Status: BLA rejected by FDA; refiled in 2007; BLA granted in April 2010; EU MAA approved in Sept. 2013

Organizations involved:

Dendreon Inc. – Manuf.; R&D; Tech.; World mark.

PharmaCell B.V. – Manuf.

Activated Cell Therapy – R&D; Tech.; Former

GlaxoSmithKline S.A. (GSK) – Manuf.

GlaxoSmithKline plc (GSK) – Parent

Diosynth RTP, Inc. – Manuf.; Former

Covance Biotechnology Services, Inc. - Former

Akzo Nobel N.V. – Parent

Gambro Healthcare, Inc. – Manuf. other

Gambro AB – Parent

Baxter International Inc. – Parent

Progenitor Cell Therapy – Manuf. other

Mayo Clinic – Manuf. other

American National Red Cross – Manuf. other

Texas A&M University – Tech.

Kirin Pharmaceuticals, Ltd. – Former

Cross ref.: See the entries for several recombinant granulocyte macrophage-colony stimulating factor (GM-CSF) products, particularly Leukine from Amgen.

Description: Provenge (APC8015) is an immunotherapeutic prostate cancer vaccine containing autologous (patient’s own) dendritic cells loaded ex vivo with (exposed to) a recombinant fusion protein (PA2024; Antigen Delivery Cassette) consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF) manufactured by culture of an insect cell line, Spodoptera frugiperda Sf21, transformed using a baculovirus expression vector system (BEVS). The PAP–GM-CSF fusion protein loaded on the surface of the dendritic cells converts them to PAP-primed Antigen Presenting Cells (APC), which after reinfusion into the donor patient stimulate cell-mediated immune (PAP-specific cytotoxic T-cells) responses to prostate tumors cells expressing PAP. PAP–GM-CSF is later administered independently as a booster vaccine, as part of the Provenge regimen. Baculovirus-expressed PAP is fused to GM-CSF through its carboxy terminus to the amino terminus of GM-CSF via a Gly-Ser linker.

Generally, two days prior to scheduled treatment, patients undergo standard leukapheresis (1.5-2.0 blood volumes; removal of leukocytes from whole blood) using the COBE Spectra Apheresis System. The patient’s peripheral blood mononuclear cells are obtained by leukapheresis approximately 3 days prior to the infusion date. [See the Leukocytes entry for further information about leukapheresis]. The leukocytes are processed to isolate antigen-presenting cells (APCs), and the APCs are cultured for 40 hours in the presence of PA2024 (PAP–GM-CSF). The cells are washed to remove unbound PAP–GM-CSF, and the cells are infused back into the donor patient by intravenous infusion. Both leukapheresis and infusion may be performed on an outpatient basis. The sensitized cells are administered again two weeks later, followed by subcutaneous injection of PAP–GM-CSF (1.0 mg; 0.5 mg into each thigh) at weeks 4, 8, and 12. A dose of Provenge contains, on average, over 900 million PAP-primed APCs. Provenge is packaged in 250 mL, sealed, patient-specific infusion bag, held in insulated polyurethane containers,

The active components of Provenge are autologous antigen-presenting cells (APCs) and PAP-GM-CSF. During culture, the recombinant antigen may bind to and be processed by APCs into smaller protein fragments. The recombinant antigen is designed to target APCs, and may help direct the immune response to PAP. Minimal residual levels of the intact PAP-GM-CSF are detectable in the final product.

Each dose (infusion bag) of Provenge contains a minimum of 50 million autologous CD54+ cells activated with PAP–GM-CSF, suspended in 250 mL of Lactated Ringer’s solution. The dating period for sipuleucel-T is 18 hours from the date of manufacture when stored at 2-8 °C (refrigerated). The date of manufacture is the time of addition of Lactated Ringer’s Injection, USP to the infusion bag at the end of cell harvest.

Provenge is shipped directly to the infusing provider. Provenge is shipped in a cardboard box with a special insulated polyurethane container inside. The insulated container and gel packs within the container are designed to maintain the appropriate transportation and storage temperature until infusion..

The cellular composition of Provenge is dependent on the composition of cells obtained from the patient’s leukapheresis. In addition to APCs, the final product contains T cells, B cells, natural killer (NK) cells, and other cells. The number of cells present and the cellular composition of each Provenge dose varies.

Provenge is not routinely tested for transmissible infectious diseases. Thus, patient leukapheresis material and Provenge may carry the risk of transmitting infectious diseases to those handling the product. Standard "universal precautions" should be followed in handling leukapheresis material and Provenge.

Provenge is the first autologous cellular immunotherapy to enter the market.

Nomenclature: Prostate Cancer Vaccine, Cellular (rDNA) [BIO]; Provenge [TR]; sipuleucel-T [USAN]; APC8015 [referring to primed dendritic cells] [SY]; prostatic acid phosphatase (PAP)--granulocyte macrophage-colony stimulating factor (GM-CSF) recombinant fusion protein-sensitized dendritic cell cancer vaccine [SY]; PA2024 [SY; referring to PAP-GM-CSF]; prostatic acid phosphatase (PAP)--granulocyte macrophage-colony stimulating factor (GM-CSF) recombinant fusion protein [SY]; PA2024-loaded APCs [SY]

As indicated by the product insert upon approval, Provenge does not have an assigned NDC. Since each patient's Provenge is unique to that patient, FDA is apparently treating each patient's Provenge as a unique product (as can be expected with fully individualized biopharmaceuticals).

