Crucell Announces Profits for Full Year 2008

Crucell achieved profitability for the fourth quarter as well as for the full year; net profit in 2008 was €14.6 million, compared to a net loss of €42.9 million in 2007. This amounted to €0.22 net profit per share, compared to a net loss per share of €0.66 in 2007.
On January 7th, 2009 Crucell announced that it was in friendly discussions with Wyeth regarding a potential combination of the two companies. On January 26th, 2009 Crucell announced that Wyeth withdrew from these discussions.
In 2008 Crucell more than doubled the production of its pentavalent children's vaccine Quinvaxem®. In 2008 supranational organizations awarded Crucell additional contracts for supplies of Quinvaxem® and Hepavax-Gene® for the period 2008 - 2009, bringing the total for the period 2007 - 2009 to $0.5 billion.
Crucell announced that Chinese authorities have approved Hepavax-Gene® for use in the private vaccine market in China.
Crucell announced that its monoclonal antibody (mAb) directed against a broad range of influenza virus strains has strongly outperformed oseltamivir, an anti-influenza drug, in preclinical tests.
In 2008 Crucell's human monoclonal antibody combination against rabies and novel vaccine against tuberculosis both entered into Phase II clinical testing.
In 2008 DSM and Crucell announced a series of important advances in antibody production using PER.C6® technology platform. For example, a PER.C6® human cell line and proprietary XD(TM) technology were employed to achieve a record yield of over 27 grams per liter of IgG antibodies.
Crucell announced that its PER.C6® technology licensee Ark Therapeutics has entered a Phase III study with its product Trinam. Ark Therapeutics is the first licensee to enter into a Phase III study with a product produced on Crucell's PER.C6® human cell line.
Crucell signed new license agreements with several parties, including CSL Ltd. and GlaxoSmithKline, as well as a second exclusive license agreement with Talecris Biotherapeutics.

Combined total revenue and other operating income for the fourth quarter were €93.7 million, compared to €75.9 in the same quarter of 2007. The increase of 23% (22% in constant currencies[1]) was driven by strong sales of paediatric vaccines, travel and endemic vaccines as well as higher license revenues.
Milestone payments for Crucell's rabies monoclonal antibody combination accounted for the increase of license revenues
Gross margins of 50%, compared to 34% in the fourth quarter of 2007. Gross margins were positively influenced by a large increase in product sales, license revenues and a positive currency impact as well as significant improvements in production performance.
Net profit in the fourth quarter of 2008 was €19.2 million versus a net loss of €4.0 million in the same quarter of 2007.
Net cash from operating activities in the fourth quarter of 2008 was €61.5 million, compared to €51.5 million in the same quarter of 2007.
Overall, the net increase in cash and cash equivalents in the fourth quarter amounted to €67.0 million, versus €56.3 million in the fourth quarter of 2007.
In anticipation of the expected further growth of Quinvaxem® in 2009, Crucell continued to build stock of Quinvaxem® in the fourth quarter of 2008.

Combined total revenue and other operating income for the full year 2008 of €283.3 million, compared to €213.1 in 2007. The increase of 33% (38% in constant currencies[1]) was largely driven by strong sales of paediatric vaccines, travel and endemic vaccines as well as higher license revenues.
Crucell achieved profitability for the full year 2008, reporting a net profit of €14.6 million, compared to a net loss of €42.9 million reported in 2007. This amounted to €0.22 net profit per share in 2008, compared to a net loss per share of €0.66 in 2007.
Operating cash flow of minus €0.3 million for the year, compared to €22.2 million in 2007, due to inventory build-up of Quinvaxem® for sales in 2009.
Cash and cash equivalents increased by €7.7 million during the year to €171.0 million at year-end 2008.

Epaxal®: The only aluminum-free vaccine against hepatitis A.
Vivotif®: The only oral vaccine against typhoid fever.
Dukoral®: The only 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: Registration submission of the Yellow Fever vaccine in Switzerland and Germany is expected in the first quarter of 2009.

Influenza - Seasonal Flu Vaccine (FluCell collaboration with sanofi pasteur): This seasonal influenza vaccine is being 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 of 2008, Crucell received a milestone payment from sanofi pasteur for 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 (CL 184): 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 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. Under the terms of the collaboration agreement with sanofi pasteur, Crucell will be responsible for 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. This antibody combination is to be used in combination with a rabies vaccine for post-exposure prophylaxis (PEP) against this fatal disease.

Positive preliminary results of our 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 in combination with a 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. Final data from this study are expected to become available in the first half of 2009.
An additional phase II study in healthy adults evaluating Crucell's monoclonal antibody in combination with another major rabies vaccine is scheduled to start in India in the second quarter of 2009.

Tuberculosis Vaccine based on AdVac®/PER.C6® Technologies: 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 vaccine candidate at all dose levels evaluated. 
Phase I:

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.
A phase I study in healthy adults in St. Louis, USA focuses 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. Data from this study specifically indicate that two injections of AERAS-402/Crucell Ad35 are immunogenic with an acceptable safety profile when used with a BCG-prime/AERAS-402/Crucell Ad35 boost interval of 84 days in BCG vaccinated healthy adults. 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.
An ongoing study in St. Louis, USA is evaluating a longer prime-boost interval.  The study has been fully enrolled and has discovered no safety issues. Immunological data is expected to be available in the first half of 2009.
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 is fully enrolled and now in its follow-up segment, with no safety issues identified. 

