Bringing innovation to global health. Crucell 2010

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1 Bringing innovation to global health Crucell

2 Contents Our mission Crucell s mission is to protect human lives from infectious diseases by bringing meaningful innovation to global health. Research and development see page 12 Crucell is a global biopharmaceutical company focusing on the research and development, production and marketing of vaccines and antibodies against infectious disease worldwide. Currently we are combating twelve major infectious diseases with our range of marketed vaccines in the paediatric, travel and endemic, and respiratory fields. In this report you can read all about our mission, vision, strategic pillars and our commitment to the principles of Corporate Social Responsibility. For inquiries, please contact Corporate Communications. communications@crucell.com. Technologies see page 20 Overview Crucell at a glance 02 Crucell: A global perspective 06 Message from our CEO 08 Our business Research and development, technologies and products 10 Research and development 12 Technologies 20 Products 26 Products see page 26 Crucell s commitment to the world Taking responsibility 32 CSR highlights in Our CSR policy 36 Our CSR achievements, ambitions and targets 40

3 2010 key highlights 01 Revenues and other operating income 2010 Revenues and other operating income ( million) 105+ mln Product sales License revenues 32.7 Service fees 6.5 Other operating income, e.g. grants 35.6 Total Vaccine doses distributed in 2010 In more than 100 countries around the world mln Research and development investment in 2010 Compared to 70.2 mln in Product sales ( million) mln 25% Product sales in % 7% 7% Paediatric Travel and endemic Respiratory Other mln Total revenues and other operating income in 2010 Compared to mln in 2009.

4 02 Overview Crucell at a glance

5 Overview Crucell at a glance 03 Crucell is a global biopharmaceutical company dedicated to bringing meaningful innovation to global health. We do this by discovering, developing, manufacturing and marketing products that combat major threats to the health of people worldwide. Our specialty is fighting infectious diseases a growing healthcare challenge.

6 04 Overview Crucell at a glance Our Company Innovation is the driving force behind our strong research and development (R&D) pipeline, with promising products in pre-clinical and clinical development. In 2010 alone, Crucell distributed more than 105 million 1 vaccine doses in more than 100 countries around the world, and invested million in R&D. Crucell is deeply committed to being a good corporate citizen: a company that creates significant value for society. Our mission is to make a truly meaningful contribution to global health by directing our proven talent for innovation towards the fight against infectious diseases. An entrepreneurial mind-set and social responsibility go hand-in-hand at Crucell. In 2010, 1,400 dedicated and skilled Crucell employees worldwide worked to bring significant benefit to the lives of people worldwide. We are fully committed to the principles of corporate social responsibility (CSR) and place great value on doing more to benefit society than we strictly must do. Our mission underlies everything we do, from our core business activities to the sharing of scientific knowledge and community outreach programs in countries where help is needed the most. The combination of our innovative technologies, our core values and creative minds drives Crucell s success, which we measure in human and business terms. Crucell is headquartered in Leiden, the Netherlands, with offices in China, Indonesia, Italy, Korea, Malaysia, Spain, Sweden, Switzerland, UK, the USA and Vietnam. Our strategy Infectious diseases are a major cause of illness and death throughout the world. The number of infectious outbreaks is increasing for many reasons: higher population density raises exposure to infectious agents, an aging population is more susceptible to infection, and a rise in global travel boosts the potential for spreading diseases across borders. In addition, natural disasters can have a devastating impact on sanitation, hygiene, infrastructure and healthcare facilities. At Crucell, we are dedicated to saving lives and preventing illness around the world. We focus strongly on unmet medical needs in developing countries, where infectious diseases exert their greatest toll. At the same time, we work to protect travelers and vulnerable groups living in industrialized countries. We target major health threats that demand innovative solutions, striving to lead rather than follow. We focus on infectious diseases because these pose an increasingly serious threat to the health of people worldwide and we have the expertise to make a real difference in this disease area. The combination of our scientific know-how, innovative technologies and quality products positions Crucell to become a major player in the biopharmaceutical arena. Our strategy is based on three business drivers: 1. A strong R&D pipeline with promising products in a range of major disease areas. 2. Cutting-edge technologies that enable the discovery, development and production of biopharmaceutical products. These proprietary technologies drive in-house innovation and generate licensing revenue. 3. A broad range of marketed vaccine products that together combat 12 major infectious diseases. 1. Our strong research and development pipeline Innovation is the driving force behind our strong and broad R&D pipeline, with promising products in pre-clinical and clinical development. Product candidates include flu-mab, an antibody effective against a 1 Figure based on Crucell s top five vaccines in terms of sales volumes: Quinvaxem, Hepavax-Gene, Epaxal, Vivotif and Inflexal V.