Biological.: Prostatic acid phosphatase (PAP) has been found in approximately 95% of prostate tumors. PAP is an enzyme found primarily in men in the prostate gland and semen. Prostate dysfunction results in the release of PAP into the blood.

Antigen Presenting Cells (APCs) are CD42-positive cells, primarily monocytes, and dendritic cells, but macrophages and T- and B-cells are also present. These cells contribute to cellular immune responses, particularly cytotoxic T-lymphocyte or T-cell (CTL) responses effective for attacking tumors.

GM-CSF is a cytokine that has pleiotropic function both in hematopoiesis and immune responses. See the GM-CSF product entries in the Recombinant DNA Products section. GM-CSF has been shown to promote differentiation and survival of dendritic cells, and GM-CSF can be used as an systemic adjuvant. Most proteins, e.g., PAP, that induce antibodies in vivo fail to induce cytotoxic T-lymphocyte or T-cell (CTL) responses, the type most desired to destroy tumors. GM-CSF fusion proteins have been shown to induce in vivo antibody responses against the immunogen fused to GM-CSF. PAP fused to GM-CSF, PAP-GM-CSF, is superior to the simple mixture of both molecules and to other conventional adjuvants for the induction of PAP-specific antibody responses.

A MHC-Class I mediated T-cell response can be stimulated by an isolated or soluble protein, when presented to the immune system as part of a complex with a dendritic cell binding protein, e.g., GM-CSF. Investigators from Dendreon discovered that this response, not previously observed using a full-length soluble antigen, can be stimulated in vitro; and showed that immunogenic fusion proteins (e.g., PAP-GM-CSF) presenting specific immunogens (e.g., PAP) to antigen presenting cells (APC), such as dendritic cells, can induce potent antigen-specific cytotoxic T-cell responses. It is believed that the protein antigen is transported over the plasma membrane of the APC in a receptor-mediated non-disruptive manner; and that the dendritic cell binding portion of the fusion protein (i.e., GM-CSF) serves to preserve the viability and functionality of the APC. Dendreon demonstrated that tumor associated proteins not previously shown to be target antigens for cytotoxic T-lymphocyte (CTL) responses can become targets by priming CTLs with GM-CSF fusion proteins in vitro.

Companies.: Dendreon Corp., CBER/FDA est. no. 1749, originally Activated Cell Therapy Inc., is the developer, manufacturer and markets Provenge. Dendreon was originally formed in 1992.

Dendreon had its original manufacturing facilities in East Hanover, NJ. Completion of an expansion of these facilities to handle commercialization of Provenge was reported in Aug. 2006, and upon approval, the company reported two other U.S. manufacturing sites were being constructed.

Dendreon has reported spending more than $560 million to develop Provenge.

In Dec. 1998, Kirin Brewery Co., Ltd. (Kirin Pharmaceuticals, Ltd.) exercised an option under a previously signed agreement to receive exclusive Asia and Pacific Rim rights to Provenge, for which Kirin paid Dendreon $1.0 million and was obligated to pay up to an additional $4.0 million in fees and milestone payments. In Feb. 1999, the companies entered into a joint research agreement relating to antigen-presenting cell (APC) product development. In Nov. 2003, Dendreon regained full development and marketing rights previously licensed to Kirin and received $20 million, in exchange for licensing Kirin patent rights relating to certain HLA-DR antibodies. This terminated Kirin’s involvement in Provenge.

Diosynth RTP, Inc. (formerly Covance Biotechnology Services, Inc.), now a subsidiary of Akzo Nobel NV, had been the contract manufacturer of PAP-GM-CSF. In Oct. 2004, Dendreon entered into a second amendment of its contract with Diosynth for PAP-GM-CSF manufacture, and Diosynth validated and manufactured PAP-GM-CSF at commercial levels to support an BLA filing (in 2006). The total contract price was $18.0 million. In March 2006, Dendreon concluded a long-term supply contract. Diosynth was to initially manufacture PAP-GM-CSF for market launch and commercial sale at its North Carolina facilities, and and might also manufacture PAP-GM-CSF at its large-scale cell culture facilities in the Netherlands once commercial demand picks up.

In Sept 2010, GlaxoSmithKline S.A. became the contract manufacturer of PAP-GM-CSF. Dendreon placed an initial order for about $8.3 million of antigen for delivery in August 2011. The terms of the agreement are through Dec. 31, 2015, unless earlier terminated, and provides an option to Dendreon to request one or more two-year extensions to the then expiring term.

Gambro Healthcare, Inc., a subsidiary of Gambro AB, is the primary provider of leukapheresis services for Provenge through its network of U.S. blood/kidney dialysis centers. In Oct. 2001, Dendreon signed an agreement with Gambro covering cell collection for Provenge using Gambro BCT’s COBE Spectra Apheresis System.

Dendreon has reported (prior to approval) performing cell processing for the manufacture of Provenge at its facility in Seattle, WA, and through third-party contracts with the Mayo Clinic (Rochester, MN), the American Red Cross (Philadelphia, PA), and Progenitor Cell Therapy (Hackensack, NJ, and Mountain View, CA). For commercial manufacture, Dendreon plans to eventually construct two or more of its own cell processing centers in the U.S. Eventually, Dendreon plans to have APC processing centers in different parts of the U.S. (and other territories where Provenge is marketed).

