to use our network. To do that, we need a smart organization. An organization with promise, which the academics can also get behind. It’s in our reach if we manage to maintain the academic profile by continuing to combine commercial and academic projects. A legal entity with a not-for-profit character.

We’re considering it, but we have a long way to go.”

It sounds like a success story. Weren’t there any hard times in the early years?

“Of course there were. At first, a lot of effort went into developing a Network Management System (NMS). We also realized the risk involved in depending on pharmaceutical companies. We had a sudden shortfall of €70 million when GSK ceased developing an antibiotic, which eliminated the work several researchers in Europe had prepared for. That was really hard for me personally. But above all else, we feel we’ve made great strides with all of our partners - academic and EFPIA - in just a few years’ time. And we’ve only just begun. So from that perspective, we have a bright future.”

"I instantly saw opportunities for scientific research, my primary motivation"

COMBACTE

ORIGINAL CALL WWW.COMBACTE.COM WWW.IMI.EUROPA.EU

THE ISSUE ANTIMICROBIAL RESISTANCE IN THE EU EVERY YEAR:

9

OVERVIEW

UNIQUE COLLABORATION

IMI ND4BB TOPICS T1

T5

T6

KILLS

T1

25.000 People

COSTS THE ECONOMY € 1.5 Billion

IMI established an unprecedented partnership between industry, academia and biotech organizations to combat antibiotic resistance in Europe

CHALLENGES

IMPROVING CLINICAL TRIALS FOR ANTIBIOTICS

COMBATTING CARBAPENEM RESISTANCE

COMBATTING RESISTANT GRAMNEGATIVE BACTERIA

T2 T3

In the development of new drugs 1

Scientific challenges

2

Regulatory challenges

3

Business challenges

ACTIONPLAN EUROPEAN COMMISSION issued in 2011

IMI NEW DRUGS 4 BAD BUGS PROGRAM issued in 2012

T4

OBJECTIVES 1

A self-sustaining antibacterial development network Expanded research and laboratory networks Optimal alignment of clinical trials with investigator sites Clinical and epidemiological data

2

THE 4 PILLARS OF COMBACTE

T5

Increased efficiency of antimicrobial drug development Align clinical trials with cutting edge molecular methodologies and trial design Deliver clinical trials with various candidate compounds from MedImmune/AstraZeneca, Aicuris, AstraZeneca, Da Volterra, The Medicines Company

T6 CLIN-Net

LAB-Net

STAT-Net

EPI-Net

High-quality clinical

High-quality laboratory

Network to improve

Network to identify and

research network in

network in Europe with

clinical trials delivery,

map existing surveillance

Europe with certification

assessment of existing

perform advanced

systems, to establish

criteria and GCP

laboratory methods,

biostatistical and PK/PD

frameworks for data

Training program

quality assessment

modelling studies, evaluate

collection to support

system, specimens and

novel clinical design

antibacterial drug

strains repository

strategies using modern

development

biostatistical concepts

T7

COMBACTE-NET Enabling Clinical Collaboration + Refining Clinical Trial Design + Clinical development of compounds for Gram-positives

TRANSLOCATION Research on penetration and efflux in Gram-negatives + Data hub + learning from R&D experience

ENABLE Discovery & development of new drugs combatting Gram-negative infections

DRIVE-AB Driving reinvestment in R&D and responsible use of antibiotics

COMBACTE-CARE Clinical development of antibacterial agents for Gram-negative, antibiotic resistant pathogens

COMBACTE-MAGNET Systemic molecules against HAIs

iABC Inhaled antibacterials in bronchiectasis and cystic fibrosis

COMBATTING BACTERIAL RESISTANCE IN EUROPE

OUR CHOICE

MICHAEL DUDLEY THE MEDICINES COMPANY

IMPRESSED

MY NETWORK

COMBACTE

13

TOGETHER

My COMBACTE Community

ANGELA STEINBACH WP2A/ REJUVENATE management team Cologne

The network of one of our colleagues in COMBACTE-NET

“In the REJUVENATE study, CLIN-Net played a key role in developing the feasibility questionnaire and organizing the site selection activities.

Interview with Michael Dudley

Working with Nienke is always a pleasure, thanks to our open

THE MEDICINES COMPANY JOINS COMBACTE-NET The Medicines Company will be joining COMBACTE-NET in early 2016 and will bring a seasoned research team and a ready-made antibiotic, suitable for immediate clinical testing. It was a quick win for COMBACTE-NET. Let’s find out what drove their decision.

Michael Dudley Senior Vice President, Head Research and Development Co-Leader Infectious Diseases Global Innovation Group The Medicines Company

Michael Dudley: “We recently developed a new improved IV formulation for minocycline, where an intravenous formulation has been available in the U.S. for years. It’s effective against Acinetobacter, a resistant bacterium found mainly in Europe. But an intravenous formulation is not available in Europe, nor was it ever tested there.”

The Medicines Company, specializing in acute hospital care and recently expanded into infectious diseases, is one of the few companies that actively markets anti-infectives as well as has a very productive research and development program in this area. Its own research team has worked together for years, which is quite unusual, with competitors buying up products and not investing in R&D. So you’d better believe they’re dedicated.

"We are impressed with their expertise"

Perfect match “The European Federation of Pharmaceutical Industries and Associations (EFPIA) put us into contact with COMBACTE-NET. Its strong network conducts both phase 1 and clinical trials in intensive care with quick access to patients across Europe. An ideal partner,” says Dudley. At that very moment, GSK withdrew its product and IMI put out an open call. The Medicines Company answered it and was selected.

“We were very keen to join, and we were particularly encouraged after our team met the academic team in September last year. So much expertise – we are really impressed.”

and cooperative relationship.”

Tomislav Kostyanev LAB-Net Antwerp “We collaborate a lot with CLIN-Net and with Nienke to select the right sites, as we did for the EURECA study. In doing so, I follow-up with the sites from LAB-Net’s perspective.

Nienke Cuperus

I have a very good working relationship with Nienke.”

CLIN-Net project officer Nienke Cuperus is responsible for maintaining contact with the sites throughout all of Europe. She is also responsible for new hospitals that are interested to join CLIN-Net, and investigators that are interested to follow the COMBACTE-NET online GCP course. Furthermore, she is involved in the site selection process and study start-up of different trials within COMBACTE.

NIENKE VERDONK Elevate Health, Utrecht “Together with Nienke, I developed the online GCP training course. Nienke is responsible for the participants and I handle the actual training itself. We work on the same floor, so it’s easy to walk over to each other when we have

Testing doses The Medicines Company aims to update existing research on minocycline dosages based on the latest insights into pharmacokinetic-pharmacodynamic relationships. They have high hopes.

Obtaining a Marketing Authorization in Europe, as well as potential supplements for U.S., is their ultimate aim. Dudley expects preliminary results from at least one of the 4 planned clinical trials by the end of 2016.

questions.”

ADRIANA Hristea Coordinator and Principal Investigator EURECA in Romania “The EURECA project is an interesting and challenging project with seven Romanian sites. Working with Nienke has been smooth sailing. She is an effective and friendly professional.”

Jesús Rodríguez Baño WP Lead Seville “Nienke is a member of the site selection committee for the EURECA study. A committee with participants from all around Europe who frequently meet in teleconferences. During these meetings we discuss the feasibility outcomes and ensure that the right sites are selected.”

TRIAL

ORIGINAL CALL WWW.COMBACTE.COM

15

ANTIBODY

SAATELLITE Testing a new approach: antibodies against hospital-associated pneumonia

SAATELLITE is adding Phase II testing to the ongoing development of a monoclonal antibody against pulmonary Staphylococcus aureus infections. Immunological approaches towards the prevention of ventilator-associated pneumonia may circumvent current and future problems of antibiotic resistance.

T

he SAATELLITE project is dedicated to address the challenge by carrying out clinical trials of MEDI4893, a promising monoclonal antibody against S. aureus ‘alpha toxin’ (AT).

Alpha toxin is a key toxin that is secreted

by S. aureus bacteria during infection.

The toxin kills a patient’s cells and damages tissues and organs, which helps microbes to spread and cause serious infections and disease. MEDI4893 is being developed by MedImmune, the global biologics research and development arm of AstraZeneca. Its first goal would be the prevention of hospital-associated pneumonia caused by S. aureus in patients who are at high risk of infection.