7 Overview Crucell at a glance 05 broad range of influenza virus strains, tuberculosis and malaria vaccines, and a rabies monoclonal antibody combination all produced on our unique PER.C6 human cell-line technology. Read more on page Our cutting-edge technologies Crucell s proprietary technologies offer unique advantages for biopharmaceutical innovation. This competitive edge is exemplified by our PER.C6 technology, which is ideally suited to the manufacture of vaccines and therapeutic proteins, such as antibodies. Compared to traditional production platforms, PER.C6 human cell-line technology provides higher yields at lower cost, as well as safety advantages. Crucell licenses its PER.C6 technology and other technologies to the biopharmaceutical industry. Important partners and licensees include, among others, Johnson & Johnson, DSM Biologics, Merck & Co., Novartis, sanofi pasteur and Pfizer/Wyeth. Read more on page Our broad range of innovative products Vaccines play a vital role in protecting against diseases and have contributed significantly to the improvement of global health. Currently we are combating twelve major infectious diseases with our range of marketed vaccines in the paediatric, travel and endemic, and respiratory fields. We are one of the major suppliers of vaccines to supranational organizations in the developing world, and the first manufacturer to launch a fully liquid pentavalent vaccine, called Quinvaxem. This innovative combination vaccine protects against five important childhood diseases. Over 200 million doses have been sold since its launch in 2006 in more than 50 GAVI (the Global Alliance for Vaccines and Immunisation) countries. With this innovation, Crucell has become a major partner in protecting children in developing countries. Other products in Crucell s core portfolio include Hepavax-Gene, a vaccine against hepatitis B; Epaxal, the only aluminum-free hepatitis A vaccine on the market; Vivotif and Dukoral, oral vaccines against typhoid and cholera, respectively; and Inflexal V, a virosomal adjuvanted vaccine against influenza. Read more on page 26. Partners and licensees In addition to our own R&D activities, we have strategic partnerships with several leading healthcare companies, such as Johnson & Johnson, DSM Biologics, Merck, Novartis and sanofi pasteur. Through these agreements, our technologies play a vital role in the development of a vast number of vaccines and antibody products.

8 06 Overview Crucell: A global perspective China Marketing and sales. 2. Italy Marketing and sales. 3. Korea Marketing and sales + Manufacturing. 4. Netherlands (Headquarters) Marketing and sales. 5. Spain Marketing and sales + Manufacturing. 6. Sweden Marketing and sales + Manufacturing. 7. Switzerland Marketing and sales + Manufacturing. 8. UK Marketing and sales. 9. USA Marketing and sales.

9 Overview Crucell: A global perspective 07 Research and development Vaccines in development: Flavimun yellow fever vaccine. Influenza Seasonal cell-based seasonal vaccine. Universal Influenza cell-based universal vaccine. Tuberculosis recombinant AdVac based vaccine. Malaria recombinant AdVac based vaccine. Ebola and Marburg recombinant AdVac based vaccine. Technologies PER.C6 human cell line for development and manufacturing. AdVac used with PER.C6 to develop recombinant vaccines. MAbstract to discover novel drug targets and identify human monoclonal antibodies. HIV recombinant AdVac -based vaccine. HPV recombinant AdVac -based vaccine. RSV recombinant AdVac -based vaccine. Human monoclonal antibodies in development: Rabies antibody combination. Influenza antibodies. Hepatitis C antibody combination. Details on page 12 STAR to enhance yields of recombinant human antibodies and proteins. Virosome a vehicle enabling the use of virus antigens in the making of vaccines. Details on page 20 Products Paediatric: Quinvaxem fully liquid vaccine to protect against five important childhood diseases. Hepavax-Gene recombinant hepatitis B vaccine. Epaxal Junior low dosage, aluminum-free hepatitis A vaccine. MoRu-Viraten vaccine for protection against measles and rubella. Travel and endemic: Epaxal aluminum-free hepatitis A vaccine. Vivotif oral typhoid vaccine. Dukoral only internationally licensed oral vaccine against cholera (and ETEC). Respiratory: Inflexal V virosomal adjuvanted influenza vaccine. Details on page 26

