Dendreon

Dendreon

Type	Public
Industry	Biomedicine
Headquarters	Seattle, Washington, USA
Products	Provenge
Services	Provenge
Employees	1497
Website	http://www.dendreon.com

Dendreon (NASDAQ: DNDN) is a Seattle based biotechnology company. Its lead product, Provenge (known generically as sipuleucel-T), is an immunotherapy for prostate cancer. It consists of a mixture of the patient's own blood cells (autologous, with dendritic cells thought to be the most important) that have been incubated with the Dendreon PAP-GM-CSF fusion protein. Phase III clinical trial results demonstrating a survival benefit for prostate cancer patients receiving the drug were presented at the AUA meeting on 28 April 2009.^[1] After going through the approval process, Provenge was given full approval by the FDA on April 29, 2010.^[2] Dendreon's stock value fell 66% on August 4, 2011 after abandoning its forecast for its debut drug Provenge.^[3]

Technology overview and pipeline

Antigen delivery cassette and antigen presenting cells

Dendreon's name derives from the "Dendritic Cell" which forms a major component of the company's product candidates that use the "Dendreon Cassette Technology" to insert a disease-specific target protein into a general platform. Their lead product, Provenge, is an example of their "rationally designed therapeutic process" intended to break immune tolerance to certain disease specific proteins. It is hypothesized that receptor mediated uptake of antigen by dendritic cells occurs when they are exposed to the Dendreon fusion protein which links the disease specific protein to a recognition protein. This approach is in contrast to other dendritic cell vaccines that use methods such as electroporation to get the DC's to present antigen related epitopes. In the case of Provenge, this disease related protein is Prostatic acid phosphatase and the signalling component is GM-CSF.

Antigen selection

Dendreon believes its process can be optimized and generalized to other diseases by exchanging the PAP component of Provenge with better targets specific to different diseased cells.^[4] Antigen selection is a significant issue with cancer vaccines in general. Presumably, therapeutic effect can be obtained by provoking a selective response against the diseased cells only. Dendreon has explored approaches to obtaining tumour-specific antigen targets under the theory that the immune system may be able to mount a more effective response than is otherwise possible against tumor associated antigens. Unaltered human PAP is expressed by normal prostate cells but recent discoveries suggest that cancer cells produce many more unique targets as well as proteins that are more highly expressed than in normal tissue.^[5] It has also been recently discovered that other enzymes expressed in nerves are identical to PAP^[6][7] and there is ongoing work to examine post-translational modifications to PAP and its correlation to disease state by Dendreon collaborators.^[8] PAP also appears to be expressed in breast cysts.^[9]

Prior work in this area has also included that of A. Sette at Epimmune and the Altered Peptide Ligand approach typified by Neurocrine Biotech's failed MS drug.

Acquired from Corvas

A nematode anticoagulant licensed to Nuvelo^[10] was acquired. Selected Corvas patents include technologies and for peptide analog synthesis and drugs that target coagulation and immune processes.

Early history

Dendreon was founded in 1992 by Edgar Engleman and Samuel Strober based on the research performed in their laboratories at the Stanford University School of Medicine.

Drs. Engleman and Strober established the company, initially named Activated Cell Therapy, in Mountain View, California after securing funding from Health Care Ventures in Edison, New Jersey.^[11] After several years the company changed its name to Dendreon and moved to Seattle, Washington.

Provenge

Main article: Provenge

Initial clinical results for Provenge in 2000 showed immune responses supporting the expected mode-of-action, as well as a PSA reduction which was thought to relate to clinical improvement.^[12] In 2006, Dendreon built a manufacturing facility in Morris Plains, New Jersey to accommodate production for a Phase III trial and possible 2007 drug approval by the U.S. Food and Drug Administration (FDA).^[13] In January 2007, the FDA accepted Dendreon's Biologic License Application (BLA) filing for Provenge.^[14]

On March 29, 2007, the FDA Office of Cellular, Tissue and Gene Therapies Advisory Committee voted 17-0 that Provenge is reasonably safe and 13-4 that the trial data showed substantial evidence that it is effective.^[15] However, on May 9, 2007, Dendreon received a letter from the FDA demanding more results and information before approval.^[16]

