Crucell Announces Third Quarter 2009 Results

• In the third quarter of 2009 total revenues and other operating income increased by 15% to €94.3 million, compared to €82.1 million in the same quarter of 2008. The increase was driven by a robust 28% growth in product sales and in particular growth of our paediatric and respiratory vaccines.
• In December 2008, Crucell announced the discovery of a new class of human monoclonal antibodies (mAbs) with the unprecedented ability to combat a broad range of influenza virus strains[1]. This breadth of protection opens up the new possibility of developing a universal means of influenza control, solving the key challenge in influenza prevention and treatment: the ease with which influenza viruses mutate, leading to new seasonal strains every year, periodic outbreaks of pandemic strains, and the emergence of drug-resistant viruses.
• The exciting therapeutic potential of this discovery attracted the attention of global leaders in healthcare innovation, which, in September 2009, resulted in a strategic collaboration between Crucell and Johnson & Johnson (JNJ). This collaboration focuses on the discovery, development and commercialization of monoclonal antibodies and vaccines for the treatment and prevention of influenza and other infectious and non-infectious diseases.
• The agreement with JNJ, with a potential deal value of over €1 billion, also includes an 18% equity investment in Crucell at a premium of 30% as well as significant milestones over the development period of the innovation programs. JNJ will hold commercialization rights for products resulting from the collaborations in all countries throughout the world with the exception of the European Union, certain additional European countries and supranational organizations, where Crucell will retain commercialization rights. Additionally Crucell holds all bulk manufacturing rights.
• The strategic collaboration with JNJ follows the announcement in August 2009 of an award to Crucell from the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health (NIH). The award was designed to support early development of Crucell's mAbs for the treatment of seasonal and pandemic influenza. The award provides funding of up to $40.7 million, with additional options that may be triggered at the discretion of the NIH worth a further $28.4 million, bringing the potential total amount to $69.1 million.
• Crucell announced $300 million worth of new awards from a large supranational organization for supplies of Quinvaxem®, the first portion of the new 3-year tender period. The new awards are the largest ever received by Crucell and cover the period 2010-2012. With only half of the original tender volume awarded to date the initial amount of $300 million is expected to grow further over the three year period. The new awards are in addition to the $500 million obtained over the tender period 2007-2009. During the first tender round in 2006, Crucell initially received an award of $230 million (Dec 2006) and received additional incremental awards of $130 million and $140 million in May and September, 2008, respectively.
• In line with Crucell's strategy to increase its market share and cost efficiency, the company announced the start of its own dedicated marketing and sales organization in the United Kingdom. The acquisition of an experienced team further strengthens Crucell's vaccine sales position in one of the largest vaccine markets in Europe.
• Detailed positive results of the Phase II Philippines study of Crucell's rabies monoclonal antibody combination (CL 184) were presented at the XX Rabies in the Americas (RITA) Conference in Quebec, Canada. The start of the third phase II clinical study in India is imminent.
• Promising preliminary results of the Phase I study of Crucell's HIV vaccine were presented at La Conférence AIDS Vaccine 2009 in Paris, France, showing that this HIV candidate vaccine is safe and immunogenic.
• Crucell announced that the PANFLUVAC consortium consisting of eight European research partners, which includes Crucell, completed the first stage of their phase I clinical trial in healthy volunteers, using a virosomal vaccine against A/H5N1 influenza.
• Crucell signed three new license agreements, which includes agreements with Australia-based Patrys Ltd., US-based TapImmune Inc. and US-based Calmune Corporation.
• Construction of the new vaccine manufacturing facility in Korea, which started in December 2008, is progressing well. First test runs are planned for the first half of 2010.