Initial approval granted approval for manufacture of Provenge at company facilities in Morris Plains, NJ. Upon approval, Dendreon reported it was expanding capacity at its New Jersey; Union City (Atlanta), Georgia (160,000 sq. ft.) and Seal Beach (184,000 sq. ft.), Orange County, Calif., manufacturing facilities in mid-2011. Thus, in 2011, Dendreon will have three manufacturing facilities. The facilities were designed by LifeTek Solutions.

In Jan. 2006, Dendreon announced a strategic reallignment to focus its resources on Provenge, including reducing its workforce by 15% or 34 employees.

In Sept. 2011, faced with unexpected low sales, Dendreon laid off 500 employees.

In July 2012, Dendreon reported it would cut 600 full-time and contractor jobs over the next 12 months, and close its original Morris Plains, NJ, factory, in a bid to save about $150 million a year in costs.

In Sept. 2013, Baxter International Inc. acquired Gambro.

In Oct, 2013, Dendreon hired PharmaCell B.V. as its CMO for European commercial production of Provenge.

In Jan. 2014, PharmaCell B.V. purchased a facility from TiGenix in Sittard-Geleen, The Netherlands, to add a second facility, further capacity, for Provenge manufacture.

Manufacture: PA2024 (PAP-GM-CSF) is a recombinant fusion protein consisting of full-length human PAP and full length human GM-CSF linked by a Gly-Ser sequence. This is manufactured under contract by Diosynth RTP, Inc. (formerly Covance Biotechnology Services, Inc.). The fusion protein was cloned in a baculovirus expression vector system (BEVS) and is expressed in Spodoptera frugiperda Sf21 insect cells adapted to grow in serum-free media. PA2024 is purified by three sequential column chromatography steps to more than 95% homogeneity. Both of the fusion protein components retain appropriate biologic activity, as demonstrated by enzymatic activity for PAP and growth promotion and adjuvant activity for GM-CSF.

The manufacturing process for Provenge incorporates two main elements: the Antigen Delivery Cassette (PAP-GM-CSF) and antigen-presenting cells (APCs). Provenge (the PAP-GM-CSF activated cells) is prepared fresh for each treatment course for each patient. The manufacture of a dose of Provenge begins with leukapheresis, a standard process for collection of white blood cells (leukocytes) and other non-red blood cells from plasma (see the Leukocytes entry), performed at one of the blood/dialysis centers of Gambro Healthcare, Inc. Leukocytes are removed from the patient’s blood through standard 1.5 to 2.0 L blood volume leukapheresis. The resulting cells are then transported within 1 hour to a local Dendreon cell processing facility, e.g., its own facilities in Seattle, WA. APCs are separated using Dendreon’s proprietary cell separation technology involving use of two density gradient separations), and incubated (cultured) in the presence of concentrated Antigen Delivery Cassette (PAP-GM-CSF) under controlled conditions. After culture, the cells are washed and suspended in Lactated Ringer’s Injection, USP for infusion back into the patient. Minimal residual levels of the intact PAP-GM-CSF are detectable in the final product.

Dendritic-cell precursors are collected by two sequential buoyant density centrifugation steps by a modification of the method of Hsu, et al. The leukapheresis product is layered over a buoyant density solution (specific gravity = 1.077 g/mL) and centrifuged at 1,000 g for 20 minutes to deplete erythrocytes and granulocytes. The interface cells are collected, washed, layered over a second buoyant density solution (specific gravity = 1.065 g/mL), and centrifuged at 805 g for 30 minutes to deplete platelets and low-density monocytes and lymphocytes. The resulting cell pellet, which contains dendritic-cell precursors, is washed and incubated in AIM media with 10 µg/mL of the target antigen (PAP-GM-CSF; PA2024). The culture media is human serum-free and contains no exogenous cytokines. After incubation for 40 hours at 37°C in 5% carbon dioxide (CO2) atmosphere, the cells ware washed and formulated at the desired clinical dose in 250 mL of lactated Ringers’ solution. Each dose of Provenge is quality control tested, including identity, purity, potency, sterility and other safety testing. This process requires less than three days from white blood cell collection to the administration of Provenge. This process provides a highly concentrated and potent product.

The potency of Provenge is in part determined by measuring the increased expression of the CD54 molecule, also known as ICAM-1, on the surface of APCs after culture with PAP-GM-CSF. CD54 is a cell surface molecule that plays a role in the immunologic interactions between APCs and T cells, and is considered a marker of immune cell activation.

Each dose is shipped and administered fresh (without cryopreservation) within 18 hours of manufacture. The lot release testing is performed by Dendreon concurrently with product packaging and shipping to the infusion center. All lot release tests must meet specifications for the product to be infused, and a product disposition form is sent to the infusion site to clear the lot for infusion. Product lot release specifications were based on a statistical analysis of historical manufacturing data and set around 3 standard deviations from the mean.

Provenge is administered as an intravenous infusion lasting about 30-60 minutes given as an outpatient procedure. Clinical trial indicate that maximum stimulation requires three infusions given at two-week intervals (followed by booster injections of PAP-GM-CSF). Patients in Provenge trials typically completed a course of cell therapy in one month.

The cell separation devices and related media that isolate the cells and other bodily fluids are manufactured by third-party contractors in compliance with cGMP. Dendreon plans to use third-party contractors to produce commercial quantities of these devices and media for Provenge,

Dendreon has manufactured product for clinical trials at multiple different manufacturing sites, with a number of these opening and closing as sales increased and later not reached expectations.. For development of the product, Dendreon performed manufacturing at one facility located in Morris Plains, NJ. Dendreon performed a comparability study comparing their Seattle, WA manufacturing site used under IND and the Morris Plains, NJ site that will be used for all commercial manufacturing. Dendreon has also compared lot release testing data from the Morris Plains, NJ site to additional contract manufacturing sites (including Diosynth RTP Inc.) used under IND. Although the range of product lots generated at each site differs, product lot averages were comparable.