Antibodies Patients in intensive-care units who need mechanical ventilation will be tested for the presence of S. aureus in their lower airways before they have developed a full-fledged infection and pneumonia.

If they are positive for the bug, they

would receive one intravenous dose of MEDI4893 antibody to help protect them from developing pneumonia. It is anticipated that no antibiotics would have to be used for preventing pneumonia, and prevention with the antibody would work against S. aureus, regardless of whether this bug is resistant to antibiotics. What’s more, this antibody approach itself is not expected to lead to new antibiotic resistance.

Next step After laboratory and animal studies, an earlier Phase I study in healthy volunteers found that MEDI4893 was generally safe to use. The SAATELLITE project will now take the next step: a randomised, double-blind, placebo-controlled Phase II study in actual patients who are at high risk of developing ventilator-associated pneumonia in an intensive-care unit. The study will test the safety, the pharmacokinetic and pharmacodynamic characteristics and

the efficacy of MEDI4893 in approximately 450 adult patients. The patients will be enrolled in approximately 60 to 80 ICUs, most of them in Europe.

Over 50 sites activated Since the study planning was launched in March 2014, more than 50 clinical sites have already been fully activated.

The early birds were located in 8 countries: Belgium, Czech Republic, France, Germany, Greece, Hungary, Spain, and Switzerland. A small number of sites remains to be put online. As of February 4, 2016, 65 patients have been enrolled and randomized in the study and have received either one intravenous dose of MEDI4893 or a placebo.

BACKGROUND

ND4BB Topic #1B - Clinical development of compounds against Gram-positive

Staphylococcus aureus is a com-

estimates, an infection adds about

beforehand, prophylactically, at

mon cause of hospital-associated

$100,000 on average to one pa-

a lower dose. An alternative and

infections. Patients who undergo

tient’s treatment costs.

potentially more durable strategy

Project

would be to harness the body’s

COMBACTE-NET WP6B

surgery, for example, can develop

bacteria

infections around the site of their

Fewer options left

immune system to keep small,

surgical wounds. Patients in inten-

S. aureus infections are treated

environmental quantities of S. au-

sive-care units (ICUs) also are at a

with antibiotics. Ever more often,

reus from growing into full-blown

double-blind, placebo-controlled,

high risk for developing serious S.

however, the infection-causing

infections. To date, however, no

single-dose, dose-ranging study

aureus infections. Infections can

strain is resistant to one or more

active immunization therapies (i.e.

of the efficacy and safety of

invade their lungs, blood, bones,

antibiotics. Methicillin-resistant

vaccines) or passive immuniza-

MEDI4893, a human monoclonal

joints, heart, or meninges, the pro-

Staphylococcus aureus (MRSA)

tion therapies (i.e. antibodies) are

antibody against Staphylococcus

tective layer around the brain.

is a prominent example, as are

available.

glycopeptides-resistant strains.

Description A Phase II randomized,

aureus alpha toxin in mechanically ventilated adult subjects.

Mechanical ventilation

As a result, doctors today are left

Objective

The most common hospital-asso-

with significantly fewer treatment

Test safety, pharmacokinetic and

ciated infection is pneumonia. It

options than some years ago.

particularly strikes intensive-care

"Doctors today are left with significantly fewer treatment options than some years ago"

pharmacodynamic characteristics and efficacy of MEDI489 in high-risk patients.

unit patients who receive mechani-

The challenge

cal ventilation to help them breath.

Despite the ongoing emergence

Hospital-associated pneumonia

and spread of resistance, antibi-

is a serious and costly condition,

otics still form our main line of

For more information please contact

with high levels of mortality. It is

defense against post-surgical S.

the Academic WP Lead Bruno Francois at

most often caused by S. aureus.

aureus infections and ventilator-

bruno.francois@chu-limoges.fr or

According to a recent study, almost

associated pneumonias. They are

one in four mechanically ventilated

either given when an infection has

Hasan Jafri

ICU patients develop pneumonia

been established or, in the case

MedImmune, AstraZeneca

from S. aureus. According to some

of surgery, by administering them

EFPIA WP Lead Hasan Jafri at jafrih@medimmune.com.

Status Ongoing; recruiting patients in up to 80 centers.

WP Leads Bruno Francois Limoges University Hospital

ACADEMICS & PHARMACEUTICALS

BRUNO FRANCOIS HASAN JAFRI

17

COLLABORATION

AMONG EXPERTS Promising new collaboration

The ongoing collaboration between academics and pharmaceutical scientists should come as no surprise. Logically speaking, we are all scientists with the same overarching interests and objectives, to develop the most effective medicines for the patients. Nevertheless, the collaboration can be deemed unique. For the first time, we are now sharing knowledge and working together at a large public-private platform to develop new insights.

This development is invigorating both parties.

T

he collaboration is the result of a more global development. We expect more from our medicines and apply higher approval standards.

There is increasing emphasis on the value of conducting research projects that are informed by real-time data. We face the threat of specific infectious diseases, including emerging antibiotic resistance among bacteria, requiring a rapid response. As a result of these trends, pharmaceutical industry and academic scientists are crossing paths with increasing frequency. For the two worlds to continue working in their own respective ‘bubbles’ would be both highly inefficient, and a waste of precious resources. Hasan Jafri, Senior Director of Clinical Research and Development at MedImmune: “At least in drug development, gone are the days when research was conducted by a handful of individuals amongst themselves. Groundbreaking results will require a genuine joining of forces.

However, transparency and true collaborative spirit are essential to the success of such partnership.”

Vast potential Bruno Francois, intensivist and Head of the Clinical Investigation Center at the University Hospital of Limoges agrees: “Clinical research contracts were always set in stone, and had to be carried out to the letter. This approach is inefficient, and leaves no room for suggestions. If we want better results, we’ll have to collaborate more closely.” The interaction between Jafri and Francois is characterized by a healthy sense of goodwill, and complementary collaboration. However, others tend to be more reticent, as commercial interests can lead to subjectivity.

Pure science can also be far removed from day-to-day practice. The participants working together in COMBACTE have no such concerns. Bruno: “There’s vast potential here. This type of intensive collaboration on a European scale is unprecedented. I have no doubt the project will generate major results for us.”

Funding makes all the difference IMI invests public funds in order to build a European network and develop anti-infectives for resistant bacteria.

Without this contribution, the development of these anti-infectives would not be commercially viable. The pharmaceutical industry also contributes substantially, committing their top tier novel molecules, resources and expertise in regulatory, assay development, and large-scale operational capability, in addition to funds - ensuring the availability of sufficient resources. This form of joint funding is proving to be a godsend in practice. Bruno Francois: “Collaborations were previously constrained by financial concerns, due to the ‘client-contractor’ model. That’s a thing of the past now.

We are equal partners, working together side by side.”

Hasan S. Jafri, MD EFPIA Coordinator and EFPIA WP Lead in COMBACTE-MAGNET and COMBACTE-NET Senior Director Clinical Research and Development Infectious Disease & Vaccines MedImmune

Bruno Francois, MD Academic Coordinator and Academic WP Lead in COMBACTE-NET Specialist in Intensive Care Medicine and Anesthesiology Head of the Clinical Investigation Center University Hospital of Limoges

ACADEMICS & PHARMACEUTICALS

BRUNO FRANCOIS HASAN JAFRI

COLLABORATION

"In future, we may collaborate on medicines for other infectious diseases, such as Ebola"

Benefits Hasan Jafri: “We are now combining academic knowledge on patients, disease mechanisms and unmet medical needs, with pharmaceutical industry’s knowledge of large-scale research and development. This will help us obtain a more comprehensive picture and undoubtedly yield more effective medicines. Rapid identification of appropriate patients throughout Europe is also invaluable to clinical testing.” MedImmune and COMBACTE have forged a strategic partnership with rapid diagnostic manufacturer Cepheid to ensure that state of the art rapid diagnostics are available to the European research hospitals collaborating on clinical studies within the network. This will help identify the study patients in a timely fashion, and contribute towards long-term capability building, another goal of the IMI program. Jafri: “In addition to collaborative

research to study the novel molecules from industry, we will be sharing our knowledge of epidemiology, statistics, regulations and operational procedures.