• Combined total revenues and other operating income for the third quarter were €94.3 million, compared to €82.1 million in the same quarter of 2008. The increase of 15% was mainly driven by strong sales of paediatric and respiratory vaccines. Travel and endemic vaccines also showed solid growth due strong sales of Epaxal®, despite the impact of reduced travel from the economic crisis.
• In line with expectations, gross margins were 39% in the quarter, compared to 50% in the same period in the prior year. The timing of development milestone payments from partners significantly influence margins and profitability in the period in which they are recognized. The third quarter of 2008 included €6.0 million milestone payments. The remaining drop in margins is due to unfavorable movement of the US Dollar versus the Euro.
• The Company achieved operating profit of €15.5 million in the third quarter of 2009 compared to €9.6 million operating profit in the same quarter of 2008.  Operating profits were positively affected by a €8.1 million impairment reversal of two state-of-the-art buildings in Bern (Switzerland). The buildings were impaired in the fourth quarter of 2006 as there was no direct use for them. The buildings are now being used as development production sites for Epaxal® (hepatitis A) and tuberculosis vaccines. The buildings have been adapted to the specific needs of the development programs, which will avoid major spending in the construction of new development facilities.  
• As part of the strategic collaboration with JNJ, the company sold 14.6 million newly issued ordinary shares to JNJ for an aggregate purchase price of €301.8 million. This included a premium of €69.5 million classified as deferred income, which will be amortized in the coming years. 
• Income taxes were €4.6 million in the third quarter, mainly due in Switzerland, Spain and Korea. The consolidated effective income tax rate was 32% in the third quarter of 2009. The consolidated profit before tax was reduced by a significant operating loss in the Netherlands as a result of R&D expenses for which no tax benefit is recognized.  
• Net cash from operating activities in the third quarter improved significantly to €72.1 million, up from minus €9.9 million in the same quarter of 2008. This was driven by the upfront payment of JNJ for participation in Crucell's development programs.
• Cash used in investing activities amounted to €118.0 million, which includes a long term deposit of €100.0 million with a maturity of over 3 months, to take advantage of higher yields on longer term deposits. 
• Net cash from financing activities in the third quarter was €235.0 million, compared to €11.3 million in the same quarter of 2008. This increase reflects the cash proceeds from the issuance of shares to JNJ. 
• Cash and cash equivalents at the end of the third quarter of €311.6 million, versus €171.0 million at year-end 2008.

• Quinvaxem®: Fully liquid pentavalent vaccine against five important childhood diseases.
• Hepavax-Gene®: Recombinant vaccine against hepatitis B.
• Epaxal® Junior: Paediatric dose (0.25mL) of Epaxal®, the only aluminum-free vaccine against hepatitis A for use in children.
• MoRu-Viraten®: Vaccine for protection against measles and rubella (for all age groups).

• Epaxal®: Aluminum-free vaccine against hepatitis A.
• Vivotif®: Oral vaccine against typhoid fever.
• Dukoral®: Oral vaccine against cholera and diarrhea caused by ETEC (enterotoxigenic E. coli). 

• Inflexal® V: A virosomal adjuvanted vaccine against influenza (for all age groups). Due to the seasonality of the product, we build inventory in the first half of the year to sell flu vaccines in the second half of the year. 

• Flavimun® - Live Attenuated Yellow Fever Vaccine (Phase III): Flavimun® was submitted for registration in Switzerland in March 2009. Submission in Germany is expected within the next few months. 

• Influenza - Seasonal Flu Vaccine (Phase II; FluCell collaboration with Sanofi Pasteur): This seasonal influenza vaccine is being developed by Sanofi Pasteur, using Crucell's PER.C6® technology. Phase II testing of the cell-based influenza vaccine was initiated in the USA in November 2007. In the third quarter of 2008, Crucell received a milestone payment from Sanofi Pasteur for progress of the Phase II trials involving healthy adult volunteers in the USA. The trials focus on the safety profile and immunogenicity of the cell-based vaccine. All data collected so far confirm that the PER.C6® cell line supports the growth of all flu virus strains in high quantities. The cell line has also been found to be commercially scalable to any desired scale and no problems related to the PER.C6® cell line have been encountered to date.