The greatest risks associated with the manufacturing of this autologous product are 1) the risk of product mix-ups and 2) the risk of product contamination. Due to these risks, there is a need to maintain strict chain of identity throughout the manufacturing and distribution process as well as the need to adhere to strict aseptic process techniques, because the product is live and cannot be sterilized. Chain of identity of all in-process and final product manufacturing steps are maintained through the use of a human-readable barcode scanning system, lot-specific unique identifiers, and multiple patient lot identifiers. Chain of identity of QC samples is also managed through barcode scanning and unique identifiers, including a second level of identifiers used exclusively in the QC lab. In addition, procedures are in place to ensure segregation and prevent cross- contamination. Infectious agent testing of patients is not required by Dendreon but may be instituted by the apheresis centers.

Provenge is exempt from CBER Lot Release testing, including no requirement for submission of product samples to CBER. The cellular product is administered fresh and has only an 18 hour shelf life. This does not allow enough time to provide samples to CBER to test the product before expiry.

FDA class: Biologic BLA

Approvals: Date = 20100429; BLA

Date = 20110310; BLA supplement; Indication = FDA approval of 36 additional workstations in its NJ faciliites, bringing this site up to 48 workstations

Date = 20110706; BLA supplement; Indication = Los Angeles immunotherapy manufacturing facility approved

Indications: [Full text of the "Indications and USAGE" of product insert/labeling]:

Provenge (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

Status: Dendreon had originally planned to file a BLA in 2002, but encountered problems. In April 2002, enrollment of patients with advanced hormone resistant prostate cancer in the second pivotal Phase III clinical trial (IMPACT; D9902 parts A and B) was suspended due to the FDA’s request for clarification regarding characterization of the cellular composition of Provenge. Patients already enrolled in the trial continued to be treated with Provenge. In Oct. 2002, FDA released the partial hold on the trial and the company resumed enrollment. After evaluation, trial D9901 approached but did not meet its primary endpoint of showing a statistically significant delay in the median time to disease progression in its overall patient population. This may have been due to inadequate immune responses in advanced patients or they did not survive long enough to show benefit. FDA indicted it would refuse to grant approval based on this data. The trial results did, however, identify a group of patients, those with tumors that had been classified as Gleason score 7 or less, who appeared to benefit most significantly by treatment with Provenge compared to patients who received placebo.

In Dec. 2002, Dendreon amended the protocol of its then ongoing second pivotal Phase III clinical trial (D9902; IMPACT) to enroll only patients with advanced hormone-resistant prostate cancer and Gleason scores of 7 or less (the population of patients that benefited the most from Provenge in the first Phase III trial, D9901). D9902 was amended to contain two parts: D9902 Part A (D9902A) including those patients enrolled regardless of Gleason score, and Part B (D9902B) restricting enrollment to those patients most like the group of patients that appeared to benefit in D9901 (Gleason scores of 7 or less).

In June 2003, Dendreon received a Special Protocol Assessment (SPA), i.e., concluded a clinical trials/development agreement with FDA, indicating that a single pivotal Phase III clinical trial (D9902B; PROTECT) would satisfactorily serve as the basis for filing a BLA for Provenge for the treatment of male patients with advanced androgen-independent prostate cancer.

In a pre-BLA meeting with FDA in fall 2005, the FDA agreed that the survival benefit observed in the D9901 study in conjunction with the supportive data obtained from study D9902A and the absence of significant toxicity in both studies would be sufficient to serve as the clinical basis of a BLA submission.

In Nov. 2005, FDA and Dendreon agreed to an amended SPA for the ongoing D9902B Phase III trial for advanced prostate cancer, now known as the IMPACT study; and granted the BLA for Provenge fast track status, allowing submission of portions of the application for review as they are completed. The amendments included opening the trial to men with all Gleason scores and patients with minimally symptomatic disease-related pain; changing the primary endpoint to overall survival, an event-driven analysis; time to objective disease progression would now a secondary endpoint; IMPACT enrollment was increased to 500 patients from 275; and the primary statistical analysis to determine efficacy would be the Cox multivariate regression model.

The BLA was accepted for filing in Jan. 2007, with priority review (6 month target for decision). Dendreon asserted that survival data from the Phase III D9901 trial and “supportive” data from the Phase III D9902A trial were sufficient to serve as the clinical basis for its BLA submission. However, neither of those trials met their initial primary endpoint of time to disease progression.

On March 29, 2007, the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee voted 17 to 0 in favor of the safety of Provenge and 13 to 4 in favor of its efficacy. FDA took a new tack, rewording the usual question it asks about efficacy. Instead of determining if the data established efficacy, FDA requested confirmation that there was “substantial” evidence of efficacy. There was speculation that this may mean FDA has established or may be open to more liberal interpretations of what constitutes proof of efficacy.

On May 8, 2007, Dendreon received a Complete Response Letter (“approvable” letter) from FDA regarding its BLA for Provenge for the treatment of asymptomatic, metastatic, androgen-independent (hormone refractory) prostate cancer. FDA requested additional clinical data in support of efficacy claims. The FDA also requested additional information with respect to the chemistry, manufacturing and controls (CMC) section of the BLA, which Dendreon expected to provide in a timely manner. Dendreon sought further clarification from FDA regarding additional clinical data (or trials) needed.