10 08 Overview Message from our CEO I am therefore delighted that talks held with Johnson & Johnson during 2010 have resulted in Crucell becoming the center of excellence for vaccines within the world s largest and possibly most respected healthcare company. As a member of the Johnson & Johnson Family of Companies, we can do so much more to make the world we live in a healthier place. The combination of our two companies will enable Crucell to further accelerate growth, and our shared expertise and talent will help to make an even bigger difference in the lives of people worldwide. We are delighted by the prospect of pursuing our mission with the support of Johnson & Johnson that shares our passion for healthcare innovation, our values and our commitment to care for people. Crucell s mission to bring meaningful innovation to global health reflects a deep commitment to improving the lives of people worldwide. This underpins everything we do as a global organization and as individuals united by a common purpose. Protecting and contributing to society in the fullest possible sense and to the best of our ability is our core business, our passion and the essence of our company. Our commitment to the principles of corporate social responsibility is a logical extension of our mission to bring innovation to global health, focusing especially on the prevention of infectious diseases. During 2010, we distributed over 105 million 1 doses of vaccines to people around the world, with the majority going to infants in developing countries. The range of vaccines we have on the market prevents twelve major infectious diseases: childhood infections, travel and endemic illnesses, and respiratory disease. We estimate that a Crucell vaccine was given to 190 individuals 2 every minute during 2010, a thought that makes us very proud. However, I believe that the best measure of our impact on global health is not the number of doses we supply, but the number of deaths and cases of disease we prevent each year. In 2010, Crucell s top-five vaccines prevented more than 3.6 million cases of infectious disease and 809,823 deaths. 1 Crucell s core business is the discovery, development and delivery of innovative solutions for major health threats. Our specialty is the creation of much-needed immunization products: vaccines that safely 1 Figure based on Crucell s top five vaccines in terms of sales volumes: Quinvaxem, Hepavax-Gene, Epaxal, Vivotif and Inflexal V. 2 Figures based on Crucell s top 5 vaccines Quinvaxem, Hepavax-Gene, Epaxal, Vivotif and Inflexal V. Total 101,666,000 doses minus 2% waste (2,033,320 doses) = 99,632,680 doses sold in 2010 / minutes in 2010 = doses administered per minute.

11 Overview Message from our CEO 09 and effectively mobilize the body s own immune defenses against infections, and antibodies that provide ready-made immune protection against invading microbes. After clean water, immunization is believed to be the most cost-effective health intervention and its key role in promoting the socioeconomic development of countries is becoming increasingly clear. The world population is predicted to reach 7 billion in 2011 and protecting these billions of individuals from infectious diseases is more important and challenging than ever. Trends such as climate change, globalization, urbanization, wider travel and population aging are presenting new opportunities for infectious pathogens to thrive and spread. Doing our utmost to tackle this problem is our primary responsibility and our privilege. It lies at the heart of Crucell. More importantly, I see that we are expanding the boundaries of that reality, day by day. Innovation is the foundation on which Crucell was built, and the fuel driving us forward. Crucell s core business is the discovery, development and delivery of innovative solutions for major health threats. Our achievements so far are thanks to the tireless efforts and dedication of our loyal employees, Crucell s most important asset. In 2010 hundreds of talented people were recruited in order to further boost our capacity to bring innovation to global health going forward. Improving healthcare access The cover photograph of this booklet shows an Expanded Program on Immunization (EPI) session set up by the nongovernmental organization Friendship in collaboration with local governmental agents in Bangladesh. The mothers holding young babies are waiting in line for their infants to receive Crucell s Quinvaxem vaccine. With support from Crucell, Friendship has set up the cold chain to enable children in these remote char areas to be immunized. This initiative is one of many described in our corporate social responsibility (CSR) report in this booklet. The EPI was established by the World Health Organization (WHO) in 1974 with the aim of ensuring that all children in all countries benefit from life-saving vaccines. The first diseases targeted by the EPI were diphtheria, pertussis (whooping cough), tetanus, measles, poliomyelitis and tuberculosis. In 1977, the WHO established global policies for immunization and set the goal of universal immunization for all children by 1990, as an essential element of the WHO strategy to achieve health for all. In 2009, an estimated 82% of children globally had received at least three doses of diphtheria tetanus pertussis vaccine (DTP3) by one year of age, which has traditionally been used as an indicator of EPI coverage. Additional vaccines have progressively been added to the original six recommended by the WHO in The EPI remains committed to the goal of universal access to all relevant vaccines for all at risk. Information on the EPI was sourced from the WHO website. Ronald H.P. Brus President and Chief Executive Officer Leiden, the Netherlands, April 18, 2011