We will also be sharing useful lessons learned on the basis of successes and failures. Typically unsuccessful past research projects were relegated to the archives, however there is greater realization that the resulting data are certainly of value to the collective scientific community. As a part of the COMBACTE project, we are now gathering these data in a joint database where it is combined with information on diseases, patient populations, studies and molecules.

This increasingly rich source of information will yield more comprehensive and accurate insights.”

The partnership in practice Both men greatly enjoy working with highly qualified and experienced ex-

perts. The partnership is characterized by a sense of mutual respect and a strong sense of shared responsibility, accountability and scientific vision. No one avoids resolving difficult issues and everyone feels free to speak their mind in a mutually respectful and constructive manner. All participants are highly motivated to make the project a success. Their drive will be much needed, especially in view of the many practical challenges ahead. These include a huge administrative burden. The registration of new medicines is subject to stringent regulations. If you then factor in the various funding regulations, the challenge starts looking almost insurmountable.

Jafri: “A lot of credit goes to IMI. We’re all trying to establish new operating procedures given the novelty of this partnership, which currently take shape over the course of our work. However, IMI has shown real flexibility and is helping us to find solutions to help ensure the success of this new paradigm. With that sort of pragmatic attitude, I have no doubt that together we’ll get there in the end.”

New standard Defining all those procedures and criteria alongside your regular tasks requires a great deal of additional effort.

However, this crucial aspect of the project will serve as a blueprint for future partnerships. Francois: “We’re currently working together to develop antiinfectives against resistant bacteria. In future, we may collaborate on medicines for other infectious diseases, such as Ebola.” Jafri adds: “The model that we are creating together is likely to work as a blueprint for a more efficient and effective way to develop novel drugs, and it is already generating a lot of interest from other regions such as USA. So it is very nice to see Europe taking a lead on creating this new paradigm for clinical research.”

BACKBONE

FRANK LEUS JOOST SCHOTSMAN

SMART

NMS BACKBONE THE SYSTEM BEHIND COMBACTE-NET

Complex networks with many interconnections. That is how a data manager views CLIN-Net and LAB-Net. The COMBACTE Network Management System (NMS) is the ICT backbone that provides an overview of, plus fast access to the networks.

In Utrecht, the NMS is manned by a team of six in the Julius Center’s data management department. They ensure the Antwerp LAB-Net and Utrecht CLIN-Net teams can access the required information from the NMS and enter new data.

When EFPIA partners want to start a new trial, the specifications are sent to these teams, who perform a site selection in the NMS.

Level of complexity The many ways in which the variables interact largely determines the complexity of the NMS’ data structure. Contacts, for instance, can be part of networks based on geography, as well as on specialism. And a laboratory can belong to a

hospital or be independent and operate on behalf of multiple hospitals. That NMS can generate the exact information needed, even at this level of complexity, gives COMBACTE-NET the power to set up trials quickly and efficiently.

The NMS stores data on the variables of approximately: 700 hospitals 500 laboratories 1,700 contacts from over 50 countries and approximately 30 underlying networks.

Key advantage The NMS offers COMBACTE participants yet another key advantage. COMBACTENET makes ample use of questionnaires.

Thanks to the NMS, respondents need only provide the information which is not yet known to COMBACTE-NET. Because up to 1,000 variables are registered per organization, the effort required of participants can be greatly reduced in this way.

19

COMBACTE-NET

ORIGINAL CALL WWW.COMBACTE.COM WWW.IMI.EUROPA.EU

21

BUILDING

COMBACTE-Net A backbone for rapid testing of new antibacterial treatments

The COMBACTE-NET (Combatting Bacterial Resistance Europe – Networks) consortium is dedicated to building strong clinical, laboratory and research networks across Europe that will enable more efficient clinical testing of potential new antimicrobial drugs.

The COMBACTE-NET consortium, fulfilling ‘Topic 1’ of the New Drugs for Bad Bugs (ND4BB) program of Europe’s Innovative Medicines Initiative (IMI), was created to meet the challenges of clinical antibiotic development. In collaboration with other consortia within the ND4BB program, the €250 Million COMBACTE-NET framework will enable more rapid and efficient development and commercialization of much-needed new antibiotic treatments and diagnostic tests.

Pan-European networks COMBACTE-NET is responsible for the establishment and building up of high-quality, pan-European networks of clinical and research sites. These networks will enable the collection of data required for accurately identifying clinical needs and coming up with ideas for developing effective new antimicrobial treatment options. Importantly, the networks will form the backbone for all clinical studies within the wider ND4BB program.

COMBACTE-NET is building up and strengthening three networks that interconnect many dozens of hospitals, laboratories and research groups all over Europe.

CLIN-Net A network of clinics and hospitals capable of quickly and reliably recruiting, treating, monitoring and reporting data on the required numbers of patients in multinational, multicenter trials at all stages of clinical drug development.

LAB-Net A network of microbiology laboratories delivering high-quality and standardized information on microbial strains and antibiotic resistance. Data from this network will guide the selection of clinical trial sites for particular treatments and will provide microbiological information that will be needed during the execution of such trials.

STAT-Net A network of academic and industry experts in the area of clinical trial design to optimize the design of Phase II and Phase III clinical trials based on advanced statistical and pharmacological modeling and the latest biostatistical and epidemiological concepts.

BACKGROUND

Furthermore, within the COMBACTE-MAGNET project, a fourth network is being established.

Called EPI-Net, this network aims to map and utilize available surveillance systems in Europe in order to optimally describe the epidemiology of antibiotic resistance and healthcare associated infections.

Clinical trials The COMBACTE-NET consortium will top off the construction of this clinical trial backbone by carrying out actual clinical trials of promising candidate drugs.

MEDI4893, an immunologic compound that was developed by MedImmune, the global biologics research and development arm of AstraZeneca. MEDI4893 is one of several candidate drugs with a new approach to fighting severe bacterial hospital infections. Instead of treating patients with antibiotics, doctors would pre-emptively harness high-risk patients with antibodies against critical parts of the bacteria. In the case of MEDI4893, high-risk patients would initially be defined as patients who need mechanical ventilation during intensive care and who carry small numbers of Staphylococcus aureus bacteria in their airways. Patients would receive antibodies against bacterial toxins that damage their organs and tissues. Two additional clinical trial programs are soon to join.

The result: insights Collaborations within the various COMBACTE-networks makes it possible to also gather accurate and standardized epidemiological surveillance data among patients across Europe, which will help give insight into, for example, risk factors for infections by specific multidrug-resistant bacteria for specific patient groups.

Antimicrobial resistance is a grow-

investments since doctors will need

ing problem worldwide. There is

to minimize prescriptions in order

an urgent need for new medicines

for the new treatments to maintain

that can treat infections by mul-

their life-saving effects.

tidrug-resistant bacteria, but few new antibacterial drugs are actually

Unprecedented knowledge

being developed. During the last

sharing

three decades, only two new

The challenge is to make gov-

classes of antibiotics made it to the

ernments, hospitals, academic

market place.

research, small and medium-sized enterprises and large pharmaceu-

Pipeline bottlenecks

tical companies work together in

Many factors contribute to the lack

new and more efficient ways. An

of novel antimicrobials in the de-

unprecedented sharing of knowl-

velopment pipeline. At the earliest

edge and resources can speed

stages, there is a need for better

up research and development of

understanding of how existing anti-

antimicrobial treatments, hopefully

biotics work, how bacteria develop

to such an extent that the problem

and spread resistance to them and

will be effectively addressed.

how novel classes of antibiotics can be designed to which ideally

"Sharing of knowledge and resources can speed up research and development of antimicrobial treatmentS"

Management Board

resistance would more slowly

Marc Bonten, UMC Utrecht

develop. Further on in the pipeline,

Academic Coordinator

any potentially new antimicrobial

Bruno François, Centre

agent faces bottlenecks on its way

Hospitalier Universitaire

to the market: the clinical trials

de Limoges

required for regulatory approval

Deputy Academic Coordinator

for use in many different clinical in-

Hasan Jafri, MedImmune

dications need very large numbers

EFPIA Coordinator

of study participants, the more so

Seamus O’Brien, AstraZeneca

because their efficacy will usually

Deputy EFPIA Coordinator

have to be compared with existing antibiotics. Such testing is not

For more information,

just very expensive but also very

visit www.combacte.com or

hard to set up because of a lack

contact Marc Bonten or Hasan Jafri

of knowledge, capacity, harmoni-

m.j.m.bonten@umcutrecht.nl

zation and organization in centers

jafrih@medimmune.com

in many different countries. After coming out of the pipeline, some novel treatments will have a hard time providing returns on all these

WWW.IMI.EUROPA.EU

23

DISTRIBUTION

FUNDING COMBACTE PROJECTS

EFPIA IN KIND

€134 mln.