On May 31, 2007, Dendreon reported having received confirmation from FDA that it will accept either a positive interim or final analysis of survival from the ongoing IMPACT study to amend the BLA. This means that new trials will not be required. Dendreon anticipates completing enrollment in the IMPACT study in 2007, with interim survival results in 2008.

FDA’s refusal to approve Provenge was highly controversial, including with many patient, disease and other interest groups and politicians protesting and lobbying for approval. Many found it objectionable that FDA had refused to approve a highly-anticipated, novel, high-tech, apparently safe and effective (e.g., received advisory committee recommendations for approval) and much-needed therapeutic for a class of patients (prostate cancer) with so few alternatives. Some critics noted that FDA has seemed to abandon accelerated approvals, e.g., that many AIDS-related therapeutics were initially approved with less supporting evidence. From the perspective of many, the company and the product had done everything well enough to deserve full approval of Provenge (with post-marketing requirements).

In March 2008, The FDA agreed to an amended Special Protocol Assessment (SPA) for a Phase III trial of Provenge. The agency confirmed it would accept a positive interim or final analysis from the IMPACT trial to amend the BLA. The amended SPA accelerated the expected timing of the final IMPACT results by approximately one year.

Dendreon expected interim results of the IMPACT trial in mid-2008, which could be sufficient to amend the BLA and obtain approval. However, final results from IMPACT were not expected until 2010. In the meantime, then presuming approval in later 2008, the company was scaling-up production at its facilities in New Jersey and Seattle, WA, and working to reduce manufacturing costs. Dendreon repored that manufacturing was not an issue with FDA.

On Nov. 2, 2009, FDA acknowledged that the BLA for Provenge was a complete response, and set a Prescription Drug User Fee Act (PDUFA) date of May 1, 2010. The FDA considers this to be a complete, Class 2 Resubmission following the action letter the company received in 2007. The BLA includeds data from the IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial, which was conducted under a Special Protocol Assessment agreement with the FDA. The resubmission also contained the othe information requested by the FDA pertaining to chemistry, manufacturing and controls section of the BLA.

On April 29, 2010, FDA granted BLA approval to Provenge. Provenge is not to subject to (exempt from) pre-approval CBER lot release requirements.

In Aug. 2010, FDA sent Dendreon a letter complainging that Provenge "promotional materials are false or misleading because they omit and minimize the risks and overstate the efficacy of Provenge."

In July 2013, the European Union Committee for Medicinal Products for Human Use (CHMP) supported approval of Provenge its backing, putting Dendreon a step closer to selling the vaccine in the region. Full approval was granted in mid-September for the treatment of asymptomatic or minimally symptomatic metastatic (non-visceral) castrate resistant prostate cancer in male adults in whom chemotherapy is not yet clinically indicated.

Trials: Provenge has been and is currently being tested in multiple pivotal Phase III trials. The first trial, D9901, was a double-blind placebo controlled trial in men with metastatic (advanced) androgen-independent prostate cancer. The trial was designed to measure a delay in time to disease progression. Time to the onset of disease-related pain was a secondary endpoint that was to be evaluated in concert with the results from a second, identical companion trial, D9902. Patients were given the option to receive salvage therapy in a separate open label study. Both protocols required patients to be followed for survival for three years after enrollment.

Trial D9901 approached, but did not meet its primary endpoint of delay in disease progression in the overall patient population in the study. Comparison of the Provenge treated group to the placebo treated group in the overall population showed a 43% benefit in delaying time to disease progression, the primary endpoint of the trial. Although the results did not achieve statistical significance for the overall population (p ≤ 0.05), the results closely approached statistical significance at p = 0.061. A group of patients, those with tumors that had been classified as Gleason score 7 or less, was identified who benefited most significantly from Provenge (compared to placebo), with Provenge delaying disease progression (p = 0.001). For these men, the probability of remaining progression-free while on the study was over two-times higher than for men treated with placebo. In addition, six months after randomization, these men had a greater than eight-fold advantage in progression-free survival compared to men who received placebo (35.9% of Provenge men vs. 4% of placebo patients). Provenge was generally well tolerated, with most side effects resolving within 24 to 48 hours.

In Jan. 12, 2004, Dendreon reported interim survival data from D9901 for men with Gleason scores of 7 and less. Based on data as of Dec. 2003, men receiving Provenge had a significant survival advantage, having on average an 89% overall increase in their survival time as compared to placebo (log rank p = 0.047, hazard ratio = 1.89). Provenge prolonged the median survival time by 8.4 months (30.7 months versus 22.3 months for placebo). At 30 months from randomization, the survival rate for Provenge treated men was 3.7 times higher than for men receiving placebo (53% versus 14%, p = 0.001).

As discussed in the Status section, the protocol for this D9901 was subsequently amended to contain two parts: D9902A includes those patients enrolled regardless of Gleason score, and D9902B restricted to patients most like the group of patients that benefited in D9901 (Gleason scores of 7 or less), and trial D9902B received a Special Protocol Assessment (SPA) from the FDA. Dendreon is currently conducting D9902B, a pivotal, randomized, double blind, placebo-controlled Phase III trial, at approximately 70 centers in the U.S.