On April 14, 2009, Dendreon announced that the results for the Phase III trial of Provenge were positive, saying there had been a reduction in the odds of death compared to the use of a placebo.^[17] On April 28, 2009, the full details of the study were released. The trial found that patients treated with Provenge lived an average of 4.1 months longer than patients treated with the control (autologous cells without the GM-CSF / PAP fusion protein).^[18]

On April 29, 2010, the FDA approved Provenge for use in the treatment of advanced prostate cancer.

Dendreonites

Some journalists have referred to Provenge supporters as "Dendreonites" and the name is in routine usage in colloquial forums.^[19] Concerns for personal safety were raised among some doctors who were thought responsible for the delay of Provenge approval.^[20] Dendreonites have questioned these doctors' objectivity; as Dr. Scher was the lead clinical trial investigator for a rival prostate cancer drug from the biotech Novacea.^[19] Their concerns motivated organized protests at the FDA and ASCO meeting by various patient and investor advocacy groups which also filed a lawsuit alleging that the FDA's decision was influenced by conflicts of interest.^[21]

List of US patents and patent applications

U.S. Patent 7,414,108 August 19, 2008 Laus; Reiner, Ruegg; Curtis L., Shapero; Michael H., Yang; Demao Composition and method for producing an immune response against tumor-related antigens. Disclosed are a novel prostatic acid phosphatase and corresponding coding region derived from mouse. Also disclosed is a method of producing an immune response against an autologous polypeptide tumor antigen by immunizing a subject with a xenogeneic polypeptide antigen, either alone, as part of a viral antigen construct, or as part of a pulsed dendritic cell preparation.

U.S. Patent 6,210,662 July 9, 2002 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu Immunostimulatory composition. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.

U.S. Patent 6,194,152 April 3, 2001 Laus; Reiner, Shapero; Michael H., Tsavaler; Larisa Prostate tumor polynucleotide compositions and methods of detection thereof. The present invention is directed to novel polynucleotides and the polypeptides encoded by them, each of which are specific to human prostate tumor cells. The present invention further provides chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, and antibodies which bind to the polypeptides of the present invention. Also provided herein are methods for producing the polypeptides of the present invention, as are detection assays that detect the presence of tumor cells in tissue or bodily fluid samples and methods for identifying novel compositions which modulate the activity of prostate tumor antigens and the use of such compositions in diagnosis and treatment of disease.

U.S. Patent 6,080,409 February 27, 2001 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu Immunostimulatory method. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.

U.S. Patent 5,976,546 December 7, 1999 Laus; Reiner, Ruegg; Curtis Landon, Wu; Hongyu Immunostimulatory compositions. Disclosed are therapeutic compositions and methods for inducing cytotoxic T cell responses in vitro and in vivo. The therapeutic compositions consist of antigen presenting cells activated by contact with a polypeptide complex constructed by joining together a dendritic cell-binding protein and a polypeptide antigen. Also disclosed are expression vectors and systems for producing the polypeptide complexes.

