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ABIRISK

Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk

Summary

A growing number of medicines are based on biological molecules such as proteins and monoclonal antibodies. These novel drugs have resulted in new, more effective treatments for a number of serious conditions. Yet sometimes these medicines trigger a response from the patient’s immune system, which can decrease the effectiveness of the drug or cause severe side effects. The aim of the IMI-funded ABIRISK project is to shed new light on the factors behind this immune response. The project, which represents the first concerted effort to solve this problem, will aid in the creation of new, safer biopharmaceuticals and also generate tools to determine how individual patients are likely to respond to them both in clinical trials and after release to the market.

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Biopharmaceuticals are drugs that are biological in origin (i.e. are made of proteins or DNA for example) and are manufactured using biotechnology. A number of biopharmaceuticals are already in use and have dramatically improved quality of life for patients with serious, hard to treat conditions such as multiple sclerosis, Crohn’s disease, diabetes, rheumatoid arthritis, haemophilia A and some cancers. However, in some patients, biopharmaceuticals can trigger an immune reaction, a phenomenon known as immunogenicity. When this happens, the immune system produces antibodies (ADAs) that neutralise the drug, which can reduce the effectiveness of the biopharmaceutical. In some patients, the immune response causes side effects such as a rash, chest pains, or a fall in blood pressure. In the most severe cases, it can trigger anaphylactic shock and even prove fatal.

Immunogenicity – the known unknowns
Diverse factors appear to be involved in immunogenicity. On the drug side, both the compound and the route and duration of administration seem to play a role, while on the patient side, the type of disease, age, genetic background and interactions with other medicines may be risk factors.  Therefore it is extremely hard to predict which biopharmaceuticals will have immunogenicity problems; although many tests exist, these are not always accurate. Furthermore, knowing which patients are at greatest risk of mounting an immune response to a given biopharmaceutical is extremely difficult.

Reducing the risks
Even though immunogenicity continues to pose a problem in the development of new drugs, until now there has been no major effort to solve the problem. Enter the ABIRISK project, which aims to give biopharmaceuticals a much-needed boost and represents the first concerted effort to tackle the immunogenicity problem by bringing together leading experts from hospitals, academia, industry and small companies. The project will set up laboratory tests to probe the immunogenicity of several biopharmaceuticals that are already used on patients. The scientists will then match their test findings with the effect the drug actually has on patients. This will help the team to develop tools that are better at predicting immunogenicity during drug development.

Many pharmaceutical companies, academic institutions and patient registries have large amounts of data on biopharmaceuticals and patients’ responses to them. In ABIRISK, these diverse databases will be assembled into a single immunogenicity databank that will help researchers pinpoint the factors that influence a drug’s immunogenicity and patients’ risk of it. This will allow the researchers to generate tools that will accurately predict whether a patient will mount an immune response to a biopharmaceutical and how that immune response will affect the efficacy and safety of the drug.

Safer, more effective drugs for patients
Immunogenicity means many patients today are denied the life-changing benefits of biopharmaceuticals. ABIRISK will ultimately result in a new generation of biopharmaceuticals with lower immunogenicity that can be safely and effectively used by more patients. In addition, the project will allow clinicians to determine which patients will respond best to which biopharmaceutical, thereby preventing patients from suffering the side effects of a drug that does not suit them.

For Europe’s pharmaceutical industry, better tests will help companies identify the safest, most effective biopharmaceuticals and weed out those that pose a high immunogenicity risk earlier in the drug development process. This will save companies both time and money. Finally, by adding to our knowledge of the mechanisms behind immunogenicity, the project will help to improve regulatory guidelines for the approval of biopharmaceuticals.

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Achievements & News

ABIRISK issues recommendations for communicating on biopharmaceuticals

IMI’s ABIRISK project has published a set of proposals  for setting up standards in the field of biopharmaceuticals. Biopharmaceuticals are medicines based on biological molecules such as proteins and antibodies. In some patients, these medicines trigger ‘immunogenicity’, an immune response that may decrease the effectiveness of the drug or cause severe side effects. ABIRISK is working to shed new light on the causes of these reactions. ###However, writing in the journal Clinical and Experimental Immunology, the project partners explain that efforts to collaborate across sectors and disciplines are hampered by a ‘lack of agreement on concepts, practices, and standardised terms and definitions related to immunogenicity’. To overcome these challenges and to advance research in this important area, the project has developed and agreed to use a set of common terms and definitions for describing the immunogenicity of biopharmaceuticals. ‘This paper is a major contribution to the field of immunogenicity to set up standards in terms of definitions and common language,’ said ABRISK project leaders Marc Pallardy of Université Paris-Sud and Dan Sikkema of GlaxoSmithKline. ‘Indeed, the lack of common terms across this field hampers the possibility to compare results and introduces confusing factors.’ The terms and definitions are set out in the paper and on the ABIRISK website. The project is keen to receive feedback on its proposals so that it can refine them further. (June 2015)