Results from the planned three year follow-up for survival on the D9901 patients were recently reported (2006). A significant survival advantage was seen in those patients who received Provenge compared to placebo. This survival benefit is greater than that observed with any type of treatment in any published Phase III study in late-stage prostate cancer. Also, at the 36-month final follow up, the percentage of patients alive in the Provenge-treated group is substantially greater than the percentage of patients who received placebo.

Promising results have also been reported from Trial P-11 designed to test Provenge in men with earlier stage, androgen-dependent prostate cancer.

In Feb. 2005, results were reported a National Cancer Institute (NCI)-sponsored open-label, 22-patient, U.S. Phase II trial (P-16) of Provenge plus Avastin (vascular endothelial growth factor monoclonal antibody from Genentech; see related entry) in androgen-dependent prostate cancer. The trial enrolled patients with prostate cancer having relapsed after prior surgical and radiation therapy. Provenge was given intravenously (IV) on weeks one, two and four. Patients received 10 mg/kg of IV Avastin immediately following Provenge and continued every two weeks thereafter until disease progression or toxicity was observed. Disease progression was defined as a doubling of the baseline or nadir PSA value or the development of metastases. Provenge plus Avastin increased median prostate specific antigen (PSA) doubling time (PSADT) by ~90% from 6.7 months pretreatment to 12.7 months (p=0.004), and 41% of patients had a decrease in absolute PSA value from baseline. Eight patients had an increase in PSADT of at least 200% compared to pretreatment. No disease progression was reported. This study provided “proof-of-concept” that Provenge has efficacy in combination with other immune-modulating prostate cancer treatments. If P-16 and P-11 final results are positive, Dendreon will likely pursue development of Provenge for earlier-stage androgen-dependent prostate cancer.

In Oct. 2005, final results were reported from Phase trial D9902A. In the three-year final survival analysis in the intent-to-treat population of this double-blind, placebo-controlled study in 98 men with asymptomatic, metastatic, androgen-independent (hormone-refractory) prostate cancer, patients who received Provenge had a 19.0 month median survival time compared with only 15.7 months for the placebo recipients. This represents a 3.3 month or 21% improvement in median survival for patients who were randomized to receive PROVENGE compared to placebo (p-value = 0.331, log-rank; HR = 1.3). This hazard ratio implies that patients receiving placebo have a relative risk of dying that is 30% higher than those patients receiving Provenge. Provenge did not achieve statistical significance for delaying the time to disease progression. A preliminary analysis of overall survival in the D9902A trial indicated that both Provenge’s survival rates and the median survival benefit, compared to placebo, showed trends that are similar to the results observed in the final three-year survival analysis of the D9901 study. A Cox multivariate regression analysis of overall survival, which adjusts for imbalances in prognostic factors known to influence survival, met the criteria for statistical significance (p-value = 0.023; adjusted HR = 1.9). At the three-year final follow up, 32% of the men in the Provenge group were alive compared to only 21% of the men in the placebo group, a 52% improvement in the survival rate. In an integrated analysis of D9901 and D9902A, a statistically significant survival benefit was observed in the overall intent-to-treat population of 225 patients. Provenge recipients had a median survival of 23.2 months compared to 18.9 months for placebo recipients, a 4.3 month or 23% improvement in median survival. This analysis was statistically significant by both log rank (p = 0.011; HR = 1.5) and Cox multivariate regression analysis of overall survival (p = 0.0006; adjusted HR = 1.8). Also, at 3 years, 33% of the men who received Provenge were alive compared to15% of the men who received placebo, a greater than 100% improvement.

In Nov. 2005, Dendreon presented data from a combined “exploratory analysis” of Phase III Studies (D9901 and D9902A) that showed a prolonged survival benefit for patients initially treated with Provenge who then went on to receive docetaxel chemotherapy after disease progression. The study evaluated survival data from 82 patients who received docetaxel chemotherapy following initial treatment with either Provenge or placebo. The median survival observed in the Provenge treated patients was 34.5 months compared to 25.4 months for patients randomized to receive placebo, a difference of 9.1 months (HR = 1.90; p-value = 0.023). Approximately 68% of the patients randomized to receive placebo also subsequently participated in a cross-over salvage protocol that allowed them to receive active cellular immunotherapy with APC8015F, a version of Provenge generated from cryopreserved cells. The median survival was 25.7 months for patients who received APC8015F followed by docetaxel, vs. 20.2 months for patients who received placebo only and subsequent treatment with docetaxel, a 14.3 month difference compared to 34.5 month median survival seen in the patients who received initial treatment with Provenge followed by docetaxel. These three groups appeared to be well balanced based on their baseline prognostic factors.

Dendreon has also conducted a double-blind placebo controlled trial (P-11) in androgen-dependent prostate cancer. In Feb. 2005, a Phase II trial (P-16) of Provenge in combination with Avastin showed that the combination increased PSA doubling time (PSADT) in patients with prostate cancer having relapsed after prior surgical and radiation therapy.

Provenge is currently (2007) continuing Provenge testing in the D9902B/IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) Phase III trial for the treatment of men with Gleason score 7 or less with asymptomatic, metastatic androgen-independent prostate cancer.

Three Phase III studies involving 737 patients were submitted to FDA to support licensure. The pivotal study was the IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial (D9902B), a 512-patient, multi-center, randomized, double blind, placebo-controlled study that evaluated men with asymptomatic or minimally symptomatic, metastatic castrate-resistant (hormone-refractory) prostate cancer (CRPC). Provenge extended median survival beyond 2-years, demonstrating a median improvement of 4.1 months compared to the control group (25.8 months vs. 21.7 months). Overall, Provenge reduced the risk of death by 22.5% compared to the control group (HR=0.775). Results from the similarly designed Study D9901 in asymptomatic metastatic CRPC patients also demonstrated a survival advantage of similar clinical magnitude as the IMPACT study.