OTHER

€7

TOTAL

COMBACTE-NET

€250 mln.

IMI

mln.

FUNDING

€109 mln.

EFPIA

€192 mln.

TRANSLOCATION, iABC, ENABLE, DRIVE A/B

TOTAL COMBACTE PROJECTS

FUNDING IMI ND4BB PROGRAM

€696

€504

mln.

IN KIND

TOTAL

COMBACTE-CARE

mln.

OTHER

€2

IMI

mln.

FUNDING

€24 mln.

TOTAL

COMBACTE-MAGNET

IMI FUNDING € 208 mln.

mln.

€85

mln.

€169

OTHER € 11 mln.

€59

mln.

EFPIA IN KIND

€92 mln.

OTHER

€2

€504 mln.

IMI

EFPIA IN KIND € 285 mln.

FUNDING

€75 mln.

mln.

ADDRESSING THE BARRIERS IN CLINICAL TRIAL DEVELOPMENT

FUNDING

TRIAL-OVERVIEW

COMBACTE CONSORTIUM

THREE CONSORTIA, FIFTEEN TRIALS

Three COMBACTE consortia, each bringing together researchers from academia and industry, will use the new European clinical and laboratory networks to perform a total of fifteen trials. Some will be prospective randomized clinical trials, others will be retrospective, observational and/ or epidemiological studies. Status updates on all COMBACTE trials are presented below.

The Efpia partners and their compounds Compound

EFPIA Partner

Project

MEDI4893

MedImmune/AstraZeneca

COMBACTE-NET

Aztreonam-Avibactam (ATM-AVI)

AstraZeneca

COMBACTE-CARE

MEDI3902

MedImmune/AstraZeneca

COMBACTE-MAGNET

AIC499

AiCuris

COMBACTE-MAGNET

WP6A ASPIRE-ICU

25

MILESTONES

WP6A ASPIRE-SSI

WP6B SAATELLITE

WP7

WP8A-B-C

WP8D

Part of:

Part of:

Part of:

COMBACTE-NET

COMBACTE-NET

COMBACTE-NET

Period:

Period:

Period:

January 2016 – June 2017

2016 – April 2017

2017 – August 2019

Status:

Status:

Status:

In preparation

In preparation

In preparation

A prospective, observational

Phase I, randomized, controlled

A Phase III, randomized, con-

study of hospital patients over

trials in healthy adult volunteers

trolled trial in hospital patients

age 50 who are receiving anti-

to test the safety of minocycline

to test the efficacy of minocy-

biotics. The study will establish

intravenous (IV), which has been

cline intravenous (IV), which

baseline Clostridium difficile in-

registered in the U.S. for treat-

has been registered in the U.S.

fection rates in preparation for a

ment of serious multidrug-

for treatment of serious multi-

Phase II/III trial of a prophylactic,

resistant Acinetobacter sp.

drug-resistant Acinetobacter

non-specific antibiotic adsorbent

infections. The study will be

sp. infections. The study, set

protecting intestinal microbio-

performed in Europe in col-

up in collaboration with The

ta during antibiotic treatment.

laboration with The Medicines

Medicines Company, will target

Performed with Da Volterra.

Company.

patients with healthcareassociated A. baumannii infections in Europe.

WP1 EURECA

WP2A REJUVENATE

WP2B

Part of:

Part of:

Part of:

COMBACTE-CARE

COMBACTE-CARE

COMBACTE-CARE

Period:

Period:

Period:

January 2015 – January 2017

March 2016 – June 2017

June 2015 – June 2018

Status:

Status:

Status:

Ongoing; recruiting patients until May 2017

Recruiting patients as of March 2016

In preparation

Part of:

Part of:

Part of:

COMBACTE-NET

COMBACTE-NET

COMBACTE-NET

Period:

Period:

Period:

March 2015 – December 2019

March 2016 – December 2019

June 2014 – September 2016

Status:

Status:

Status:

A prospective observational

A Phase II, pharmacokinetic

A Phase III, randomized, compar-

Selecting study sites and recruiting patients

Protocol development

Ongoing, recruiting patients

study on cohorts of patients

and safety study of aztreon-

ative clinical trial to determine

with serious carbapenem-re-

am-avibactam (ATM-AVI),

the efficacy and safety of

sistant Gram-negative bacterial

a beta-lactam-beta lactamase in-

aztreonam-avibactam (ATM-AVI)

A prospective, observational,

A prospective, observational,

A Phase II, randomized, dou-

infections. It aims to learn how

hibitor combination intended to

for the treatment of serious bac-

epidemiologic cohort study of

epidemiologic cohort study of

ble-blind, placebo-controlled

patients across Europe are

treat serious bacterial infections,

terial infections caused by Gram-

ICU patients with healthcare-

patients undergoing surgery to

trial to test the safety and effica-

currently treated and which sub-

in patients with complicated

negative bacteria including

associated infections caused

determine the incidence of S.

cy of MEDI4893, a monoclonal

groups of patients respond well

intra-abdominal infections (cIAI).

metallo-beta-lactamase produc-

by Staphylococcus aureus or

aureus surgical site infections

antibody against Staphylococcus

to which treatments.

The trial will be carried out in

ing MDR pathogens. This global

Pseudomonas aeruginosa. In

(SSI). In about 20 sites in 10

aureus, developed to prevent

Spain, France and Germany in

study will be carried out with

about 30 sites in 10 European

European countries, bacterial

ventilator-associated pneumonia

collaboration with AstraZeneca.

AstraZeneca, the COMBACTE-

countries, bacterial isolates,

isolates, serum samples and data

in adult ICU patients. The trial,

CARE EFPIA Coordinator, and

serum samples and data will be

will be collected to identify the

performed in collaboration with

will be funded in part by the US

collected to assess patient-

patient-related, pathogen-

MedImmune, the global biologics

Biomedical Advanced Research

related and contextual risk

related, and contextual risk fac-

research and development arm

and Development Authority

factors for infection.

tors for the development of

of AstraZeneca, will involve up to

(BARDA).

S. aureus SSI.

80 ICUs and about 450 patients.

TRIAL-OVERVIEW

COMBACTE CONSORTIUM

WP3A

MILESTONES

WP3B

WP4A EVADE

MY NETWORK

COMBACTE

My COMBACTE Community

Katina Kardamanidis Project Officer CLIN-Net in Utrecht

The network of one of our colleagues in COMBACTE

“We were both at the EVADE study kick-off in Paris last June.

Drieke and I had the chance to

Part of:

Part of:

Part of:

COMBACTE-MAGNET

COMBACTE-MAGNET

COMBACTE-MAGNET

Period:

Period:

Period:

-

-

January 2015 – January 2018

Status:

Status:

Status:

In preparation

In preparation

Selecting and preparing study sites

Complimentary to ASPIRE-ICU

A mathematical modeling effort

A Phase II, randomized, con-

(WP6A in COMBACTE-NET), this

to describe the burden, including

trolled safety and efficacy

WP3A, expands specimen anal-

the development of anti-micro-

trial of MEDI3902, a bispecific

ysis of the ASPIRE-ICU cohort

bial resistance, of P. aeruginosa

monoclonal antibody against

participants to detection and

infections among ICU patients.

two Pseudomonas aeruginosa

characterization of P. aeruginosa

These models include estab-

proteins, for the prevention of

pneumonia among these ICU pa-

lished and innovative approach-

ventilator-associated pneu-

tients. Study data will contribute

es to explore interrelationships

monia in adult ICU patients. In

to the assessment of host- and

among pathogen, patient, and

collaboration with MedImmune/

pathogen-related factors on

the environment and help to

AstraZeneca, up to 120 ICUs will

the incidence of P. aeruginosa

choose the interventions with

participate in the study.

ICU pneumonia. This will further

the greatest impact, either singly

“We work in the same hospital

optimise patient selection for

or in combination.

and meet almost daily to

briefly speak each other there.

Now we speak weekly during different teleconferences.