12 10 Our business Research and development, technologies and products At Crucell we bring meaningful innovation to global health. We do this by discovering, developing, manufacturing and marketing products that combat major threats to the health of people worldwide. Our specialty is fighting infectious diseases a growing healthcare challenge. In the following pages we highlight Crucell s key innovations in the field of research and development, our cutting-edge technologies and robust product portfolio. Research and development mln Invested in research and development in mln Doses distributed in Technologies 100 countries Crucell vaccines were distributed in more than 100 countries in Products

13 Our business Research and development, technologies and products 11 Development stage Discovery/ Pre-clinical Phase I Phase II Phase III Marketed Description Marketed products: Quinvaxem Fully liquid vaccine for protection against five childhood diseases. Hepavax-Gene Recombinant hepatitis B vaccine. Epaxal Junior Low-dosage, aluminum-free hepatitis A vaccine (0.25ml). MoRu-Viraten Vaccine for protection against measles and rubella. Epaxal Aluminum-free hepatitis A vaccine. Vivotif Oral typhoid vaccine. Dukoral Only internationally licensed oral vaccine against cholera. Inflexal V Virosomal adjuvanted influenza vaccine. Vaccines in development: Flavimun Yellow fever vaccine. Tuberculosis Recombinant AdVac -based tuberculosis vaccine. 1 Malaria Recombinant AdVac -based malaria vaccine. 2 Ebola and Marburg Recombinant AdVac -based Ebola and Marburg vaccine. 2 HIV Recombinant AdVac -based HIV vaccine. 3 Cell-based Influenza Seasonal influenza vaccine produced on PER.C6. Universal influenza Universal influenza vaccine produced on PER.C6. HPV Recombinant AdVac -based HPV vaccine. 4 RSV Recombinant AdVac -based RSV vaccine. 5 Human monoclonal antibodies in development: Rabies antibody combination Mix of two monoclonal antibodies for post-exposure treatment of rabies. 6 Influenza antibodies Hepatitis C antibody combination 1 Partnered with Aeras. 2 Partnered with NIH/NIAID, GSK. 3 Partnered with Harvard. 4 Human papilloma virus (HPV), partnered with Johnson & Johnson. 5 Respiratory syncytial virus (RSV), partnered with Johnson & Johnson. 6 Partnered with sanofi pasteur. Antibodies neutralizing a wide range of influenza subtypes, including H5 and H1. Neutralizing monoclonal antibody combination across all genotypes tested.

14 12 Our business Research and development

15 Our business Research and development 13 Crucell s research efforts focus on developing vaccines and antibodies that address infectious disease and unmet medical needs. In this section you can read more about the discovery and development of next-generation medical products facilitated by our range of innovative technologies.