The BLA safety evaluation of Provenge was based on 601 prostate cancer patients in four randomized clinical trials who underwent at least one leukapheresis procedure. The most common adverse events (incidence ≥15%) were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Serious adverse events reported in the Provenge group included acute infusion reactions (within 1 day of infusion) and cerebrovascular events. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the Provenge group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the Provenge group.

As of of its FDA approval, to fulfill a post marketing requirement and as a part of the company's commitment to patients, Dendreon pledged to conduct a post-marketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T. The schedule was set: Final Protocol Submission: June 30, 2010; Study Completion Date: December 31, 2015; and Final Report Submission: September 30, 2016. In four randomized clinical trials in prostate cancer patients, cerebrovascular events were observed in 3.5% of patients in the Provenge arm compared with 2.6% of patients in the control arm.

Results from the pivotal Phase III IMPACT study were published in in the July 29, 2010, New England Journal of Medicine. Provenge demonstrated a statistically significant improvement in overall survival compared to control in men with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC).

Tech. transfer: U.S. 5,976,546 and 6,210,662, a continuation, “Immunostimulatory compositions,” are assigned to Dendreon Corp. U.S. 6,210,662 patent has three claims: “1. A therapeutic composition, comprising activated, isolated antigen presenting cells, wherein said cells are stimulated by exposure in vitro to a trimer having three polypeptide conjugate subunits, each composed of a fusion protein having PAP as an N-terminal moiety and GM-CSF as a C-terminal moiety, and wherein said cells are effective to activate T-cells to produce a multivalent cytotoxic cellular immune response against PAP, at a T-cell activation level that is higher than that produced by such antigen presenting cells stimulated by PAP alone. 2. The therapeutic composition according to claim 1, wherein said conjugate subunits further comprise, between said N-terminal moiety and said C-terminal moiety, a linker peptide. 3. The therapeutic composition according to claim 1, wherein said conjugate subunits are fusion proteins produced by translation of a continuous nucleotide coding sequence.” Both patents effectively cover the composition-of-matter of the PAP-GM-CSF used to prime antigen presenting cells (APCs).

U.S. 6,080,409, “Immunostimulatory method,” assigned to Dendreon, further claims methods of priming autologous APCs using PAP-GM-CSF.

U.S. 6,121,044, assigned to Dendreon, claims methods for culture and differentiation of dendritic cells from isolated peripheral blood lymphocytes and dendritic-precursor cells, including culture in a cross-linked collagen matrix.

In Jan. 2008, Dendreon reported receiving a European Patent (0 870 022 B1) broadly covering Provenge. The patent covers the composition of matter of Provenge as well as the company's other active cellular immunotherapy product candidates utilizing Dendreon's Antigen Delivery Cassette(TM) technology. The patent also covers methods of activating antigen presenting cells in vitro with certain fusion proteins developed by Dendreon, including the PAP-GM-CSF fusion protein that is used in Provenge.

Recombinant baculovirus expression systems (BEVS) and associated insect cell lines were originally patented by Texas A&M University, including U.S. 4,745,051; 4,879,236; 5,155,037; and 6,194,152. In June 1999, Proteins Sciences Corp. and Texas A&M University announced an agreement to combine their intellectual property and know-how regarding BEVS. Protein Sciences became the exclusively sublicensing party for the combined BEVS technologies. A representative from Protein Sciences reported that the original BEVS U.S. patents are now expired, and that Dendreon is not a licensee (although, as Provenge approval nears, both Dendreon and Protein Sciences will likely examine the need for licensing more closely).

Disease: Prostate cancer is the most common solid tumor malignancy in men in the U.S., with over one million men currently diagnosed with the disease. Approximately 2% of men over the age of 40 years (or 1.3 million men) in the U.S. are living with prostate cancer, although many may not yet be diagnosed. The aging of the population and decline in mortality rate are expected to increase this prevalence by an average of almost 8% annually, more than doubling the U.S. overall prevalence of prostate cancer to 2.9 million cases by 2011. The American Cancer Society estimates that there are annually 230,000 new cases of prostate cancer diagnosed in the U.S. and about 29,900 deaths (in 2004). The prevalence of androgen dependent prostate cancer in the U.S. and Europe is ~ 600,000 men, which is about four times greater than the prevalence of androgen-independent prostate cancer.

Androgen-independent prostate cancer is an advanced stage of prostate cancer in which prostate tumor growth is no longer regulated by androgens. In contrast, androgen-dependent prostate cancer is an earlier stage of the disease in which the tumor growth is still regulated by androgens. The Gleason score is the most commonly used prostate cancer scoring system. It is performed at the time of diagnosis and is considered an important prognostic indicator for prostate cancer. The Gleason score is a measure of the aggressiveness of a patient’s tumor and ranges in score from 2-10.

Metastatic prostate cancer is usually initially treated with androgen (male sex hormones, e.g., testosterone) deprivation, e.g., by removal of the testes and/or anti-androgenic drug treatment, which achieves stabilization or regression of disease in more than 80% of patients. However, despite androgen deprivation and secondary hormonal manipulations, all patients eventually develop hormone-refractory prostate cancer (HRPC). The median survival for HRPC patients is ~1 year. To date, no therapeutic has been shown to prolong survival in HRPC patients, and prospectively validated palliative interventions are few. New therapeutics for treatment of HRPC are urgently needed.