• Human Monoclonal Antibodies against a broad range of Influenza strains (Preclinical): Crucell's scientists discovered a set of human monoclonal antibodies that provide immediate protection and neutralize the broadest range of H5N1 strains in preclinical models. When the most powerful of these antibodies was tested in preclinical models for prevention or treatment of a potentially lethal H5N1 infection, it was shown to prevent death and cure the disease.
• In a preclinical study, Crucell's mAb CR6261 was compared with the anti-influenza drug oseltamivir (Tamiflu) in terms of its value for flu prevention and treatment. In December 2008, Crucell announced that its monoclonal antibody strongly outperformed the anti-influenza drug in these tests. The results were presented at IBC's 19th Annual International Conference on Antibody Engineering in San Diego, USA.
• The flu strains tested included the 'bird flu' strain H5N1, which experts fear has the potential to cause a pandemic, and H1N1, which is similar to a descendant of the flu virus that caused the devastating pandemic in 1918. Importantly, the study showed that CR6261 provides immediate protection against the influenza virus, suggesting that it will be able to prevent disease spread. In contrast, oseltamivir was less efficacious and in some cases not effective at all. The characterization of the antibody was described in the online journal PLoS ONE on December 16, 2008.
• In August 2009 Crucell received an award from the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH) for the development of its monoclonal antibodies for the treatment of seasonal and pandemic influenza. The award provides funding of up to $40.7 million, with additional options that may be triggered at the discretion of the NIH worth a further $28.4 million, bringing the potential total amount to $69.1 million.
• In September JNJ, through its subsidiary Ortho-McNeil-Janssen Pharmaceuticals, Inc., and Crucell entered into a strategic collaboration focusing on the discovery, development and commercialization of monoclonal antibodies and vaccines for the treatment and prevention of influenza and other infectious and non-infectious diseases.
• The immediate focus of the collaboration will be the development and commercialization of a universal monoclonal antibody product (flu-mAb) for the treatment and prevention of influenza. The focus of the long-term innovation collaboration will be on new discovery programs leading to the development and commercialization of a universal influenza vaccine as well as the development of monoclonal antibodies and/or vaccines directed against up to three other infectious and non-infectious disease targets.

• Rabies Human Monoclonal Antibody Combination/CL184 (Phase II): Crucell's monoclonal antibody combination against rabies is being developed in close collaboration with Sanofi Pasteur using Crucell's PER.C6® manufacturing technology. In 2008, Crucell initiated two Phase II studies in the USA and the Philippines. Promising Phase I data in 2007 showed no serious adverse effects and demonstrated the expected rabies neutralizing activity upon administration. The rabies human monoclonal antibody combination was granted a Fast Track designation by the FDA Department of Health and Human Services, ensuring priority handling of the regulatory dossier. Under the terms of the collaboration agreement with Sanofi Pasteur, 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 such as UNICEF, while Sanofi Pasteur will have exclusive distribution rights for all other territories and co-exclusive distribution rights in China. This antibody combination is designed to be used in combination with a rabies vaccine for post-exposure prophylaxis (PEP) against this fatal disease.
• Positive preliminary results of the Phase II US study were presented to rabies experts at the 19th annual RITA meeting in Atlanta on October 1, 2008. These results triggered another milestone payment from Sanofi Pasteur at the end of September, as part of the total eligible amount of €66.5 million. 
• A second Phase II clinical study evaluating the monoclonal antibody combination together with a rabies vaccine in healthy children and adolescents was conducted in the Philippines from May to October 2008. The completion of this study triggered another milestone payment from Sanofi Pasteur, at the end of October. In June 2009, Crucell announced the results of the Philippines study, which showed that the antibody combination was safe and well tolerated. Neutralizing activity levels in subjects given the antibody product were similar to those in subjects given human immunoglobulin (HRIG), the current standard for inducing immediate, passive immunity. All study participants reached adequate immunity levels. This study in children further broadens the potential patient population for Crucell's rabies monoclonal antibody combination. Detailed results of this study have been presented at the XX Rabies in the Americas RITA conference in Quebec, Canada on 20 October 2009. 
• Plans to start an additional Phase II clinical study are progressing well after recent approval received from the Drug Controller General of India. This third Phase II study will be carried out at Lotus Laboratories in Bangalore, India and is planned to start within the next six months. The rationale for this study is to collect safety and neutralizing activity data of the CL184 antibody in combination with the vaccine in a simulated rabies post-exposure prophylaxis setting to be used in Phase III.