Drieke seems well-organized, well-informed and friendly.”

Bruno François Academic WP lead in Limoges

clinical trials and aim to improve

discuss progress and action

the diagnosis and prognosis

points. This is exceptional.

Most COMBACTE colleagues

for control of P. aeruginosa HAI

I hardly ever see, but in

(HAP and VAP) in the ICU.

Drieke Vandamme

countless conference calls I speak to them more often than my wife.”

WP4B

WP4C

Drieke Vandamme is Project Coordinator for the academic partners of COMBACTE MAGNET’s WP4A study MEDI3902 – also called EVADE – in Limoges.

Drieke is responsible for the coordination between the academic partners. For example, her tasks include liaising with the various sites to ensure the

WP5 RESCUING

Part of:

Part of:

Part of:

COMBACTE-MAGNET

COMBACTE-MAGNET

COMBACTE-MAGNET

Period:

Period:

Period:

Post January 2018

-

January 2015 – December 2016

study proceeds in a uniform and streamlined manner everywhere. She also maintains contact with the EFPIA partners, especially with MedImmune, the global

Status:

Status:

Status:

biologics research and development arm of AstraZeneca.

In preparation

In preparation

Collecting data

A Phase III, randomized,

An open label study to de-

A retrospective observation-

controlled efficacy trial of

termine the safety and PK of

al study to assess the clinical

MEDI3902, a bispecific mon-

MEDI3902 in children at risk for

management and treatment out-

oclonal antibody against two

developing Pseudomonas aerug-

comes of hospitalized patients

Pseudomonas aeruginosa

inosa infection.

with complicated urinary tract

proteins, for the prevention of

infections in countries with a

ventilator-associated pneumonia

high prevalence of multidrug-

in ICU patients. This will be the

resistant Gram-negative bacteria,

follow-up to the Phase II EVADE

including Bulgaria, Greece,

study, also carried out with

Hungary, Israel, Italy, Romania,

MedImmune/AstraZeneca.

Turkey, and Spain. Performed in collaboration with AiCuris.

27

TOGETHER

Mark Eickhoff Senior Clinical Project Manager, Gaithersburg

Philippe Eggimann Medical Researcher in Lausanne

“Drieke and I handle the coordination of all

“Drieke and I collaborate actively in

operational aspects of the WP4A study. She is

two ND4BB clinical projects. It’s partly

an intelligent, composed, and delightful person

thanks to her that I’m able to work

with whom to work. Drieke has been integral to

in a stimulating environment where

ensuring a smooth collaboration between the

these complex projects are conducted

academic and EFPIA partners.”

successfully.”

Jean Chastre Medical Researcher in Paris “Drieke has been very involved in establishing and conducting the WP4A study.

Cooperation in a study such as this one needs to be very close, and Drieke ensures that it is indeed the case.”

COMBACTE-MAGNET

ORIGINAL CALL WWW.COMBACTE.COM WWW.IMI.EUROPA.EU

29

KNOWLEDGE

BACKGROUND Pathogenic bacteria that are resistant to

COMBACTE-MAGNET Intensive-care units: front line in the war against antibiotic resistance

With antibiotic resistance on the rise, COMBACTE-MAGNET focuses its attention on the most vulnerable category of patients: those who are critically ill and being treated in intensive-care units.

COMBACTE-MAGNET stands for Combatting Bacterial Resistance in Europe - Molecules against Gram-negative Infections. It is a large consortium that brings together researchers from five pharmaceutical companies and more than thirty leading academic medical centers from 10 European countries to meet the considerable challenge. Together they will increase our understanding of the needs of patients and doctors in intensive care units across Europe and use that knowledge to advance the development of well targeted, life-saving treatments.

The consortium will, for instance, analyze data about current microbial threats, treatment and drug resistance patterns in European countries where ICU patients are most at risk. They will gather information on biological markers of Pseudomonas aeruginosa infections, create mathematical models of the infection’s effects, and provide a better understanding of why various patients may respond differently to infections. Such knowledge will enable researchers to design more efficient and effective clinical trials of new molecules.

EPI-Net: a network of epidemiologic data and expertise The consortium will exchange information with the pan-European clinical, laboratory and statistical networks that are being created by the COMBACTE-NET consortium. COMBACTE-MAGNET itself will oversee the creation of a fourth network, called EPI-Net, which will harmonise and connect various European systems of disease surveillance by linking clinical, microbiologic, and public health data. EPI-Net will add to the general COMBACTE-NET backbone by strengthening our ability to monitor the spread of healthcare-associated infections and antibiotic resistance across Europe.

Trials of two potential new medicines Furthermore, the COMBACTE-MAGNET consortium will perform pharmaceutical trials of two potential new treatments, both of which have shown promise in research done so far. One of the two candidate treatments is MEDI3902, a bispecific monoclonal antibody that inhibits two key virulence factors of Pseudomonas aeruginosa, PcrV and Psl. MEDI3902 was developed by MedImmune, the global biologics research and development arm of AstraZeneca, as a new way of keeping pulmonary P. aeruginosa infections in check: with antibodies rather than antibiotics. It has shown promising activity against P. aeruginosa in laboratory and animal studies, and has undergone Phase I safety testing in adult humans. The COMBACTE-MAGNET consortium will carry out Phase II and Phase III studies in adult ICU patients to learn more about the antibody’s safety, its optimal dosing, and its efficacy in ICU patients. In parallel, a Phase I safety and pharmacokinetics study in children at risk for developing Pseudomonas aeruginosa infections will also be carried out. Its aim is to demonstrate that the MEDI3902 antibody can be safely administered to children and provide data on dosing in children.

many antibiotics are a major threat to the health of all of us. But no people are more vulnerable to multidrug-resistant microbes than critically ill patients who are receiving intensive care. Already weakened patients in hospitals’ intensive care units (ICUs) are

"EPI-Net will strengthen our ability to monitor the spread of healthcare associated infections and antibiotic resistance across EuropE"

particularly prone to infections of their urinary tract, or their intra-abdominal area.

For them especially, becoming infected with a multidrug-resistant pathogen can prove to be fatal. Very often, ICUassociated infections are caused by Gramnegative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. In recent years, more and more often these microbes turn out to have become resistant to an array of antimicrobial drugs.

Need for better options Clearly there is an urgent need for better options to deal with the threat. Novel ways are needed to detect and identify ICU-associated infections early and then to keep those infections in check. We also need drugs that target Gram-negative pathogens for cases where infections are growing no matter what. The reality is, however, that the drug development pipeline for new antibiotic compounds has been running dangerously dry. Over the course of the last three decades, only two new classes of antibiotics have managed to reach the market. That leaves growing

A new beta-lactam antibiotic The other candidate drug is AIC499, potentially a new and potent member of the family of so-called beta-lactam antibiotics. Given alone or in combination with a beta-lactamase inhibiting drug (BLI), AIC499 has shown strong activity against a broad range of multidrug-resistant strains of P. aeruginosa and Acinetobacter, both in laboratory and animal studies. AIC499 is being developed by the Germany-based biotechnology firm AiCuris. The COMBACTE-MAGNET consortium will carry out Phase I and Phase II trials to assess the safety and the efficacy of AIC499. They will provide researchers with knowledge of how the human body processes the compound and how it should be dosed.

numbers of patients at grave risk and therefore presents our health care system with a major challenge.

Management Board Marc Bonten, UMC Utrecht Academic Coordinator Alisdair MacGowan, North Bristol NHS Trust Deputy Academic Coordinator Hasan Jafri, MedImmune EFPIA Coordinator Cuong Vuong, AiCuris Deputy EFPIA Coordinator For more information, visit www.combacte.com or contact Marc Bonten or Hasan Jafri m.j.m.bonten @umcutrecht.nl jafrih@medimmune.com

TRIAL

ORIGINAL CALL WWW.COMBACTE.COM

31

DATA

Fighting drug-resistant complicated urinary tract infections

RESCUING RESCUING is laying the groundwork for improvements in management and treatment of patients with healthcare-associated complicated urinary tract infections with multidrug-resistant bacteria, a growing problem in intensive-care units in Europe.