Medical: The recommended course of therapy for Provenge is three complete doses, given at approximately 2-week intervals. In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range 1 to 15 weeks). The maximum dosing interval has not been established. Each leukapheresis produces one dose; therefore the patient undergoes 3 separate leukapheresis procedures. Each leukapheresis product goes through the identical manufacturing process to produce a unique lot of sipuleucel-T. If a lot fails to meet requirements for quality, the patient must undergo an additional leukapheresis to make a new lot of product. Each dose is shipped and administered fresh (without cryopreservation) within 18 hours of manufacture. The lot release testing is performed concurrently with product packaging and shipping to the infusion center. All lot release tests must meet specifications for the product to be infused and a product disposition form is sent to the infusion site to clear the lot for infusion.

Market: Provenge could potentially attain blockbuster status. Presuming Provenge is used by 100,000+ androgen-independent (advanced) or other prostate cancer patients annually, and presuming a cost of $10,000 for the treatment (which could be an underestimate), this would result in sales of over $1 billion annually. However, with its expected relatively high cost, and with it not being a cure, not preventing tumors, not alleviating pain, and with its, perhaps, marginal efficacy in terms of extending survival, Provenge may have a hard time gaining reimbursement from insurers. If Provenge is adopted as the standard-of-care for prostate cancer treatment, with its expense and complexity, this will complicate clinical testing of future therapies.

Total 2011 revenue/sales awas $228 million, well short of the $400 million the company and many analysts had projected. 2010 revenue for Provenge was $48 million. In 2011, Dendreon planned to increase its sales force to approximately 100 reps to service approximately 450 centers by the end of the year. IN Sept. 2011, with lower sales than projected, Dendreon laid off 500 staff, 25% of its work force, mostly at manufacturing sites.

The price set by Dendreon upon approval was $93,000, i.e., $31,000 for each of the three Provenge infusions. As can be expected, with Provenge only adding months to life expectancy, its cost is controversial. It has been reported that even under the best case scenario, Provenge would cost $300,000 per QALY (quality of life year). This cost is about $23,000 per month of life extension, based on the Phase III study that found that Provenge extended life by 4.1 months.

The high total cost is a barrier to many, particularly when patients have to pay for 20% of it. Although the price tag on Provenge is $93,000, surveyed payers put the true cost at more like $100,000 to $120,000, including infusion charges. Another factor holding back sales is physician reticence in prescribing Provenge. If a doctor prescribes Provenge and a month later the patient learns his insurer denied the claim, the doctor is out $93,000. That will put a sizeable hole in the cash flow of even larger practices.

Upon FDA approval, Dendreon reported having capacity for manufacture of 2,000 treatments in the first year of marketing, about 25% of projected eventual capacity. Demand was expected to surpass supply in the first year.

In June 2011, the Centers for Medicare and Medicaid Services (CMS) issued a final National Coverage Decision (NCD) for PROVENGE requiring Medicare contractors to cover the use of PROVENGE for treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (i.e,. Medicare will pay for Provenge). The NCDl standardizes coverage processes across the country for all Medicare patients with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer and provides the local Medicare Administrative Contractors (MACs) specific criteria, consistent with the label, on how PROVENGE should be covered. PROVENGE was issued a product specific Q-code, which allows for electronic submission of claims and is expected to accelerate time to payment for physicians.  The CMS coverage was further refined and extended in in Nov. 2011, including coverage of infusion costs.

Sales have been very disappointing for Dendreon and lower than had been expected. Cowen & Co. had projected 2016 sales of $1.5 billion, but sales are and will be nowhere near this.

Upon approval, Dendreon made Provenge available through ~50 centers, all of which had been approved clinical trial sites, and expected to increase capacity over the next year. The increased capacity included anticipated licensure of its expanded New Jersey; Atlanta, Georgia and Orange County, Calif., manufacturing facilities in mid-2011.

Upon approval, Dendreon expected to have 125 sales staff marketing Provenge.

In July 2010, a survey of medical and pharmacy directors from 50 national and regional insurers by Reimbursement Intelligence reported that two-thirds did not have concerns that the vaccine is available, but 65% may restrict patient access in some form, and 74% expected to require some form of prior authorization, such as documented use of two courses of hormonal therapy, with only 19% indicating no restrictions. And 46% would not reimburse without prior chemotherapy treatment, while 56% will require documented metastatic disease for reimbursement. Since then Aetna and Humana offer coverage, albeit with some restrictions. Also, 46% agreed that oncologists will be hit harderst by Provenge, as urologists and aphresis centers are given the opportunity to administer the vaccine.

In July 2012, Dendren reported that there is still a lot of work to do in terms of marketing to physicians, especially those new to the product. Many are not yet persuaded about the merits of the clinical trial data that underpin Provenge; many need to be made comfortable with the truly one-of-a-kind prescribing and logistics process; and many more need to be confident they will get effectively reimbursed. In the past year, the FDA has approved Johnson & Johnson's ($JNJ) Zytiga and Medivation's ($MDVN) Xtandi.

Zytiga from Johnson & Johnson, which costs $5,000 a month, was approved after Provenge giving patients the option of this oral treatment. Provenge tends to be used as the “foundation of care” which is given first, and which still allows doctors the flexibility to prescribe Zytiga later. Xtandi from Medivation is yet another recently-approved drug competing with Provenge for prostate cancer treatment.