• Tuberculosis Vaccine (AdVac®/PER.C6® Technology based; Phase II):  Development of the candidate vaccine AERAS-402/Crucell Ad35 is being carried out in collaboration with the Aeras Global TB Vaccine Foundation. Data from all AERAS-402/Crucell Ad35 trials support the immunogenicity and acceptable safety profile of the TB candidate vaccine at all dose levels evaluated.
• Phase II: In October 2008 enrollment for the first Phase II study of AERAS-402/Crucell Ad35 in Cape Town, South Africa was started. The study is being conducted by the University of Cape Town Lung Institute in conjunction with the South African Tuberculosis Vaccine Initiative. The candidate vaccine is being tested in 116 adults who have had active TB. This study is currently enrolling. No evidence of an unacceptable safety issue has been found in its dose escalation design after enrollment and vaccination of 60 subjects to date.
• Phase I: The US Phase I trial in healthy adults not previously immunized with Bacille Calmette-Guérin (BCG), the traditional TB vaccine, has been completed and has demonstrated that AERAS-402/Crucell Ad35 is safe in this population. 
• Results of a second study in South Africa showed encouraging results, notably CD8-cell immune responses that are much higher than those seen in humans in any previous TB vaccine study.
• Two Phase I studies in healthy adults in St. Louis, USA, focusing on the immunogenicity and safety of two AERAS-402/Crucell Ad35 boost doses administered at three to six month intervals after BCG priming in healthy adults have been completed. Data from these studies specifically indicate that two injections of AERAS-402/Crucell Ad35 are immunogenic, with an acceptable safety profile, when used with a BCG-prime in combination with the AERAS-402/Crucell Ad35 candidate vaccine in BCG vaccinated healthy adults, regardless of the boosting interval. This immune response is greater than that detected in the absence of BCG prime, supporting the possible utility of AERAS-402/Crucell Ad35 as a booster vaccine. BCG prime alone shows limited efficacy.
• In October 2008, a Phase I clinical trial of the jointly developed TB vaccine was started in Kenya. The study is being conducted by the KEMRI/Walter Reed Project-Kisumu at their Kombewa Clinical Trials Center near Kisumu, in Western Kenya. Its main objective will be to test the safety of the candidate vaccine in BCG-vaccinated adults with or without latent tuberculosis. This study has been completed, with ongoing analysis and no safety issues identified.
• In April 2009, a Phase I clinical trial in infants of the jointly developed TB candidate vaccine AERAS-402/Crucell Ad35 was started in South Africa. This is the first clinical trial designed to test this candidate vaccine in infants. The Phase I study of AERAS-402/Crucell Ad35 is being conducted by the South African Tuberculosis Vaccine Initiative (SATVI) in the Western Cape region of South Africa. The main objective of the study is to test the safety of the TB candidate vaccine in infants previously vaccinated with BCG vaccine, which is currently the only vaccine, licensed to help prevent TB. This study is fully enrolled and dosing is ongoing. No safety issues have been identified.

• Malaria Vaccine (AdVac®/PER.C6® Technology based; Phase I): Crucell and its collaborator, the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), are conducting a Phase I trial in the USA for a recombinant malaria vaccine, Ad35-CS, based on the company's AdVac® technology and PER.C6® manufacturing platform. The candidate vaccine is made by inserting the gene for the circumsporozoite protein (CSP) from the Plasmodium falciparum malaria parasite into adenoviral vectors, which act as a 'vehicle' for vaccination delivery. The study is being carried out at two sites, Vanderbilt University in Nashville, Tennessee and Stanford University in Palo Alto, California. All four cohorts have been enrolled, and ongoing safety monitoring has revealed no significant safety concerns to date. Boost vaccinations for the fourth and final group of volunteers is underway. Preliminary examination of the blinded data from the first four cohorts indicates that the vaccine is immunogenic. Detailed analysis of the data awaits completion of the fourth cohort and unblinding of the data.
• In July 2009 Crucell announced a new collaboration with US-based MVI and USAID MVDP to accelerate development of a promising new type of malaria vaccine. Through funding from the USAID MVDP, the partners will conduct studies to determine the effectiveness of Crucell's novel prime-boost vaccine approach against the malaria parasite P. falciparum. This approach uses Crucell's proprietary recombinant adenoviruses (a type of virus associated with the common cold and other mild respiratory infections), to deliver a malaria antigen to the immune system. Using Crucell's AdVac® technology with two different adenovirus vectors-Ad35 and Ad26-as delivery mechanisms, this approach seeks to elicit a protective immune response obtained from delivering the circumsporozoite protein (CSP).

• Multivalent Filovirus (Ebola & Marburg) Vaccine (AdVac®/PER.C6® Technology based; Phase I): In October 2008 Crucell announced that it has secured a NIAID/NIH award to advance the development of Ebola and Marburg vaccines, with the ultimate aim of developing a multivalent filovirus vaccine. The award provides funding of up to $30 million, with additional options, which may be triggered at the discretion of the NIH, worth a further $40 million. The Phase I study of an adenovirus 5 (Ad5)-based Ebola vaccine that Crucell is developing in partnership with the Vaccine Research Center (VRC) of the NIAID/NIH, showed safety and immunogenicity at the doses evaluated. Based on these results, a second Phase I study of an Ebola and/or Marburg vaccine is anticipated. This will use alternative multivalent adenovirus vectors that are able to bypass pre-existing immunity against Ad5. 