• 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 is being tested in 82 adults who have had active TB. No evidence of an unacceptable safety issue has been found in its dose escalation design.

Malaria Vaccine based on AdVac®/PER.C6® Technologies: 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 U.S. The study is being carried out at two sites, Vanderbilt University in Nashville, Tennessee and Stanford University in Palo Alto, California. 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 ongoing. Preliminary results of the first three cohorts are expected before the end of the first quarter of 2009. Further updates on this program will be communicated in our first quarter 2009 results.

Multivalent Filovirus (Ebola & Marburg) Vaccine based on AdVac®/PER.C6® Technologies: In October 2008 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 adenovirus 5 (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 that 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, 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 (10^11 vp/dose) is currently enrolling subjects.

Alternative Adenovirus Serotype Technologies: In November 2008, 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.

Human Monoclonal Antibodies against a broad range of Influenza: 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 preclinical models for prevention or treatment of a potentially lethal H5N1 infection, this antibody 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 in terms of their value for flu prevention and treatment. In December 2008 Crucell announced that its monoclonal antibody had strongly outperformed the most current 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 the strain responsible for 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.

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

Crucell announced in October 2008 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, Korea. All parties involved have agreed on the time line and conditions of this relocation, enabling a smooth transition to the new production facility. Construction activities at the new site have started and are well on track. The new facility will enable the further growth and efficient production of Quinvaxem® and Hepavax-Gene®. The investments in the new facility are expected to total approximately €50 million, with the majority of spend in 2009.

Crucell announced in November 2008 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.

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

Crucell today announces a non-exclusive PER.C6® research license agreement with Canada-based Cangene Corporation for the development of several undisclosed antibodies. Financial details of the agreement were not disclosed. [October 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 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]

DSM Biologics and Crucell announced that Hungary-based Gedeon Richter Plc. signed a commercial license agreement allowing Gedeon Richter to develop and produce certain biopharmaceuticals on the PER.C6® platform.  Other terms of the agreement were not disclosed. [November 2008]

Crucell today announces a non-exclusive PER.C6® research license agreement with Netherlands-based Synthon B.V. for the production of biosimilar proteins. Financial details of the agreement were not disclosed. [November 2008]

Crucell today announces a non-exclusive PER.C6® research license agreement with Norway-based Affitech AS for the development of several undisclosed antibodies. Financial details of the agreement were not disclosed. [November 2008]

Crucell announced a second exclusive commercial license agreement with North Carolina-based Talecris Biotherapeutics for an undisclosed and specific protein and the exclusive rights to produce that protein using a PER.C6® cell line.
Crucell will receive an upfront payment of $1.5 million following the execution of the agreement and will be eligible for milestone payments of approximately $20 million. Further financial details of the agreement were not disclosed. [December 2008]

DSM Biologics and Crucell announced that Australia-based CSL Ltd. signed a license agreement allowing CSL to develop protein therapeutics for multiple undisclosed disease targets on the PER.C6® platform. Under the terms of the agreement, CSL is responsible for the development of protein and antibody products resulting from this alliance. Financial terms of the agreement were not disclosed. [December 2008]

DSM Biologics and Crucell announced that GlaxoSmithKline (GSK) signed a research license agreement allowing GSK to research a recombinant protein on the PER.C6® platform. Financial terms of the agreement were not disclosed. [December 2008]

Crucell today announces a non-exclusive PER.C6® commercial license agreement with Australian-based Elm Biotech Pty Ltd, managed by pharmaBank Pty Ltd, for the production of an adenovirus-vectored Gene Therapy product. Financial details of the agreement were not disclosed. [December 2008]

Crucell today announces two non-exclusive PER.C6® commercial license agreements with Netherlands-based ProFibrix B.V. for the development of recombinant fibrinogen and a second undisclosed recombinant protein. Financial details of the agreement were not disclosed. [December 2008]

Different aspects of improved adenoviral AdVac® vectors and AdVac® technology, in New Zealand, Eurasia, and the U.S.
Rabies virus-neutralizing antibodies, in Europe
PER.C6® protein expression technology, in Japan and the U.S.
Improved materials for use in MAbstract® technology, in Canada
Improvements in PER.C6® expression technology, in Europe
Virus purification technology, in Europe
Antiviral compound screening using PER.C6® technology, in Europe

Crucell announced a non-exclusive STAR® research and commercial license agreement with Pennsylvania-based Centocor, Inc. for the production of monoclonal antibodies. Financial details of the agreement were not disclosed. [January 2009]

On January 7th, 2009 Crucell announced that it was in friendly discussions with Wyeth regarding a potential combination of the two companies. On January 26th, 2009 Crucell announced that Wyeth withdrew from these discussions.

PDF file including financials