T

he RESCUING project is gathering observational data about the treatment of about 1,000 patients with complicated urinary tract infections. The data is taken from 25 medical centers located in 8 countries where the prevalence of multidrug-resistant Gram-negative bacteria is seen to be high: Bulgaria, Greece, Hungary, Israel, Italy, Romania, Turkey, and Spain. Data will be collected retrospectively for about 40 consecutive patients in all of these centers. All included patients were hospitalized between 1 January 2013 and 31 December 2014.

Each patient record in the study will contain, for example: information about demographics, co-morbidities, functional capacity, place of infection, predisposing risk factors. It will also contain clinical data, clinical pathology data, microbiological data, imaging test data, data on infection management, antibi-

otic therapy and clinical outcomes, and details of discharge and, if applicable, readmission and/or death. All patients will be followed up for up to two months after their discharge from the hospital.

Apart from determining patient outcomes and identifying risk factors that were associated with treatment failures and poor clinical outcomes, the study will provide detailed insights into, for example: current demographical and clinical characteristics of intensive care patients who develop complicated urinary tract infections; the most important multidrug-resistant Gram-negative bacteria and the antibiotics against which they carry resistance; risk factors associated with developing with multi-drug resistant complicated urinary tract infections; current clinical management of patients with complicated urinary tract infections;

risk factors associated with early treatment failures; duration of patients’ hospital stays and antibiotic therapies; mortality rates; costs involved with the clinical management of multidrug-resistance problems both at the level of individual patients and (with the help of modeling data) that of the applicable countries.

Results The study’s outcomes will help identify the optimal treatments and clinical management procedures for patients with multidrug-resistant complicated urinary tract infections under the current conditions. They will also help identify the patient categories and clinical centers that can be used to optimize future Phase II and/or Phase III randomized clinical trials of novel candidate drugs.

For more information please contact the Academic WP Lead Miquel Pujol at mpujol@bellvitgehospital.cat or EFPIA WP Lead Irith Wiegand at magnet@aicuris.com.

BACKGROUND

ND4BB Topic #6. Systemic molecules against

Critically ill patients in intensive

ing especially when the bacteria

tions, the average ICU patient with

healthcare-associated infec-

care units (ICUs) are prone to

are resistant to multiple drugs. At

a complicated urinary tract infec-

tions due to clinically challenging

bacterial infections of the lungs

present there is no clear picture

tion is older, has been diagnosed

Gram-negative pathogens

and airways, urinary tract, and

of the overall impact of compli-

with more disorders (including

Project

intra-abdominal area. Very often

cated urinary tract infections with

chronic renal failure) and receives

COMBACTE-MAGNET WP5

these infections are caused by

multidrug-resistant bacteria. Nor

more medication than ever before.

Gram-negative bacteria such

do we know much about how the

as Pseudomonas aeruginosa,

challenge is currently managed.

The challenge

Klebsiella pneumoniae, and

Estimates from the European

There is a need for contemporary

to assess the clinical management

Escherichia coli. Increasingly

Center for Disease Prevention and

and more detailed data on the

and outcomes of hospitalized pa-

however these bacteria turn out

Control (ECDC) over 2011-2012

impact of complicated health-

tients with complicated urinary tract

to be resistant to third-generation

suggested that more than 1% of ICU

care-associated urinary tract

infection (cUTI) in countries with

cephalosporins and other antibiot-

patients have a healthcare-associ-

infections with multidrug-resistant

high prevalence of multidrug-

ics of last resort. There is an urgent

ated urinary tract infection, which

Gram-negative bacteria in intensive

resistant Gram-negative bacteria.

need for new antimicrobial agents,

would translate into approximately

care units in European countries

Main objective

yet the development pipeline is

15,000 patients in Europe on any

that are most at risk. Information

To determine the outcome of

running dry.

given day. Most of those infections

is needed about the cost to

hospitalized patients with cUTI and

were due to Enterobacteriaceae, of

healthcare systems, about how

identify the risk factors associated

15,000 patients

which on average more than 30%

the problem is currently managed,

with treatment failure in this cohort

Urinary tract infections (UTIs)

were resistant to third-generation

about patients’ current response

are highly prevalent worldwide.

cephalosporins and 7% to carba-

to salvage treatments, about their

Status

In hospitals, particularly with-

penems.

clinical outcomes, and about risk

Collecting patient information

factors that can be modified to

until March 2016.

WP Leads

in intensive-care settings, UTIs

Description A multinational, multicenter, retrospective, observational cohort study

of patients.

easily turn ‘complicated’ because

Aging population

optimize those. Last but not least,

patients’ immune systems are

Apart from significant changes in

we need data that can optimize

Miquel Pujol

suppressed because of underlying

the bacteria, there are changes in

future clinical trials of promising

Bellvitge University Hospital

illnesses. Complicated urinary tract

the characteristics of patients as

treatment candidates.

Irith Wiegand

infections can get life-threaten-

well: in aging European popula-

AiCuris

GCP TRAINING

MIQUEL EKKELENKAMP

33

LEARN

ALL SITES GCP CERTIFIED “In the past two years, the TWO DAYS FacE-to-face training course has been successfully concluded in Switzerland, Serbia and Spain�

One of the most important objectives of CLIN-Net is to create a European network for conducting high-quality clinical research, which is why Good Clinical Practice (GCP) is an essential part of COMBACTE-NET.

"Together with PharmaTrain, COMBACTE-NET hopes to standardize the GCP training program by introducing levels to the program and concluding it with a compulsory final exam"

GCP is the international ethical and scientific quality standard for setting up, conducting and reporting clinical research. Furthermore, the GCP guidelines define the roles of the most important parties involved in the research and identify essential documents for clinical studies.

At least one certified principal researcher Preferably all researchers within CLIN-Net are GCP certified. If not the principal researcher of each CLIN-Net site must in any event be GCP certified. Principal researchers lacking this certification are required to first take the online or face-to-face GCP training course. In collaboration with Elevate Health, COMBACTE-NET offers the online training course free of charge.

COMBACTE-NET provides the face-to-face training course in cooperation with the European Forum for Good Clinical Practice (EF-GCP) and the network in the country in question.

Two-day face-to-face training course If there is enough interest in a country COMBACTE-NET can organize a two-day faceto-face training course. In the past two years, the training course has been successfully concluded in Switzerland, Serbia and Spain.

COMBACTE-CARE

ORIGINAL CALL WWW.COMBACTE.COM WWW.IMI.EUROPA.EU

35

HETEROGENEITY

BACKGROUND

COMBACTE-CARE Meeting the challenge of carbapenem-resistant Enterobacteriaceae

With carbapenem-resistant Gram-negative bacteria on the rise worldwide, COMBACTECARE (Combatting Bacterial resistance in EuropeCarbapenem Resistance) is laying the groundwork for tests of new and more effective treatments for when our current assortment of antibiotics will no longer suffice.

The COMBACTE-CARE consortium intends to meet the CRE challenge. The project’s aims are to better understand current management of clinical management and outcomes of hospitalised patients with (CRE) infections; to analyse clinical and microbiological data to provide new insights for novel clinical trial designs; and to make recommendations for the development of novel antibiotics to treat resistant infections. Furthermore the consortium will make a significant contribution to the development of Aztreonam-avibactam (ATM-AVI) for patients with serious infections including those caused by metallo-β-lactamase producing Gram-negative pathogens, which at present are very difficult to treat.

First clinical studies underway The EURECA study is a prospective observational research assessment of the clinical management of

patients with infections caused by CRE or carbapenem-resistant Acinetobacter. The study will start data collection soon. It will be supported by an already operational cohort for the identification of biomarkers in critically ill patients. The REJUVENATE study is a pivotal trial that will evaluate the pharmacokinetics and safety of ATM-AVI in patients with complicated intra-abdominal infections.

The study will recruit its first patient before April 2016. COMBACTE-CARE will also provide medical leadership and European sites to a global, collaborative Phase III clinical trial designed to evaluate the safety and efficacy of ATM-AVI for the treatment of serious infections with Gram-negative bacteria resistant to other antibiotics but are susceptible to the combination.

In all, the COMBACTE-CARE consortium includes 18 academic centers and 3 pharmaceutical companies, with AstraZeneca operating as coordinator.

In building new capacity, COMBACTE-CARE will focus in particular on clinical sites in countries in south-eastern Europe, where rates of multi-drug resistance and CRE in particular are already well on their way to becoming endemic.