16 14 Our business Research and development Our strong research and development pipeline Innovation is the driving force behind Crucell s future growth supported by a strong R&D pipeline. Our scientists focus on the discovery and development of much-needed solutions for major threats to human health particularly vaccines and antibodies for the prevention and treatment of infectious diseases. This has resulted in a broad pipeline of investigational products with the potential to revolutionize the fight against diseases such as influenza, rabies, malaria and tuberculosis. Vaccine development: based on AdVac technology AdVac technology involves the use of novel adenoviral vectors, such as Ad35 and Ad26, in vaccines for diseases caused by viruses, bacteria or parasites. These vectors are harmless adenoviruses that have been disabled so that they cannot replicate. A vector functions as an efficient gene taxi, delivering into the human body a fragment of DNA that carries the code for a protein of a specific pathogen. Once inside the body, the vectors express (produce) these proteins and present them to the person s immune system, which mounts its protective response. Using this versatile vaccine vector platform in combination with our PER.C6 manufacturing technology, we are working with our partners to develop vaccines against major threats to human health, including tuberculosis, malaria, Ebola and Marburg, HIV, human papilloma virus (HPV) and respiratory syncytial virus (RSV). See page 17. Tuberculosis (Phase II) Crucell joined forces with the nongovernmental organization (NGO) Aeras Global TB Vaccine Foundation in 2004 to develop a safe, effective and affordable vaccine against tuberculosis (TB). The traditional TB vaccine developed more than 85 years ago, Bacille Calmette Guérin (BCG), does not reliably prevent pulmonary disease the most common form of TB so there is a great need for a better alternative. Together with Aeras, we are developing the novel TB vaccine candidate AERAS-402/Crucell Ad35. The vaccine is based on Crucell s innovative AdVac technology, which uses novel harmless adenoviruses as vaccine vectors (vehicles). We are using the adenovirus 35 (Ad35) vector for this particular vaccine. AERAS-402/Crucell Ad35 is being designed as a booster vaccine that will be given to people who have previously been vaccinated with the traditional TB vaccine or an improved, recombinant version of the BCG vaccine that is being developed by Aeras. The BCG vaccine will prime (prepare) the immune system to fight off TB infection and the AERAS-402/ Crucell Ad35 will be given later to boost this initial immune response. Data from AERAS-402/Crucell Ad35 clinical trials (Phase I and II) support the immunogenicity and acceptable safety profile of the candidate TB vaccine. In 2009, an estimated 1.7 million people died of tuberculosis. Source: WHO, Global TB Control 2010 report. Tuberculosis Estimated new TB cases (all forms) per 100,000 population in >300 No estimate

17 Our business Research and development 15 Malaria Countries or areas at risk of transmission in Transmission occurs Limited risk of transmission No report Source: WHO, World Malaria Report Malaria (Phase I) Malaria is one of the most prevalent infections in tropical and subtropical regions. Children and pregnant women are most severely affected. According to the World Health Organization (WHO), half of the world s population is at risk of malaria, and an estimated 225 million cases led to 781,000 deaths in There is currently no licensed vaccine to protect people against malaria, a disease caused by infection with the Plasmodium parasite and transmitted by mosquitoes. Therapies are available for malaria patients, but the worsening problem of drug resistance in many parts of the world is making adequate treatment and control of malaria increasingly difficult. In addition, many insecticides are no longer useful against the mosquitoes that transmit the disease. Crucell is working in collaboration with a number of research groups to develop a safe, effective and affordable vaccine against Plasmodium falciparum, the most lethal of the four species of malaria parasite that infect humans. Crucell s approach is based on our innovative AdVac technology, which uses novel, harmless adenoviruses as vaccine delivery vehicles (vectors). In April, 2010, Crucell entered into an agreement with GlaxoSmithKline Biologicals (GSK) to collaborate on developing a second-generation malaria vaccine candidate. Crucell is contributing the recombinant malaria vaccine candidate Ad35-CS, based on Crucell s PER.C6 and AdVac technologies, while GSK is contributing its late-stage malaria vaccine candidate RTS,S/AS. The collaborative partners aim to advance this new vaccine candidate into human clinical studies with the support of the PATH Malaria Vaccine Initiative (MVI). Clinical efficacy challenge trials sponsored by the MVI will be initiated in 2011 at the US Walter Reed Army Institute of Research, providing all agreements are finalized. Pending the results of these Phase I/IIa trials, Crucell and GSK expect to advance the prime boost candidate in further clinical studies with the support of public or non-profit partners who are interested in accelerating the development of a malaria vaccine. In May 2010, Crucell announced the start of a new Phase I clinical study in Burkina Faso, West Africa. Crucell is developing its malaria vaccine vector, Ad35-CS, in collaboration with National Institute of Allergy and Infectious Diseases (NIAID)/ National Institutes of Health (NIH), the Centre National de Recherche et de Formation sur le Paludisme (CNRFP) in Burkina Faso, and the Noguchi Memorial Institute for Medical Research at the University of Ghana. Enrolment has been completed and boost vaccinations are ongoing. This is the first study evaluating the safety and immunogenicity of this AdVac -based malaria vaccine vector candidate in a population living in a malaria endemic area. Ebola and Marburg (Phase I) Ebola and Marburg are among the world s most lethal viral diseases. Both Ebola and Marburg are among the few viruses causing hemorrhagic fever, a severe, often fatal disease in humans. There are currently no vaccines or antiviral therapies available for either disease. Crucell is developing a multivalent filovirus vaccine against Ebola and Marburg in collaboration with the Vaccine Research Center of the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The candidate vaccine is based on Crucell s proprietary adenoviral vector technology and is produced using Crucell s PER.C6 technology.