• HIV Vaccine (AdVac®/PER.C6® Technology based; Phase I): The Investigational New Drug Application (IND) for Phase I of the trial with Harvard Medical School (supported by the NIH) was approved by the FDA in January 2008. In April 2008, Crucell announced the start of a Phase I clinical study of the novel recombinant HIV vaccine, using adenovirus serotype 26 (rAd26) as vector, that Crucell is jointly developing with the Beth Israel Deaconess Medical Center. The rAd26 vector is specifically designed to avoid the pre-existing immunity to the more commonly used adenovirus serotype 5 (Ad5). The Phase I clinical study is being conducted at the Brigham and Women's Hospital in Boston, USA and is focused on assessing the safety and immunogenicity of the vaccine. Enrollment is ongoing and involves 48 healthy volunteers. Dose escalation has proceeded without difficulty and the third cohort has been fully enrolled. Boost vaccinations are ongoing. On 21 October 2009 preliminary results of the Phase I study were presented at La Conférence AIDS Vaccine 2009 in Paris, France. The presentation was given by Dr Dan H. Barouch, MD, PhD, Associate Professor of Medicine, Division of Vaccine Research, Department of Medicine at the Beth Israel Deaconess Medical Center (BIDMC) in Boston, USA. The preliminary results of this study show that this HIV candidate vaccine is safe and immunogenic.

• Alternative Adenovirus Serotype Technologies: In November 2008, the leading scientific journal Nature published a study that demonstrated the value of Crucell's alternative adenovirus serotype technologies. Using Crucell's AdVac® vaccine technology and PER.C6® manufacturing technology, scientists engineered the rare adenovirus serotypes Ad26 and Ad35 to express a protein of SIV, the non-human primate equivalent of HIV. Rare serotype adenoviral vectors-such as rAd26 and rAd35 vectors- have been developed by Crucell to provide more potent prime-boost vaccine regimens. The study, which investigated the immunogenicity and protective efficacy of different vaccination regimes using rAd26, rAd35 or rAd5 as a prime, followed by a boost with rAd5, showed that in particular the rAd26/rAd5 combination elicits a strong T-cell immune response and provides protection against the HIV-like virus in non-human primate models. Crucell has several vaccines in development using alternative rAd26 and rAd35 vectors, including vaccines against malaria and tuberculosis.

• Hepatitis C Antibody Combination (Preclinical): In August 2009 Crucell obtained an exclusive license from Stanford University (Palo Alto, California) for the development of an antibody combination against the hepatitis C virus. A large panel of fully human monoclonal antibodies against the hepatitis C virus (HCV) is being evaluated by Crucell in a proof of concept phase. The monoclonal antibodies have been found to neutralize HCV across all genotypes tested and each recognizes a different part of the HCV surface protein.

• Blood Coagulation Factor VL/C (Research): Preclinical work on this program continues but conclusive proof of concept is not expected in the near future.

• Crucell announced a non-exclusive PER.C6® research license agreement with Australia-based Patrys Ltd. for the production of several undisclosed antibodies. Financial details of the agreement were not disclosed. [July 2009]
• Crucell today announces a non-exclusive PER.C6® research license agreement with US-based TapImmune Inc. for use in its vaccine development programs. Financial details of the agreement were not disclosed. [September 2009]
• Crucell today announces an agreement with US-based Calmune Corporation, including an exclusive license on an undisclosed antibody based on Calmune's technology and a co-development for the discovery of new antibodies against the same target. Financial details of the agreement were not disclosed. [September 2009].

• Monoclonal antibodies against rabies, in the U.S. and Singapore
• AdVac® based malaria vaccines, in Australia
• Production of antibody fragments using PER.C6® expression technology, in Australia
• Elements of STAR® technology, in India
• Improvements in PER.C6® expression technology, in New Zealand
• Purification of AdVac® vectors, in Europe and New Zealand

• Crucell expects its combined full-year 2009 total revenues and other operating income to grow 20% in constant currencies. 
• Operating profit for 2009 is expected to improve significantly compared to 2008.
• Maintain current strong cash position.
• Crucell does not expect its results to be materially affected by the global recession.

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