"Carbapenemresistant bacteria are usually resistant to most other antibiotics as welL"”

Among the emerging threats

previous therapy and may have

because of microbes’ growing

significant underlying disease. At

resistance to antibiotics, the rise

present, physicians have few good

of multi-drug resistant Gram-

options when they are confronted

negative bacterial pathogens is

with a patient who turns out to have

among the greatest. Increasingly,

a serious CRE infection.

hospital patients who get infected

"In Europe, numbers of infections with carbapenem-resistant E. coli or Klebsiella are steadily growiNG"

by the Enterobacteriaceae family of

Enormous heterogeneity

bacteria (such as Escherichia coli

We do know that there are many

or Klebsiella pneumoniae) or other

different types of carbapenem-

species such as Pseudomonas

resistant bacterial strains. More

aeruginosa and Acinetobacter

than 20 resistance genes have so

baumannii no longer respond

far been reported, including NDM,

effectively to treatment with

KPC, VIM, and OXA-48. This enor-

carbapenems – a key drug of last

mous heterogeneity makes it very

resort when treatments with other

difficult to detect CRE infections

antibiotics have already failed.

early on during routine microbio-

Carbapenems belong to an im-

logical screenings. It also makes it

portant class of antibiotics, called

hard to identify the best available

beta lactams. Other antibiotics in

therapy for patients with a CRE

this class include penicillins and

infection and to develop effective

cephalosporins. That helps explain

alternative antibiotic treatments

why carbapenem-resistant bacteria

for a range of rare but emerging

are usually resistant to most other

resistance problems. In practice,

beta-lactam antibiotics as well.

physicians resort to various empiric

However, Carbapenem-Resistant

combinations of older antibiotics,

Enterobacteriaceae (CRE) are

which often have serious side ef-

in fact multidrug- (MDR) if not

fects. There is limited knowledge of

extensively-drug (XDR) resistant to

how safe and effective these alter-

many classes of antibiotics includ-

native strategies really are. Gaining

ing beta-lactams.

knowledge about more effective treatments against CRE is urgent,

Few good options

but setting up effective trials for

Globally, bacterial resistance to

such a diverse bacterial adversary

carbapenems is on the rise. The US

is a daunting task in itself.

Centers for Disease Control and Prevention (CDC) have called CRE

Management Board

one of the top-3 drug-resistant mi-

Marc Bonten, UMC Utrecht

crobial threats to the United States.

Academic Coordinator

In Europe, the numbers of infec-

Jesús Rodríguez Baño, Hospital

tions with carbapenem-resistant E.

Universitario Virgen Macarena

coli and Klebsiella are still relatively

Deputy Academic Coordinator

small, but they are steadily grow-

Seamus O’Brien, AstraZeneca

ing, according to reports submitted

EFPIA Coordinator

to the European Antimicrobial Resistance Surveillance System

For more information,

network (EARS-Net). Most of these

visit www.combacte.com or contact

reports have come from countries

Marc Bonten or Seamus O’Brien

in south-eastern Europe — for now.

CRE infections are most common

m.j.m.bonten@umcutrecht.nl

in hospitals and other healthcare

seamus.obrien@astrazeneca.com

settings. Infections can be very serious as the patient has failed

QUOTES

COMBACTE CONSORTIUM

37

COMMITMENT

Which of your contributions to the COMBACTE project are you most proud of

What is the essence of the COMBACTE project for you

?

?

“A blind date leading to an arranged marriage with Big Pharma, but in the end it may become true love!”

Stephan Harbarth Academic WP Lead of STAT-Net

“Being involved in developing

the original concepts for the COMBACTE projects from the beginning and now seeing them actually recruiting patients to evaluate novel therapies for antibiotic resistant infections.”

Seamus O’Brien EFPIA Coordinator in COMBACTE-CARE EFPIA Deputy Coordinator in COMBACTE-NET

“To provide a framework and mechanism in which we

“Academy and industry collaborating to speed up

develop drugs for AMR that would otherwise not be

development of new antimicrobials as a part of the

developed. The success can already be seen in the

needed answer for a big public health problem:

progress in (amongst other items) the

antimicrobial resistance.”

COMBACTE-MAGNET and COMBACTE-CARE programs.”

David Wilson EFPIA WP Lead of STAT-Net AstraZeneca Infection Statistics Lead

Jesús Rodríguez Baño Academic WP Lead of WP1 in COMBACTE-CARE Academic WP Co-Lead of WP2 in COMBACTE-MAGNET Partner in COMBACTE-NET Member of the Management Board of COMBACTE-CARE

“A multifaceted approach to contribute, with new tools, to the reduction of antimicrobial resistance burden.”

Evelina Tacconelli Academic WP Lead of EPI-Net in COMBACTE-MAGNET Partner of DRIVE-AB

National Coordinator in Spain for CLIN-Net

“Being involved in the transformation from call initiation to project progression with all this opportunities to collaborate with public and private partners.”

Cuong Vuong

“The achieved level of collaboration of more than 40 academic partners and 6 pharmaceutical partners within 3 years and the smooth ‘acquisition’ of new industrial partners in the open call.”

EFPIA Deputy Coordinator in COMBACTE-MAGNET

Marc Bonten

EFPIA WP Lead for the AiCuris molecule AIC499

Academic Coordinator in all three COMBACTE projects

SPECIALISTS

MARK ESSER CHRISTINE LAMMENS

39

RESPECT

Microbiologist & Mark Esser, MedImmune Both working in

“I

received my Ph.D. in microbiology and immunology in Charlottesville, Virginia, U.S. I worked at the U.S. National Institutes of Health before moving into pharmaceutical product development, first at Merck & Co. I worked on pediatric vaccines, HIV vaccines, an HPV vaccine and a Staphylococcus aureus vaccine. So when I joined MedImmune in 2010, I had learned a lot about vaccines and global health.”

Daily activities “At MedImmune, which is the global biologics research and development arm of AstraZeneca, I direct translational medicine for vaccines and infectious diseases.

I oversee our biomarker, diagnostic and precision medicine strategy in the area of infectious diseases.

This includes candidate vaccines and antibodies

for serious bacterial infections. In COMBACTE-NET, I have co-led LAB-Net, which creates a European laboratory network. For three COMBACTE-trials that involve MedImmune candidate antibody products, I oversee work on diagnostics and biomarkers. For me, COMBACTE is a critical endeavor.”

Enthusiastic “I find these studies incredibly exciting because by using antibodies, we really hope to develop a new approach in preventing or treating S. aureus and Pseudomonas diseases. We hope to move away from the traditional ‘treat first and ask questions later’ antibiotics approach. With the advance of real-time diagnostics, we may be able to identify infected patients early in the infectious process and treat them with pathogen specific antibodies.

That could not only prevent

full-blown pneumonias, it could also prevent us from harming the gut’s microbiome or building resistance.

‘Pre-emptive treatment’ is what we like to call it. For me it’s also really exciting and beneficial to partner with public research. Industry has expertise in developing a medicine, but working with some of the leading minds in academic research really made us be more creative.

They challenged us, for example, to use the latest technologies for diagnostic testing, and to assess a patient’s immune response by looking at hundreds of targets and not just one or two antigens.”

Personal drive “Both my parents died pretty young from cancer, so I am passionate about using the very best of public biomedical research to prevent and treat disease. We in indus-

try know how to develop compounds, run big clinical trials and put together regulatory filings, but being able to combine that with the creativity and insight from some of the best minds in academia in Europe is a game-changer and will ensure that we can deliver new medicines to patients. Some people in academia may hesitate about working with industry, but I think getting together, spending time and working together, as we have done in COMBACTE, can really build collegiality and trust, and produce urgently needed new medicines.”

Microbiologist

Christine Lammens, University of Antwerp

COMBACTE

“I

was trained as an analyst, but I also have a B.Sc. in Chemistry.

I manage the Laboratory of Medical Microbiology of the University of Antwerp, Belgium.”

Daily activities “We are a research lab, we do not provide routine services like a hospital lab typically does. There are about thirty of us in the lab, twelve at the bench, others doing administrative work for COMBACTE or resistance in general. I myself oversee the work plans, the protocols, the data analyzes, things like that. Antimicrobial resistance is our main theme. We know all about resistance genes and profiles and how to detect them. Our role in COMBACTE-NET is to set up and support the pan-European network of hospital, central and research laboratories. As a coordina-

tor I am on the road at least twice a month, visiting team members and labs all over Europe, for example to explain study protocols. We’ve also done three workshops in Eastern Europe, where we train people in techniques used in COMBACTE trials.”