18 16 Our business Research and development In August 2010, Crucell announced its participation in an international Phase I clinical trial in the United States and Africa of a combination of two AdVac -based AIDS vaccine candidates, Ad26.ENVA.01 and Ad35-ENV, in healthy adults who are not infected with HIV. The clinical trial, which will be led by the International AIDS Vaccine Initiative (IAVI), represents a collaboration between IAVI, Crucell, the Ragon Institute, and Beth Israel Deaconess Medical Center (BIDMC), a major teaching hospital of Harvard Medical School. In 2008, an estimated 2.7 million people were newly infected with HIV. Source: WHO. Every 17,5 seconds one person dies of AIDS. Source: Stop Aids Now! HIV (Phase I) Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immune deficiency syndrome (AIDS), a condition in which the immune system progressively fails, leading to life-threatening infections. Over the past 25 years, HIV infection resulting in AIDS has claimed millions of lives, devastated communities, and enormously frustrated efforts to fight poverty, improve global health and promote economic development. According to the 2010 Progress Report (a joint report by UNAIDS, Unicef and WHO), the HIV epidemic remains a major global public health challenge, with a total of 33.4 million people living with HIV worldwide. In 2008 alone, 2.7 million people were newly infected with HIV. The Ad26.ENVA.01 vaccine candidate used in this study is developed and manufactured by Crucell, while the Ad35-ENV vaccine is developed by IAVI. Both vaccines candidates are based on Crucell s proprietary AdVac technology. The planned Phase 1 trial of the vaccine combination represents a key step towards proof of concept studies to evaluate the efficacy of the vaccine combination in humans. HPV (Discovery/Pre-clinical) Genital infection with human papilloma virus (HPV) is very common in both men and women and usually spontaneously clears within one year after infection. In about 1% of individuals, however, HPV persists and ultimately results in genital neoplastic lesions. 1 Source: WHO, factsheet on rabies.