ABIRISK haemophilia paper wins prize

paper by scientists from IMI project ABIRISK won the clinical research award at the Seventh Edition of the Martín Villar Research Awards. The awards, named after Spanish haematologist Martín Villar, recognise research published by young scientists working in the field of blood coagulation and related disorders, such as haemophilia. Many medicines ###are based on biological molecules such as proteins and monoclonal antibodies. These novel drugs have resulted in new, more effective treatments for many conditions including haemophilia, a serious disease in which the blood fails to clot following injury. Yet sometimes these medicines trigger a response from the patient’s immune system, and this can decrease the effectiveness of the drug or cause severe side effects. The ABIRISK project is investigating the causes of this immune response. In this paper, the researchers identify for the first time variations in a specific gene that are associated with a strong immune response to the haemophilia treatment Factor VIII. Around 30% of haemophilia A patients develop an immune response to Factor VIII treatment, and the researchers suggest that their findings could pave the way for new ways of preventing the immune system from blocking the action of Factor VIII.
(September 2014)

Genes could influence effectiveness of MS treatment, ABIRISK reveals
The effectiveness of one of the main drugs used to treat multiple sclerosis (MS) could be influenced by patients’ genes, according to new research from IMI’s ABIRISK project published in PLoS ONE. The findings could influence treatment ###decisions in the future. MS is a neurological disease in which the immune system attacks the protective coating around nerve cells. The frontline treatment for MS is beta interferon (IFNβ), which comes in two types – IFNβ-1a and IFNβ-1b. However, around a fifth of patients develop high levels of antibodies that neutralise the drug, reducing its effectiveness. In this study, the researchers reveal that patients carrying certain genetic variants are at greater risk of developing high levels of antibodies, and suggest that this could help determine treatment decisions in the future. However they caution that their results should be confirmed in additional studies, and emphasise that the factor with the strongest influence on the risk of developing antibodies is the way the drug is prepared and administered. Patients who receive IFNβ-1a as an intramuscular injection are at the lowest risk (under 10%) of developing neutralising antibodies, while patients who receive it as a subcutaneous injection face a much higher risk (around 30%). Patients taking IFNβ-1b face the greatest risk (almost 50%).
(April 2014)

Participants

EFPIA

  • GlaxoSmithKline Research & Development Limited, Brentford, UK
  • Bayer Pharma AG, Berlin, Germany
  • IPSEN Innovation SAS, Paris, France
  • Merck KGaA, Darmstadt, Germany
  • Novartis Pharma AG, Basel, Switzerland
  • Novo Nordisk A/S, Bagsværd, Denmark
  • Pfizer Limited, Sandwich, UK
  • Sanofi-Aventis Research and Development, Paris, France
  • UCB Pharma SA, Brussels, Belgium

Universities, research organisations, public bodies, non-profit groups

  • Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
  • Academisch Medisch Centrum, Amsterdam, the Netherlands
  • Academisch Ziekenhuis Leiden – Leids Universitair Medisch Centrum, Leiden, the Netherlands
  • Centre National de la Recherche Scientifique, Paris, France
  • Commissariat a L’Energie Atomique et aux Energies Alternatives, Paris, France
  • DRK-Blutspendedienst Baden-Württemberg – Hessen gemeinnützige GmbH, Mannheim, Germany
  • Fondazione per l’Istituto di Ricerca in Biomedicina, Bellinzona, Switzerland
  • Fundació Institut de Recerca de L'hospital Universitari Vall D'hebron, Barcelona, Spain
  • Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif, Paris, France
  • Höpitaux de Paris, Paris, France
  • Istituto Giannina Gaslini, Genova, Italy
  • Johann Wolfgang Goethe Universität, Klinikum und Fachbereich Medizin, Frankfurt, Germany
  • Karolinska Institutet, Stockholm, Sweden
  • Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
  • Medizinische Universität Innsbruck, Innsbruck, Austria
  • Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel, Langen, Germany
  • Queen Mary and Westfield, University of London, London, UK
  • Rambam Medical Center, Haifa, Israel
  • Region Hovedstaden, Hillerød, Denmark
  • Università di Firenze, Firenze, Italy
  • Universitätsklinikum Bonn, Bonn, Germany
  • Universitätsklinikum Düsseldorf, Düsseldorf, Germany
  • University College London, London, UK
  • University Hospital Basel, Basel, Switzerland
  • Univerzita Karlova v Praze, Prague, Czech Republic

SMEs

  • ALTA Ricerca e Sviluppo in Biotecnologie Srlu, Siena, Italy
  • Biomonitor A/S, Copenhagen, Denmark 
    SciCross AB, Skovde, Sweden

Facts & Figures

Start Date 01/03/2012
End Date 28/02/2017
   
Contributions    €
IMI funding 18 170 217
EFPIA in kind   9 358 093
Other   5 404 688
Total cost 32 932 998

 

Links and Documents

Project website: www.abirisk.eu

IMI funding per project participant

Contact

Project Coordinator
Daniel Sikkema
GlaxoSmithKline
USA

Tel: +1 610 270 6054
E-mail: dan.x.sikkema[AT]gsk.com

Managing Entity for EU funds
Marc Pallardy
INSERM UMR 996
France

Tel: +33 1 46 83 54 92
E-mail: marc.pallardy[AT]u-psud.fr