Enthusiastic “COMBACTE is a bit different from earlier European projects in which we participated. Here we also cooperate and share with pharmaceutical companies. I think the two worlds can definitely complement each other and help drug development and clinical studies along. In industry, people work a bit differently than in academia. By working together, we can learn from each other, make both our work better. I find that people really look forward to joining the network, learning new things. Their enthusiasm is what I get in return.”

Personal drive “I really enjoy coming to places different from mine, and I like helping people make progress. It is also very important to see how some labs have to work in very different settings. Our first COMBACTE-NET workshop was in Kosovo, Albania, and for me that was really special. It suddenly hit me that things can be quite simple in Antwerp but very complicated elsewhere. When my lab needs some new reagent, I will just go online and in two days it will be delivered.

In other places, procurement procedures for the same reagent can take up to six months. I was also struck by seeing equipment that was no longer used because the lab couldn’t afford the consumables after an international project had ended.

Our biggest challenge may be to keep our network operational after COMBACTE-NET

has ended. Support will then have to come from companies seeing the advantage.

I’m optimistic, because I’ve already been called for more information. That shows you that there is real demand for our work.”

TRIAL

ORIGINAL CALL WWW.COMBACTE.COM

41

INSIGHTS

"EURECA will focus in particular on building capacity in clinical sites in south-eastern Europe"

EUREcA Getting ready to fight carbapenem-resistant BACTERIA

EURECA is setting the first steps towards a greater understanding of the serious infections caused by carbapenem-resistant bacteria, which present a growing menace to hospitals in Europe and elsewhere.

E

URECA, due to start data collection, is the first research project within COMBACTE-CARE, the ND4BB program that aims to meet the challenge of developing new antibiotics against Gram-negative multi-drug resistant bacteria. First, EURECA has set out to better understand how patients with serious CRE infections are currently being managed in Europe. To that end, the project is obtaining high quality prospective observational data about cohorts of patients, about the pathogens that infected them, about the treatments they receive and about the clinical outcomes of those treatments.

Because EURECA is part of the overall ND4BB program, it will work closely together with the pan-European clinical, laboratory, statistical and surveillance networks that are being built simultaneously. EURECA will, for example, collect microbiological and biomolecular data on the pathogens that are encountered.

BACKGROUND

ND4BB Topic #5. Clinical development of

Analyzes of that database of biomarkers will provide new epidemiological insights and help direct the development of novel diagnostics, novel antimicrobial agents and novel clinical trial designs.

All cohort data is collected in such a way that scientists may be able to also use the patients as historical controls in future clinical trials. For example, patients are followed as they are seen by the assessing physician and data will be collected at time intervals which will be most relevant when applying to new treatment regimens. In doing so, EURECA will aim to limit the number of patients that need to be enrolled in future trials, which will significantly speed up product development and approval.

The patient cohorts will include newborns, children as well as adults.

EURECA will focus in particular on building capacity in clinical sites in south-eastern Europe, where growing

CRE infection rates have been reported in recent years. Around 50 hospitals in Spain, Italy, Greece, Turkey, Serbia, Croatia, Bosnia and Herzegovina, Albania, Macedonia, Kosovo, Bulgaria, and Romania will participate in the project.

Multi-drug resistant Gram-negative

the many different resistance genes

antibacterial agents for Gram-

bacteria (MDR-GNB) represent a

they are facing, there is limited

negative antibiotic-resistant

grave and growing threat to public

adequately validated treatment of

health. That’s not just true for the

last resort.

pathogens Project COMBACTE-CARE WP1

world in general, but for Europe as well. And within this rather

The challenge

large group of microbial dangers,

There have been no clinical trials

infections with carbapenem-

to test the safety and efficacy of

observational cohort study under

resistant Enterobacteriaceae (CRE)

various combinations of older anti-

patients with serious carbapenem-

are especially worrisome: they

biotics against various CRE sub-

resistant Enterobacteriaceae (CRE)

are being reported in growing num-

types. There is not even a clear

or Acinetobacter baumannii (CRAB)

bers, often with bad and even fatal

picture of how CRE-infected pa-

infections.

clinical outcomes.

tients are being treated now across

Objective

the world. Novel diagnostics and

Obtain high-quality observational

No good diagnostics

treatments have to be developed

data to inform novel treatments and

Carbapenem-resistant bacteria are

and tested urgently, despite the

future randomized clinical trials.

most often found in hospitals and

hurdles of setting up randomized

other clinical settings. These days,

clinical trials. Before scientists

For more information please contact the Academic

when doctors are confronted with

can even get to that, however, key

WP Lead Jesús Rodríguez-Baño at jesusrb@us.es or

CRE cases, they face a problem.

knowledge gaps have to be filled in.

the EFPIA WP Lead Seamus O’Brien at

Today there are no good diagnos-

Ultimately, EURECA will lead the way towards better management of patients with complicated intra-abdominal infections (cIAI), healthcare-associated pneumonia (HCAP), complicated urinary tract infections (cUTI), and bloodstream infections (BSI) due to carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii (CRAB).

seamus.obrien@astrazeneca.com.

tics to identify CRE precisely and early. And even when they can confirm which CRE and which of

Description Prospective, multicenter,

Objective Status Ongoing; recruiting patients until May 2017.

WP Leads Jesús Rodríguez-Baño Hospital Universitario Virgen Macarena Seamus O’Brien AstraZeneca

"EURECA will work closely together with the pan-European clinical, laboratory, statistical and surveillance networks"

5 2

50 26

4 2

18 7

23 18

1 1

4 1

23 17

2 1

1 1

50 32

1 1

1 1 5 5

22 14

7 7

3 0

1 1

8 7

11 7 49 5

13 6 3 2

10 5

27 7

30 17

5 4

3 3

15 5

8 6

6 5 5 4

13 4

28 4

10 2 2 2

58 44

5 4

6 6

4 4 22 11

6 6

10 8

3 2

1 1

11 6

12 6

5 5 20 20

26 7 35 16 10 1

47 41 62 28

19 15

11 8

29 13

19 9 43 16

Turkey

Cyprus

Greece

Bulgaria

Moldova

Romania

1 1

5 1

32 25

Macedonia

1 0

3 1

1 0

Latvia

Lithuania

9 6

3 2

1 0

Kosovo

No participant

Albania

Laboratories 2014

Serbia

Hospitals 2014

Montenegro

Participant

Finland

Laboratories 2015

Slovakia

Croatia

Poland

Slovenia

Czech Republic

Austria

Italy

10 10

2 1

0 0

Sweden

Germany

Denmark

Norway

France

Luxembourg

Netherlands

Belgium

Spain

United Kingdom

Portugal

Ireland

Iceland

Hospitals & Laboratories

Switzerland

COMBACTE Network

Hospitals 2015

Israel

43

GROWTH

Hungary

NMS

Bosnia and Herzegovina

THE NETWORK

22 11

1 1 1 1

20 10 8 3

NATIONAL COORDINATORS

MIQUEL EKKELENKAMP

PIONEERING

THE ESSENTIAL ROLE OF NATIONAL COORDINATORS When it comes to efficiently building a strong clinical network, the CLIN-Net team works with national coordinators in the various European countries as much as possible. In some cases this will be teams of coordinators, particularly if multiple networks from a single country join the COMBACTE-NET Consortium.

COMBACTE-NET will rely on the active involvement of national coordinators to maintain a more personal relationship with the member sites. Personal acquaintance with investigators at the various hospitals and past collaboration with them will undoubtedly facilitate more efficient site selection, and hopefully keep investigators motivated during trials. Furthermore, its experience will enable the national coordinator’s team to assist sites that have difficulty starting studies or achieving patient recruitment.

In many cases, national coordinators can also be approached to be the principle investigators for COMBACTE studies in their country.

National coordinators are experienced investigators who maintain a network of clinical researchers or are in the process of establishing one. They assist in the selection of sites that will be approached to participate in studies (and study feasibility assessments) and are expected to help get sites interested in participation.

45

WWW.COMBACTE.COM | INFO@COMBACTE.COM

This research project receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115523 | 115620 | 115737 resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution.