Crucell Announces Third Quarter 2008 Results

• Combined total revenue and other operating income for the quarter of €82.1 million compared to €62.6 in the same quarter of 2007. The increase of 31% (38% in constant currencies) was largely driven by strong sales of paediatric vaccines as well as license income.
• Increase of license revenues mainly driven by milestone payments for the results of the Phase II clinical study of Crucell's rabies monoclonal antibody combination and for sanofi pasteur's seasonal influenza vaccine FluCell.
• Gross margins of 50% compared to 36% in the third quarter of 2007. Gross margins in the third quarter of this year are positively influenced by a significant increase in license revenue, sales of our flu product
  (Inflexal® V) and better production yields, as well as improved plant utilization due to higher volumes.
• Net income in the third quarter of 2008 of €12.3 million versus a net loss of €4.5 million in the same quarter of 2007.
• Cash and cash equivalents at the end of the third quarter amounted to €103.9 million versus €163.2 million at year-end 2007. Deterioration of cash flow and working capital in the first three quarters of 2008 was expected and is due to the seasonality of our business.
• Net cash used in operating activities in the third quarter of 2008 was €9.9 million, caused by a €26 million net increase in working capital, compared to net cash used in operating activities of €5.5 million in the same quarter of 2007.
• In anticipation of the expected further growth of Quinvaxem® in 2009, we will continue to build stock of Quinvaxem® in the fourth quarter of 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 for children against hepatitis A. The product is currently under registration in selected countries worldwide. Sales in South America are progressing well and a European launch is being planned.
• MoRu-Viraten®: Vaccine for protection against measles and rubella (for all age groups).

• Epaxal®: The only aluminium-free vaccine against hepatitis A.
• Vivotif®: The only oral vaccine against typhoid fever.
• Dukoral®: The only oral vaccine against diarrhea caused by cholera and 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 the flu products in the second half of the year.

• Flavimun® - Live Attenuated Yellow Fever Vaccine: Crucell's management expects the registration submission of the Yellow Fever vaccine in Switzerland and Germany in the first quarter of 2009.

• Influenza - Seasonal Flu Vaccine (FluCell collaboration with sanofi pasteur): The seasonal influenza vaccine developed by Crucell's partner sanofi pasteur, using PER.C6® technology. Phase II testing of the cell based influenza vaccine was initiated in the U.S. in November 2007. In the third quarter 2008, Crucell received a milestone payment from sanofi pasteur for the progress of the Phase II trials involving healthy adult volunteers in the U.S. The trials focus on the safety profile and immunogenicity of the cell-based vaccine.

• Rabies Human Monoclonal Antibody Combination: Crucell's rabies monoclonal antibody combination, developed in close collaboration with sanofi pasteur using Crucell's PER.C6® manufacturing technology. In 2008 Crucell initiated two Phase II studies in the U.S. and in 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. In the collaboration with sanofi pasteur Crucell will be responsible for the manufacturing of the final 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.
  Positive preliminary results of our Phase II U.S. study were presented at the 19th annual RITA meeting in Atlanta on October 1, 2008. There was no serious adverse event reported. 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. This antibody combination is to be used in combination with a rabies vaccine for post-exposure prophylaxis (PEP) against this fatal disease.

• Tuberculosis Vaccine based on AdVac®/PER.C6® Technologies:  The development of the candidate vaccine AERAS-402/Ad35 is being carried out in collaboration with the Aeras Global TB Vaccine Foundation.
  Phase I:
• U.S. 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/Ad35 is safe in this population. 
• Preliminary 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.
• A third phase I study in healthy adults in St. Louis, U.S. focuses on the immunogenicity and safety of two AERAS-402/Ad35 boost doses administered at three to six month intervals after BCG priming in healthy adults.
• In October, a Phase I clinical trial of the jointly developed TB vaccine was started in Kenya. The study will be conducted by the Walter Reed Project-Kenya at Kombewa, near Kisumu, Western Kenya. Its main objective will be to test the safety of the candidate vaccine in healthy adults, all of whom have been previously vaccinated with the BCG vaccine and a subset of whom show evidence of exposure to TB.
  Phase II:
• In October enrollment for the first Phase II study of AERAS-402/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 Institute. The candidate will be tested in 82 adults who have had active TB. 

• Malaria Vaccine based on AdVac®/PER.C6® Technologies: Crucell and its partner, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), are conducting a Phase I trial in the U.S. The study is being carried out on two sites, VanderBilt and Stanford University. The first three cohorts have been enrolled and ongoing safety monitoring has revealed no significant safety concerns to date, but formal analysis awaits unblinding of the data. Enrollment for the fourth and final group of volunteers is still ongoing and initial findings of this Phase I trial are expected in the first quarter of 2009.

• Multivalent Filovirus Vaccine (Ebola & Marburg) based on AdVac®/PER.C6® Technologies: In October Crucell announced that it has secured a NIAID/NIH contract aimed at advancing the development of Ebola and Marburg vaccines, ultimately leading to a multivalent filovirus vaccine. The contract provides funding of up to $30 million, with additional options that may be triggered at the discretion of the NIH worth a further $40 million. The Phase I study of an Ad5 based Ebola vaccine, being developed 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 adenovirus vectors which are able to by-pass pre-existing immunity against Ad5.

• HIV Vaccine based on AdVac®/PER.C6® Technologies: 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, 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, U.S. and is focused on assessing the safety and immunogenicity of the vaccine. Enrollment is ongoing and involves 48 healthy volunteers.

• This Week Nature Published a Study which Demonstrates the Value of Crucell's Alternative Adenovirus Serotype Technologies: Using Crucell's AdVac® vaccine- 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 regimes. 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.

• H5N1 - Human Monoclonal Antibodies against Flu: Crucell's scientists discovered a set of human monoclonal antibodies that provides immediate protection and neutralizes the broadest range of H5N1 strains in preclinical models. When tested in pre-clinical models for prophylactic or therapy of a potentially lethal H5N1 infection, this antibody was shown to prevent death and cure the disease. Currently a study to demonstrate the effectiveness of this antibody compared to Oseltamivir is being carried out.

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

• DSM Biologics and Crucell announced that the high-titer fed-batch process developed at the PERCIVIA PER.C6® Development Center, their joint venture in Cambridge, U.S. was recently scaled up to 250 Liters by DSM Biologics scientists at their GMP facility in Groningen, The Netherlands. They successfully achieved 8 grams per liter for an IgG expressed by PER.C6® cells using chemically defined cell culture medium in a SUB (single-use bioreactor). This result is further confirmation that PER.C6® cell lines provide a reliable, versatile and commercially feasible production platform for manufacturing large quantities of therapeutic proteins easily and affordably. This latest result also demonstrates the reliable performance of the PER.C6® cell line under conventional fed-batch production conditions, which are widely used in the industry. Earlier this year Crucell reported record-breaking protein yields of 27 grams per liter - biomass corrected - using DSM's innovative XD(TM) technology.

• Lonza and Crucell entered into a co-exclusive manufacturing, sales and distribution agreement related to the PERMEXCIS(TM) cell culture medium developed by Crucell for PER.C6® cells. Under this agreement, Lonza will manufacture the medium, and in addition will market and sell it on a global basis. Financial details of the agreement were not disclosed. [September 2008]
  The PERMEXCIS(TM) medium is a chemically defined cell culture medium that does not contain human- or animal-derived components. PERMEXCIS(TM) medium was developed for the cultivation of PER.C6® cells and has been designed for use in the large-scale manufacture of biopharmaceutical products, including vaccines. This novel medium has proven, in a comparison study performed by Crucell, to provide higher viral vaccine product yields in PER.C6® based manufacturing processes than some of the current available media for PER.C6® cells on the market.

• Crucell announced that it has signed an exclusive, commercial license agreement with North Carolina-based Talecris Biotherapeutics for an undisclosed and specific protein to be produced using a PER.C6® cell line. Crucell received an upfront payment of $2.5 million following the execution of the agreement and will be eligible for milestone payments of approximately $30 million across multiple indications. Further financial details of the agreement were not disclosed. [September 2008]

• Crucell announced a non-exclusive PER.C6® research license agreement with Birmingham-based Vaxin Inc. for their research and development of a vaccine for the prevention/treatment of Alzheimer's disease for humans as well as for an additional undisclosed field. Financial details of the agreement were not disclosed. [September 2008]

• Crucell announced that an agreement was reached to relocate Crucell's Korean production facility from the Shingal site in Yongin City, Korea to the Incheon Free Economic Zone. All parties involved have agreed on the time line and conditions of this relocation, enabling a smooth transition to the new production facility. With engineering well underway, construction activities at the new site are starting. The new facility will enable the further growth and efficient production of Quinvaxem® and Hepavax-Gene®. No further details were provided. [October 2008]

• Crucell announced a non-exclusive PER.C6® research license agreement with the Australian-based company Arana Therapeutics, Ltd for the production of monoclonal antibodies. Financial details of the agreement were not disclosed. [October 2008]

• Crucell announced a non-exclusive PER.C6® research license agreement with the Australian-based company Abraxis Bioscience, Inc., for the production of proteins. Financial details of the agreement were not disclosed. [October 2008]

• Crucell announced the sale of its fully-owned subsidiary Etna Biotech Srl (Catania, Italy) to Zydus Cadila (Ahmedabad, India). The sale results in net proceeds for Crucell of several hundred thousand Euros. This transaction is in line with Crucell's increased focus on the strengths of its core business. [November 2008]

• Crucell announced a non-exclusive manufacturing, sales and distribution agreement with Berlin-based Biochrom AG related to the PERMEXCIS(TM) cell culture medium developed by Crucell for PER.C6® cells.
  Biochrom is one of the leading European manufacturers of tissue culture media, animal sera, and buffers for the pharmaceutical industry. Established in 1981, the company manufactures and distributes the full range of products related to mammalian cell culturing technologies. Biochrom will manufacture the medium, and in addition will market and sell it in the European Union, Switzerland, Turkey, Russia and Israel. Financial details of the agreement were not disclosed. [November 2008]

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