19 Our business Research and development 17 In November 2010, Crucell announced the start of a discovery program leading to the development and commercialization of a therapeutic HPV vaccine. The discovery program is part of a strategic collaboration, signed in September 2009 with Johnson & Johnson, through its subsidiary Ortho-McNeil-Janssen Pharmaceuticals, Inc., to develop innovative products, including antibodies for influenza prevention and treatment. RSV (Discovery/Pre-clinical) Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness in infants and children. RSV-induced disease is the last of the major paediatric diseases for which no preventive vaccine is available. Current prevention in developed countries is based on the administration of a costly RSV-neutralizing antibody, which is given to high-risk infants, in particular premature newborns. RSV also induces severe disease in immunocompromized adults and elderly people with weak immune systems, for whom the RSV antibody is not available. In June 2010, Crucell announced the start of a discovery program leading to the development and commercialization of a universal RSV vaccine. The vaccine will be designed to prevent severe infections with the most common RSV strains in infants and the elderly. This discovery program is part of a strategic collaboration with Johnson & Johnson, signed in September As an encouragement towards the RSV research community, Crucell sponsored the VII Respiratory Syncytial Virus Symposium held in December 2010 and established the Innovation Award for RSV Research. This support highlights Crucell s long-standing commitment to improve the health of people worldwide by advancing the fight against infectious diseases. Antibody development Antibodies are proteins made naturally by cells of the body s immune system. They function as one of the body s principal defense mechanisms against pathogens disease-causing agents such as parasites, viruses or bacteria. As antibodies recognize and bind to invading pathogens, ultimately eliminating them, they play a crucial role in protecting humans against disease. Rabies antibody combination (Phase II) Rabies is a viral disease of mammals and is most often transmitted through the bite of a rabid animal. The virus infects the central nervous system, causing encephalitis (inflammation of the brain) and ultimately death if appropriate medical intervention is not given promptly. Every year, more than 15 million people worldwide receive a post-exposure preventive regimen to avert the disease. This is estimated to prevent 327,000 rabies deaths annually. 1 Nevertheless, an estimated 55,000 individuals exposed to rabies virus mostly children die each year. Most of those who die receive a rabies vaccine only, rather than the proper post-exposure treatment consisting of anti-rabies antibodies as well as a vaccine. Concerns about the availability and safety of the current, blood-derived antibody treatment have prompted the search for a safe, effective and affordable alternative.

20 18 Our business Research and development Since January 2008, the route toward global availability of this next-generation, life-saving rabies biological has been facilitated by a strategic partnership between Crucell and sanofi pasteur, a world leader in rabies immunization. Under the terms of this agreement, Crucell will be responsible for manufacturing the commercial product and has retained exclusive distribution rights in Europe, co-exclusive distribution rights in China and the rights to sell to supranational organizations, while sanofi pasteur will have exclusive distribution rights for all other territories and co-exclusive distribution rights in China. A planned Phase II trial in India is expected to start in the first half of This study is designed to collect data on the safety and neutralizing activity of the rabies antibody combination plus vaccine in a simulated rabies post-exposure prophylaxis setting. An estimated 55,000 individuals exposed to rabies virus mostly children die each year. Source: WHO. Crucell scientists in collaboration with scientists from Thomas Jefferson University (TJU) in Philadelphia and the US Centers for Disease Control and Prevention in Atlanta, USA to discover a combination of human monoclonal antibodies (mabs) for the post-exposure treatment of rabies. Crucell s innovative MAbstract and PER.C6 technologies played a crucial role in the discovery and development of this promising therapy. The candidate mab product is designed to be used together with rabies vaccine. Preclinical studies conducted during 2004 indicated that the mab combination could neutralize (inactivate) rabies virus at least as effectively as blood-derived human rabies immune globulin (HRIG), the current gold standard for providing immediate protection against rabies virus. Since then, the rabies mab combination has successfully progressed through phase I clinical trials in the USA and India (in ) and phase II trials in the USA and the Philippines. The US Food and Drug Administration (FDA) has granted the rabies mab combination Fast Track status, paving the way for priority handling of the regulatory dossier. Human monoclonal antibodies against a broad range of influenza strains (Pre-clinical) Imagine a single product that could solve all the problems currently limiting influenza control. It would have to reliably protect all subgroups of the population especially the elderly against serious illness and death, regardless of the causal viral strain. Ideally, it would both prevent and cure influenza. In December 2008, Crucell announced the discovery of a new class of mabs with this extraordinary potential. Crucell also reported the results of preclinical studies involving a representative of this new mab class, CR6261. The antibody was shown to neutralize a broad range of influenza viruses, including the currently circulating H1N1 seasonal flu strains (genetic descendants of the virus responsible for 40 million deaths during the pandemic of ) and the highly pathogenic H5N1 ( bird flu ) virus. More recent tests have shown that CR6261 also combats the novel H1N1 virus that caused the 2009 pandemic. 1 Source: US National Library of Medicine, National Institute of Health.