References

1. ^ "AUA IMPACT Trial Presentation Summary". http://files.shareholder.com/downloads/DNDN/579103823x0x290327/0d56dd47-8426-46dd-ab31-705983b009ca/DNDN_42809_IMPACT_Webcast_Slides_FINAL.pdf. 
2. ^ "UPDATE 3-U.S. FDA OKs Dendreon's prostate cancer vaccine". Reuters. 29 April 2010. http://www.reuters.com/article/idUSN2919838820100429. Retrieved 2010-05-02. 
3. ^ Berkrot, Bill (04 August 2011). "Dendreon plunges as Provenge prospects wither". Reuters. http://www.reuters.com/article/2011/08/04/dendreon-idUSL3E7J43V720110804. Retrieved 2011-08-04. 
4. ^ "BBC Global News." Interview by Julian King and Otis Brawley. GlobalNews (0400 GMT). BBC UK Podcast. London. 30 April 2010. Podcast.
5. ^ Rickman DS, Pflueger D, Moss B, et al. (April 2009). "SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer". Cancer Research 69 (7): 2734–8. doi:10.1158/0008-5472.CAN-08-4926. PMID 19293179. 
6. ^ Zylka MJ, Sowa NA, Taylor-Blake B, et al. (October 2008). "Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine". Neuron 60 (1): 111–22. doi:10.1016/j.neuron.2008.08.024. PMC 2629077. PMID 18940592. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2629077. 
7. ^ Zimmermann H (March 2009). "Prostatic acid phosphatase, a neglected ectonucleotidase". Purinergic Signalling 5 (3): 273–5. doi:10.1007/s11302-009-9157-z. PMC 2717315. PMID 19322680. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2717315. 
8. ^ White KY, Rodemich L, Nyalwidhe JO, et al. (February 2009). "Glycomic Characterization of Prostate Specific Antigen and Prostatic Acid Phosphatase in Prostate Cancer and Benign Disease Seminal Plasma Fluids". Journal of Proteome Research 8 (2): 620–30. doi:10.1021/pr8007545. PMC 2651839. PMID 19128049. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2651839. 
9. ^ Erbas H, Erten O, Irfanoglu ME (December 2007). "Prostatic acid phosphatase in breast cyst fluid". The Malaysian Journal of Pathology 29 (2): 95–9. PMID 19108401. 
10. ^ Mungall D (March 2004). "rNAPc2. Nuvelo". Current Opinion in Investigational Drugs 5 (3): 327–33. PMID 15083600. 
11. ^ "Activated Cell Therapy Announces New Executive Management Team" (Press release). Activated Cell Therapy. 30 August 1995. http://www.allbusiness.com/company-activities-management/company-structures/7150150-1.html. Retrieved 30 June 2009. 
12. ^ Small EJ, Fratesi P, Reese DM, et al. (1 December 2000). "Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells". Journal of Clinical Oncology 18 (23): 3894–903. PMID 11099318. http://www.jco.org/cgi/pmidlookup?view=long&pmid=11099318. 
13. ^ Timmerman, Luke (9 August 2006). "Building factory a balancing act for Dendreon". The Seattle Times. http://archives.seattletimes.nwsource.com/cgi-bin/texis.cgi/web/vortex/display?slug=dendreon090&date=20060809. Retrieved 29 June 2009. 
14. ^ Feuerstein, Adam (16 March 2007). "Dendreon's Date with Destiny". TheStreet.com. http://www.thestreet.com/newsanalysis/biotech/10343101.html. Retrieved 29 June 2009. 
15. ^ "US panel: Dendreon cancer therapy appears to work". Reuters. 29 March 2007. http://www.reuters.com/article/governmentFilingsNews/idUSN2723384020070329. Retrieved 30 June 2009. 
16. ^ Herper, Matthew (9 May 2007). "Dendreon's Dilemma". Forbes.com. http://www.forbes.com/2007/05/09/dendreon-provenge-fda-biz-sci_cx_mh_0509dendreon.html. Retrieved 9 May 2007. 
17. ^ Pollack, Andrew (14 April 2009). "Promising Test for Dendreon’s Prostate Cancer Drug". The New York Times. http://www.nytimes.com/2009/04/15/business/15cancer.html. Retrieved 30 June 2009. 
18. ^ [1]^{[dead link]}
19. ^ ^{a b} "CNBC Article on Dendreonite Requests". http://classic.cnbc.com/id/22259592. 
20. ^ Stein, Rob. "FDA Delay In Cancer Therapy Is Attacked". The Washington Post. http://www.washingtonpost.com/wp-dyn/content/article/2007/07/05/AR2007070502149_pf.html. Retrieved 2010-05-01. 
21. ^ Roan, Shari (December 31, 2007). "Protest Descriptions". The Los Angeles Times. http://articles.latimes.com/2007/dec/31/health/he-prostate31. 

External links

• Official Company website
• FDA Provenge information page
• Official Provenge website